INTRODUCTION.



Current and emerging avenues for Alzheimer’s disease drug targets.LOERA-VALENCIA, R.1; CEDAZO-MINGUEZ , A. 1; KENIGSBERG, P.3; PAGE, G.4; DUARTE, A.5,6; GIUSTI, P.7; ZUSSO, M.7; ROBERT, P.8; FRISONI, G.B.9; CATTANEO, A.9; ZILLE, M. 10,11,12; BOLTZE, J.10,11; CARTIER, N.13; BUEE, L.14; JOHANSSON, G.1; WINBLAD, B.1,2.1Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Centre for Alzheimer Research, Division of Neurogeriatrics, Solna, Sweden.2Karolinska University Hospital. Theme Aging. Karolinska University Hospital. Stockholm, Sweden. 3Fondation Médéric Alzheimer.30 rue de Prony. Paris, France 4Neurovascular Unit βand Cognitive impairments – EA3808 University of Poitiers, France.5CNC- Center for Neuroscience and Cell Biology, University of Coimbra. Coimbra, Portugal.6Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Casa Costa Alem?o - Pólo II, Rua D. Francisco de Lemos. Coimbra, Portugal.7Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Largo "Egidio Meneghetti" 2. Padova, Italy.8CoBTeK - lab, CHU Nice University C?te d’Azur, Nice, France.9University Hospitals and University of Geneva, Geneva, Switzerland.10Dept. of Translational Medicine and Cell Technology, Fraunhofer Research Institution for Marine Biotechnology and Cell Technology, M?nkhofer Weg 239a. Lübeck, Germany.11Institute of Medical and Marine Biotechnology, University of Lübeck, Ratzeburger Allee 160. Lübeck, Germany.12Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Ratzeburger Allee 160. Lübeck, Germany.13Preclinical research platform. INSERM U1169/MIRCen Commissariat à l’énergie atomique, Fontenay aux Roses ; Université Paris-Sud Orsay, France.14Univ. Lille, Inserm, CHU-Lille, LabEx DISTALZ, Alzheimer & Tauopathies, Lille, France.Current and emerging avenues for Alzheimer’s disease drug targets.Contents TOC \o "1-3" \h \z \u INTRODUCTION. PAGEREF _Toc532397942 \h 4Different treatment approaches based on pathogenesis PAGEREF _Toc532397943 \h 6Amyloid beta in Alzheimer’s disease: an overview PAGEREF _Toc532397944 \h 6Positron Emission Tomography (PET), Biomarkers and early diagnosis in AD PAGEREF _Toc532397945 \h 7Clinical trials and Immunotherapy in AD PAGEREF _Toc532397946 \h 8Chaperones and mitochondria: new and old options for AD therapeutics PAGEREF _Toc532397947 \h 11Tauopathies PAGEREF _Toc532397948 \h 14Synaptic Plasticity and AD PAGEREF _Toc532397949 \h 24Epigenetics and AD PAGEREF _Toc532397950 \h 32Blood-Brain Barrier (BBB) targets PAGEREF _Toc532397951 \h 35Blood Brain Barrier PAGEREF _Toc532397952 \h 35Blood-Brain Barrier in AD PAGEREF _Toc532397953 \h 37Peripheral impact in AD brain PAGEREF _Toc532397954 \h 37Chemokines as critical targets for diagnosis or therapeutic strategies PAGEREF _Toc532397955 \h 40Neurovascular junction damage and therapeutic targets: Insights from preclinical research on vascular dementia and microbleeds PAGEREF _Toc532397956 \h 43Background and rationale PAGEREF _Toc532397957 \h 43Preclinical research in vascular dementia: state of the art PAGEREF _Toc532397958 \h 44Preclinical research on post-hemorrhage neuronal damage: novel insights PAGEREF _Toc532397959 \h 49Gut microbiota and AD PAGEREF _Toc532397960 \h 51Gut microbiota and the immune system in AD PAGEREF _Toc532397961 \h 51The landscape of a specific AD microbiome PAGEREF _Toc532397962 \h 53AD as a metabolic syndrome PAGEREF _Toc532397963 \h 56Restoring Insulin Action & Glucose Metabolism in AD: Our Short-Term Perspectives PAGEREF _Toc532397964 \h 56Rationale PAGEREF _Toc532397965 \h 56Uncertainties in Drug Development in AD PAGEREF _Toc532397966 \h 58Opportunities in Drug Development in AD PAGEREF _Toc532397967 \h 59Conclusions PAGEREF _Toc532397968 \h 67Restoring brain cholesterol metabolism by CYP46A1 gene therapy PAGEREF _Toc532397969 \h 69Molecular mechanisms behind glucose and cholesterol metabolism for developing AD PAGEREF _Toc532397970 \h 75Alterations of the Renin-Angiotensin System in the brain in AD PAGEREF _Toc532397971 \h 76Insulin aggregation in AD PAGEREF _Toc532397972 \h 80DISCUSSION AND PERSPECTIVES PAGEREF _Toc532397973 \h 81Acknowledgments PAGEREF _Toc532397974 \h 85REFERENCES PAGEREF _Toc532397975 \h 86INTRODUCTION. Alzheimer?s disease (AD) is a steadily growing global epidemic. Estimates suggest more than 47 million people worldwide were affected in 2015 and a staggering 131 million is predicted 30 years from now PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ccm9va21leWVyPC9BdXRob3I+PFllYXI+MjAwNzwvWWVh

cj48UmVjTnVtPjMxMjY8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2Ny

aXB0Ij4xLTQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zMTI2PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzUzODA1NjkiPjMxMjY8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJyb29rbWV5ZXIsIFIuPC9hdXRo

b3I+PGF1dGhvcj5Kb2huc29uLCBFLjwvYXV0aG9yPjxhdXRob3I+WmllZ2xlci1HcmFoYW0sIEsu

PC9hdXRob3I+PGF1dGhvcj5BcnJpZ2hpLCBILiBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy

aWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgQmlvc3RhdGlzdGljcywgSm9obnMg

SG9wa2lucyBCbG9vbWJlcmcgU2Nob29sIG9mIFB1YmxpYyBIZWFsdGgsIEpvaG5zIEhvcGtpbnMg

VW5pdmVyc2l0eSwgQmFsdGltb3JlLCBNRCwgVVNBLiByYnJvb2tAamhzcGguZWR1PC9hdXRoLWFk

ZHJlc3M+PHRpdGxlcz48dGl0bGU+Rm9yZWNhc3RpbmcgdGhlIGdsb2JhbCBidXJkZW4gb2YgQWx6

aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFsemhlaW1lcnMg

RGVtZW50PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjE4Ni05MTwvcGFnZXM+PHZv

bHVtZT4zPC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMDc8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5KdWw8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTUy

LTUyNzkgKEVsZWN0cm9uaWMpJiN4RDsxNTUyLTUyNjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjE5NTk1OTM3PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xOTU5NTkzNzwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmphbHouMjAw

Ny4wNC4zODE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48

QXV0aG9yPkJyb29rbWV5ZXI8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxSZWNOdW0+MzE3Njwv

UmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MzE3NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz

PjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVh

diIgdGltZXN0YW1wPSIxNTM1MzgwNjg1Ij4zMTc2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10

eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1

dGhvcnM+PGF1dGhvcj5Ccm9va21leWVyLCBSLjwvYXV0aG9yPjxhdXRob3I+RXZhbnMsIEQuIEEu

PC9hdXRob3I+PGF1dGhvcj5IZWJlcnQsIEwuPC9hdXRob3I+PGF1dGhvcj5MYW5nYSwgSy4gTS48

L2F1dGhvcj48YXV0aG9yPkhlZXJpbmdhLCBTLiBHLjwvYXV0aG9yPjxhdXRob3I+UGxhc3NtYW4s

IEIuIEwuPC9hdXRob3I+PGF1dGhvcj5LdWt1bGwsIFcuIEEuPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBCaW9zdGF0aXN0aWNzLCBV

bml2ZXJzaXR5IG9mIENhbGlmb3JuaWEsIExvcyBBbmdlbGVzLCBVU0EuIHJicm9va21leWVyQHVj

bGEuZWR1PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+TmF0aW9uYWwgZXN0aW1hdGVzIG9m

IHRoZSBwcmV2YWxlbmNlIG9mIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZSBpbiB0aGUgVW5pdGVk

IFN0YXRlczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbHpoZWltZXJzIERlbWVudDwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz42MS03MzwvcGFnZXM+PHZvbHVtZT43PC92b2x1bWU+

PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZSBGYWN0b3JzPC9rZXl3b3Jk

PjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLyplcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+Q29tbXVuaXR5IEhlYWx0aCBQbGFubmluZzwva2V5d29yZD48a2V5d29yZD5EYXRhIENvbGxl

Y3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkluY2lkZW5j

ZTwva2V5d29yZD48a2V5d29yZD5Nb2RlbHMsIFN0YXRpc3RpY2FsPC9rZXl3b3JkPjxrZXl3b3Jk

PlByZXZhbGVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+KlNhbXBsaW5nIFN0dWRpZXM8L2tleXdvcmQ+

PGtleXdvcmQ+VW5pdGVkIFN0YXRlcy9lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48

ZGF0ZXM+PHllYXI+MjAxMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1k

YXRlcz48L2RhdGVzPjxpc2JuPjE1NTItNTI3OSAoRWxlY3Ryb25pYykmI3hEOzE1NTItNTI2MCAo

TGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjEyNTU3NDQ8L2FjY2Vzc2lvbi1udW0+PHVy

bHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVk

LzIxMjU1NzQ0PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzMwNTIyOTQ8

L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5qYWx6LjIwMTAuMTEu

MDA3PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhv

cj5GZXJyaTwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJlY051bT4zMjEwPC9SZWNOdW0+PHJl

Y29yZD48cmVjLW51bWJlcj4zMjEwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3Rh

bXA9IjE1MzUzODA5MDMiPjMyMTA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkZlcnJpLCBDLiBQLjwvYXV0aG9yPjxhdXRob3I+UHJpbmNlLCBNLjwvYXV0aG9yPjxhdXRo

b3I+QnJheW5lLCBDLjwvYXV0aG9yPjxhdXRob3I+QnJvZGF0eSwgSC48L2F1dGhvcj48YXV0aG9y

PkZyYXRpZ2xpb25pLCBMLjwvYXV0aG9yPjxhdXRob3I+R2FuZ3VsaSwgTS48L2F1dGhvcj48YXV0

aG9yPkhhbGwsIEsuPC9hdXRob3I+PGF1dGhvcj5IYXNlZ2F3YSwgSy48L2F1dGhvcj48YXV0aG9y

PkhlbmRyaWUsIEguPC9hdXRob3I+PGF1dGhvcj5IdWFuZywgWS48L2F1dGhvcj48YXV0aG9yPkpv

cm0sIEEuPC9hdXRob3I+PGF1dGhvcj5NYXRoZXJzLCBDLjwvYXV0aG9yPjxhdXRob3I+TWVuZXpl

cywgUC4gUi48L2F1dGhvcj48YXV0aG9yPlJpbW1lciwgRS48L2F1dGhvcj48YXV0aG9yPlNjYXp1

ZmNhLCBNLjwvYXV0aG9yPjxhdXRob3I+QWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlLCBJbnRlcm5h

dGlvbmFsPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+U2Vj

dGlvbiBvZiBFcGlkZW1pb2xvZ3ksIEluc3RpdHV0ZSBvZiBQc3ljaGlhdHJ5LCBLaW5nJmFwb3M7

cyBDb2xsZWdlLCBMb25kb24sIFVLLiBjLmZlcnJpQGlvcC5rY2wuYWMudWs8L2F1dGgtYWRkcmVz

cz48dGl0bGVzPjx0aXRsZT5HbG9iYWwgcHJldmFsZW5jZSBvZiBkZW1lbnRpYTogYSBEZWxwaGkg

Y29uc2Vuc3VzIHN0dWR5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkxhbmNldDwvc2Vjb25kYXJ5

LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4yMTEyLTc8L3BhZ2VzPjx2b2x1bWU+MzY2PC92b2x1bWU+

PG51bWJlcj45NTAzPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvZWNvbm9taWNzLyplcGlkZW1pb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+Q29zdCBvZiBJbGxuZXNzPC9rZXl3b3JkPjxrZXl3b3JkPipEZWxwaGkgVGVjaG5p

cXVlPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD4qR2xvYmFsIEhl

YWx0aDwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5

d29yZD48a2V5d29yZD5NZXRhLUFuYWx5c2lzIGFzIFRvcGljPC9rZXl3b3JkPjxrZXl3b3JkPk1p

ZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlByZXZhbGVuY2U8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAwNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkRlYyAxNzwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0NzQtNTQ3WCAoRWxlY3Ryb25pYykmI3hEOzAxNDAt

NjczNiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTYzNjA3ODg8L2FjY2Vzc2lvbi1u

dW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3Yv

cHVibWVkLzE2MzYwNzg4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzI4

NTAyNjQ8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvUzAxNDAtNjcz

NigwNSk2Nzg4OS0wPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENp

dGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVjTnVtPjI3Mjwv

UmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MjcyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+

PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2

IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzEiPjI3Mjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlw

ZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRo

b3JzPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48YXV0aG9yPkFtb3V5ZWwsIFAuPC9hdXRo

b3I+PGF1dGhvcj5BbmRyaWV1LCBTLjwvYXV0aG9yPjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhv

cj48YXV0aG9yPkJyYXluZSwgQy48L2F1dGhvcj48YXV0aG9yPkJyb2RhdHksIEguPC9hdXRob3I+

PGF1dGhvcj5DZWRhem8tTWluZ3VleiwgQS48L2F1dGhvcj48YXV0aG9yPkR1Ym9pcywgQi48L2F1

dGhvcj48YXV0aG9yPkVkdmFyZHNzb24sIEQuPC9hdXRob3I+PGF1dGhvcj5GZWxkbWFuLCBILjwv

YXV0aG9yPjxhdXRob3I+RnJhdGlnbGlvbmksIEwuPC9hdXRob3I+PGF1dGhvcj5Gcmlzb25pLCBH

LiBCLjwvYXV0aG9yPjxhdXRob3I+R2F1dGhpZXIsIFMuPC9hdXRob3I+PGF1dGhvcj5HZW9yZ2Vz

LCBKLjwvYXV0aG9yPjxhdXRob3I+R3JhZmYsIEMuPC9hdXRob3I+PGF1dGhvcj5JcWJhbCwgSy48

L2F1dGhvcj48YXV0aG9yPkplc3NlbiwgRi48L2F1dGhvcj48YXV0aG9yPkpvaGFuc3NvbiwgRy48

L2F1dGhvcj48YXV0aG9yPkpvbnNzb24sIEwuPC9hdXRob3I+PGF1dGhvcj5LaXZpcGVsdG8sIE0u

PC9hdXRob3I+PGF1dGhvcj5LbmFwcCwgTS48L2F1dGhvcj48YXV0aG9yPk1hbmdpYWxhc2NoZSwg

Ri48L2F1dGhvcj48YXV0aG9yPk1lbGlzLCBSLjwvYXV0aG9yPjxhdXRob3I+Tm9yZGJlcmcsIEEu

PC9hdXRob3I+PGF1dGhvcj5SaWtrZXJ0LCBNLiBPLjwvYXV0aG9yPjxhdXRob3I+UWl1LCBDLjwv

YXV0aG9yPjxhdXRob3I+U2FrbWFyLCBULiBQLjwvYXV0aG9yPjxhdXRob3I+U2NoZWx0ZW5zLCBQ

LjwvYXV0aG9yPjxhdXRob3I+U2NobmVpZGVyLCBMLiBTLjwvYXV0aG9yPjxhdXRob3I+U3Blcmxp

bmcsIFIuPC9hdXRob3I+PGF1dGhvcj5UamVybmJlcmcsIEwuIE8uPC9hdXRob3I+PGF1dGhvcj5X

YWxkZW1hciwgRy48L2F1dGhvcj48YXV0aG9yPldpbW8sIEEuPC9hdXRob3I+PGF1dGhvcj5aZXR0

ZXJiZXJnLCBILjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNz

PkRlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBD

ZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2YgTmV1cm9nZXJpYXRyaWNz

LCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIEh1ZGRpbmdlLCBTd2VkZW47IERlcGFydG1lbnQgb2Yg

R2VyaWF0cmljIE1lZGljaW5lLCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRp

bmdlLCBTd2VkZW4uIEVsZWN0cm9uaWMgYWRkcmVzczogYmVuZ3Qtd2luYmxhZC1zd2VkaXNoYnJh

aW5wb3dlckBraS5zZS4mI3hEO0NlbnRyZSBIb3NwaXRhbGllciBSZWdpb25hbCBVbml2ZXJzaXRh

aXJlIGRlIExpbGxlLCBJbnN0aXR1dCBQYXN0ZXVyIGRlIExpbGxlLCBJTlNFUk0gVTExNjcgUklE

LUFHRSwgVW5pdGUgZCZhcG9zO0VwaWRlbWlvbG9naWUgZXQgZGUgU2FudGUgUHVibGlxdWUsIExh

YmV4IERJU1RBTFosIExpbGxlLCBGcmFuY2UuJiN4RDtEZXBhcnRtZW50IG9mIEVwaWRlbWlvbG9n

eSBhbmQgUHVibGljIEhlYWx0aCwgRmFjdWx0eSBvZiBNZWRpY2luZSwgVG91bG91c2UgVW5pdmVy

c2l0eSBIb3NwaXRhbCwgVG91bG91c2UsIEZyYW5jZS4mI3hEO1dvbGZzb24gQ2VudHJlIGZvciBB

Z2UtUmVsYXRlZCBEaXNlYXNlcywgS2luZyZhcG9zO3MgQ29sbGVnZSBMb25kb24sIExvbmRvbiwg

VUsuJiN4RDtDYW1icmlkZ2UgSW5zdGl0dXRlIG9mIFB1YmxpYyBIZWFsdGgsIFVuaXZlcnNpdHkg

b2YgQ2FtYnJpZGdlLCBDYW1icmlkZ2UsIFVLLiYjeEQ7Q2VudHJlIGZvciBIZWFsdGh5IEJyYWlu

IEFnZWluZyBhbmQgRGVtZW50aWEgQ29sbGFib3JhdGl2ZSBSZXNlYXJjaCBDZW50cmUsIFVuaXZl

cnNpdHkgb2YgTmV3IFNvdXRoIFdhbGVzLCBTeWRuZXksIE5TVywgQXVzdHJhbGlhLiYjeEQ7RGVw

YXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIENlbnRl

ciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEaXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIEth

cm9saW5za2EgSW5zdGl0dXRldCwgSHVkZGluZ2UsIFN3ZWRlbi4mI3hEO0luc3RpdHV0IGRlIGxh

IE1lbW9pcmUgZXQgZGUgbGEgTWFsYWRpZSBkJmFwb3M7QWx6aGVpbWVyLCBJTTJBLCBJTlNFUk0s

IEluc3RpdHV0IGR1IENlcnZlYXUgZXQgZGUgbGEgTW9lbGxlIEVwaW5pZXJlLCBVTVItUzk3NSwg

R3JvdXBlIEhvc3BpdGFsaWVyIFBpdGllLVNhbHBldHJpZXJlLCBVbml2ZXJzaXRlIFBpZXJyZSBl

dCBNYXJpZSBDdXJpZS1QYXJpcyA2LCBQYXJpcywgRnJhbmNlLiYjeEQ7U2Nob29sIG9mIE51cnNp

bmcgYW5kIE1pZHdpZmVyeSwgTGEgVHJvYmUgVW5pdmVyc2l0eSwgTWVsYm91cm5lLCBWSUMsIEF1

c3RyYWxpYTsgRGVwYXJ0bWVudCBvZiBOdXJzaW5nLCBVbWVhIFVuaXZlcnNpdHksIFVtZWEsIFN3

ZWRlbi4mI3hEO0RpdmlzaW9uIG9mIE5ldXJvbG9neSwgRmFjdWx0eSBvZiBNZWRpY2luZSwgVW5p

dmVyc2l0eSBvZiBCcml0aXNoIENvbHVtYmlhLCBWYW5jb3V2ZXIsIEJDLCBDYW5hZGEuJiN4RDtE

ZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgQ2Vu

dGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIEFnaW5nIFJlc2VhcmNoIENlbnRlciwgS2Fyb2xp

bnNrYSBJbnN0aXR1dGV0LCBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0dlbmV2YSBVbml2ZXJzaXR5

IEhvc3BpdGFscyBhbmQgVW5pdmVyc2l0eSBvZiBHZW5ldmEsIEdlbmV2YSwgU3dpdHplcmxhbmQ7

IElSQ0NTIENlbnRybyBTYW4gR2lvdmFubmkgZGkgRGlvIEZhdGViZW5lZnJhdGVsbGksIEJyZXNj

aWEsIEl0YWx5LiYjeEQ7TWNHaWxsIENlbnRlciBmb3IgU3R1ZGllcyBpbiBBZ2luZywgQWx6aGVp

bWVyJmFwb3M7cyBEaXNlYXNlIFJlc2VhcmNoIFVuaXQsIGFuZCBEb3VnbGFzIE1lbnRhbCBIZWFs

dGggVW5pdmVyc2l0eSBJbnN0aXR1dGUsIE1vbnRyZWFsLCBRQywgQ2FuYWRhLiYjeEQ7QWx6aGVp

bWVyIEV1cm9wZSwgTHV4ZW1ib3VyZyBDaXR5LCBMdXhlbWJvdXJnLiYjeEQ7RGVwYXJ0bWVudCBv

ZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6

aGVpbWVyIFJlc2VhcmNoLCBEaXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIEthcm9saW5za2Eg

SW5zdGl0dXRldCwgSHVkZGluZ2UsIFN3ZWRlbjsgRGVwYXJ0bWVudCBvZiBHZXJpYXRyaWMgTWVk

aWNpbmUsIEthcm9saW5za2EgVW5pdmVyc2l0eSBIb3NwaXRhbCwgSHVkZGluZ2UsIFN3ZWRlbi4m

I3hEO0RlcGFydG1lbnQgb2YgTmV1cm9jaGVtaXN0cnksIEluZ2UgR3J1bmRrZS1JcWJhbCBSZXNl

YXJjaCBGbG9vciwgTmV3IFlvcmsgU3RhdGUgSW5zdGl0dXRlIGZvciBCYXNpYyBSZXNlYXJjaCwg

U3RhdGVuIElzbGFuZCwgTlksIFVTQS4mI3hEO0RlcGFydG1lbnQgb2YgUHN5Y2hpYXRyeSwgVW5p

dmVyc2l0eSBvZiBDb2xvZ25lLCBDb2xvZ25lLCBHZXJtYW55OyBHZXJtYW4gQ2VudGVyIGZvciBO

ZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcyAoRFpORSksIEJvbm4sIEdlcm1hbnkuJiN4RDtEZXBh

cnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgQ2VudGVy

IGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0cmljcywgS2Fy

b2xpbnNrYSBJbnN0aXR1dGV0LCBIdWRkaW5nZSwgU3dlZGVuOyBEZXBhcnRtZW50IG9mIEdlcmlh

dHJpYyBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIdWRkaW5nZSwg

U3dlZGVuOyBEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29j

aWV0eSwgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIEFnaW5nIFJlc2VhcmNoIENlbnRl

ciwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO1BlcnNvbmFs

IFNvY2lhbCBTZXJ2aWNlcyBSZXNlYXJjaCBVbml0LCBMb25kb24gU2Nob29sIG9mIEVjb25vbWlj

cyBhbmQgUG9saXRpY2FsIFNjaWVuY2UsIExvbmRvbiwgVUsuJiN4RDtSYWRib3VkdW1jIEFsemhl

aW1lciBDZW50cmUgYW5kIERlcGFydG1lbnQgb2YgR2VyaWF0cmljIE1lZGljaW5lLCBSYWRib3Vk

IFVuaXZlcnNpdHkgTWVkaWNhbCBDZW50ZXIsIE5pam1lZ2VuLCBOZXRoZXJsYW5kcy4mI3hEO0Rl

cGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBDZW50

ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2YgVHJhbnNsYXRpb25hbCBBbHpo

ZWltZXIgQmlvbG9neSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBIdWRkaW5nZSwgU3dlZGVuOyBE

ZXBhcnRtZW50IG9mIEdlcmlhdHJpYyBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhv

c3BpdGFsLCBIdWRkaW5nZSwgU3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ks

IENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNo

LCBEaXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIEthcm9saW5za2EgSW5zdGl0dXRldCwgSHVk

ZGluZ2UsIFN3ZWRlbjsgTGFib3JhdG9yeSBvZiBDaGVtaWNhbCBCaW9sb2d5ICZhbXA7IFNpZ25h

bCBUcmFuc2R1Y3Rpb24sIFRoZSBSb2NrZWZlbGxlciBVbml2ZXJzaXR5LCBOZXcgWW9yaywgTlks

IFVTQS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9sb2d5IGFuZCBBbHpoZWltZXIgQ2VudGVyLCBW

VSBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBOZXVyb3NjaWVuY2UgQ2FtcHVzLCBBbXN0ZXJk

YW0sIE5ldGhlcmxhbmRzLiYjeEQ7RGVwYXJ0bWVudCBvZiBQc3ljaGlhdHJ5IGFuZCB0aGUgQmVo

YXZpb3JhbCBTY2llbmNlcyBhbmQgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIEtlY2sgU2Nob29s

IG9mIE1lZGljaW5lLCBMZW9uYXJkIERhdmlzIFNjaG9vbCBvZiBHZXJvbnRvbG9neSBvZiB0aGUg

VW5pdmVyc2l0eSBvZiBTb3V0aGVybiBDYWxpZm9ybmlhLCBMb3MgQW5nZWxlcywgQ0EsIFVTQS4m

I3hEO0NlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoIGFuZCBUcmVhdG1lbnQsIERlcGFydG1l

bnQgb2YgTmV1cm9sb2d5LCBCcmlnaGFtIGFuZCBXb21lbiZhcG9zO3MgSG9zcGl0YWwgYW5kIE1h

c3NhY2h1c2V0dHMgR2VuZXJhbCBIb3NwaXRhbCwgSGFydmFyZCBNZWRpY2FsIFNjaG9vbCwgQm9z

dG9uLCBNQSwgVVNBLiYjeEQ7RGFuaXNoIERlbWVudGlhIFJlc2VhcmNoIENlbnRyZSwgRGVwYXJ0

bWVudCBvZiBOZXVyb2xvZ3ksIFJpZ3Nob3NwaXRhbGV0LCBVbml2ZXJzaXR5IG9mIENvcGVuaGFn

ZW4sIENvcGVuaGFnZW4sIERlbm1hcmsuJiN4RDtDbGluaWNhbCBOZXVyb2NoZW1pc3RyeSBMYWJv

cmF0b3J5LCBEZXBhcnRtZW50IG9mIE5ldXJvc2NpZW5jZSBhbmQgUGh5c2lvbG9neSwgVGhlIFNh

aGxncmVuc2thIEFjYWRlbXkgYXQgdGhlIFVuaXZlcnNpdHkgb2YgR290aGVuYnVyZywgTW9sbmRh

bCwgU3dlZGVuOyBVQ0wgSW5zdGl0dXRlIG9mIE5ldXJvbG9neSwgUXVlZW4gU3F1YXJlLCBMb25k

b24sIFVLLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkRlZmVhdGluZyBBbHpoZWltZXIm

YXBvcztzIGRpc2Vhc2UgYW5kIG90aGVyIGRlbWVudGlhczogYSBwcmlvcml0eSBmb3IgRXVyb3Bl

YW4gc2NpZW5jZSBhbmQgc29jaWV0eTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5MYW5jZXQgTmV1

cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjQ1NS01MzI8L3BhZ2VzPjx2b2x1

bWU+MTU8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVp

bWVyIERpc2Vhc2UvKnRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QmlvbWVkaWNhbCBSZXNlYXJj

aC9lY29ub21pY3MvKm9yZ2FuaXphdGlvbiAmYW1wOyBhZG1pbmlzdHJhdGlvbjwva2V5d29yZD48

a2V5d29yZD5EZW1lbnRpYS8qdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5FdXJvcGU8L2tleXdv

cmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTY8

L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BcHI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNi

bj4xNDc0LTQ0NjUgKEVsZWN0cm9uaWMpJiN4RDsxNDc0LTQ0MjIgKExpbmtpbmcpPC9pc2JuPjxh

Y2Nlc3Npb24tbnVtPjI2OTg3NzAxPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI2OTg3NzAxPC91cmw+PHVy

bD5odHRwczovL2FjLmVscy1jZG4uY29tL1MxNDc0NDQyMjE2MDAwNjI0LzEtczIuMC1TMTQ3NDQ0

MjIxNjAwMDYyNC1tYWluLnBkZj9fdGlkPTA3N2YwODE1LWNiNTYtNDBjNS1hZGJmLWY4YmZhYTVi

YzlhNyZhbXA7YWNkbmF0PTE1MzQ0OTUyNjBfODFmMDJhM2RmYjhkYmNiMDFjY2NlYzEyZTI5ZjZj

ZWU8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEw

LjEwMTYvUzE0NzQtNDQyMigxNikwMDA2Mi00PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3Jl

Y29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ccm9va21leWVyPC9BdXRob3I+PFllYXI+MjAwNzwvWWVh

cj48UmVjTnVtPjMxMjY8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2Ny

aXB0Ij4xLTQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zMTI2PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzUzODA1NjkiPjMxMjY8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJyb29rbWV5ZXIsIFIuPC9hdXRo

b3I+PGF1dGhvcj5Kb2huc29uLCBFLjwvYXV0aG9yPjxhdXRob3I+WmllZ2xlci1HcmFoYW0sIEsu

PC9hdXRob3I+PGF1dGhvcj5BcnJpZ2hpLCBILiBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy

aWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgQmlvc3RhdGlzdGljcywgSm9obnMg

SG9wa2lucyBCbG9vbWJlcmcgU2Nob29sIG9mIFB1YmxpYyBIZWFsdGgsIEpvaG5zIEhvcGtpbnMg

VW5pdmVyc2l0eSwgQmFsdGltb3JlLCBNRCwgVVNBLiByYnJvb2tAamhzcGguZWR1PC9hdXRoLWFk

ZHJlc3M+PHRpdGxlcz48dGl0bGU+Rm9yZWNhc3RpbmcgdGhlIGdsb2JhbCBidXJkZW4gb2YgQWx6

aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFsemhlaW1lcnMg

RGVtZW50PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjE4Ni05MTwvcGFnZXM+PHZv

bHVtZT4zPC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMDc8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5KdWw8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTUy

LTUyNzkgKEVsZWN0cm9uaWMpJiN4RDsxNTUyLTUyNjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjE5NTk1OTM3PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xOTU5NTkzNzwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmphbHouMjAw

Ny4wNC4zODE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48

QXV0aG9yPkJyb29rbWV5ZXI8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxSZWNOdW0+MzE3Njwv

UmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MzE3NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz

PjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVh

diIgdGltZXN0YW1wPSIxNTM1MzgwNjg1Ij4zMTc2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10

eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1

dGhvcnM+PGF1dGhvcj5Ccm9va21leWVyLCBSLjwvYXV0aG9yPjxhdXRob3I+RXZhbnMsIEQuIEEu

PC9hdXRob3I+PGF1dGhvcj5IZWJlcnQsIEwuPC9hdXRob3I+PGF1dGhvcj5MYW5nYSwgSy4gTS48

L2F1dGhvcj48YXV0aG9yPkhlZXJpbmdhLCBTLiBHLjwvYXV0aG9yPjxhdXRob3I+UGxhc3NtYW4s

IEIuIEwuPC9hdXRob3I+PGF1dGhvcj5LdWt1bGwsIFcuIEEuPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBCaW9zdGF0aXN0aWNzLCBV

bml2ZXJzaXR5IG9mIENhbGlmb3JuaWEsIExvcyBBbmdlbGVzLCBVU0EuIHJicm9va21leWVyQHVj

bGEuZWR1PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+TmF0aW9uYWwgZXN0aW1hdGVzIG9m

IHRoZSBwcmV2YWxlbmNlIG9mIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZSBpbiB0aGUgVW5pdGVk

IFN0YXRlczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbHpoZWltZXJzIERlbWVudDwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz42MS03MzwvcGFnZXM+PHZvbHVtZT43PC92b2x1bWU+

PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZSBGYWN0b3JzPC9rZXl3b3Jk

PjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLyplcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+Q29tbXVuaXR5IEhlYWx0aCBQbGFubmluZzwva2V5d29yZD48a2V5d29yZD5EYXRhIENvbGxl

Y3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkluY2lkZW5j

ZTwva2V5d29yZD48a2V5d29yZD5Nb2RlbHMsIFN0YXRpc3RpY2FsPC9rZXl3b3JkPjxrZXl3b3Jk

PlByZXZhbGVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+KlNhbXBsaW5nIFN0dWRpZXM8L2tleXdvcmQ+

PGtleXdvcmQ+VW5pdGVkIFN0YXRlcy9lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48

ZGF0ZXM+PHllYXI+MjAxMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1k

YXRlcz48L2RhdGVzPjxpc2JuPjE1NTItNTI3OSAoRWxlY3Ryb25pYykmI3hEOzE1NTItNTI2MCAo

TGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjEyNTU3NDQ8L2FjY2Vzc2lvbi1udW0+PHVy

bHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVk

LzIxMjU1NzQ0PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzMwNTIyOTQ8

L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5qYWx6LjIwMTAuMTEu

MDA3PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhv

cj5GZXJyaTwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJlY051bT4zMjEwPC9SZWNOdW0+PHJl

Y29yZD48cmVjLW51bWJlcj4zMjEwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3Rh

bXA9IjE1MzUzODA5MDMiPjMyMTA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkZlcnJpLCBDLiBQLjwvYXV0aG9yPjxhdXRob3I+UHJpbmNlLCBNLjwvYXV0aG9yPjxhdXRo

b3I+QnJheW5lLCBDLjwvYXV0aG9yPjxhdXRob3I+QnJvZGF0eSwgSC48L2F1dGhvcj48YXV0aG9y

PkZyYXRpZ2xpb25pLCBMLjwvYXV0aG9yPjxhdXRob3I+R2FuZ3VsaSwgTS48L2F1dGhvcj48YXV0

aG9yPkhhbGwsIEsuPC9hdXRob3I+PGF1dGhvcj5IYXNlZ2F3YSwgSy48L2F1dGhvcj48YXV0aG9y

PkhlbmRyaWUsIEguPC9hdXRob3I+PGF1dGhvcj5IdWFuZywgWS48L2F1dGhvcj48YXV0aG9yPkpv

cm0sIEEuPC9hdXRob3I+PGF1dGhvcj5NYXRoZXJzLCBDLjwvYXV0aG9yPjxhdXRob3I+TWVuZXpl

cywgUC4gUi48L2F1dGhvcj48YXV0aG9yPlJpbW1lciwgRS48L2F1dGhvcj48YXV0aG9yPlNjYXp1

ZmNhLCBNLjwvYXV0aG9yPjxhdXRob3I+QWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlLCBJbnRlcm5h

dGlvbmFsPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+U2Vj

dGlvbiBvZiBFcGlkZW1pb2xvZ3ksIEluc3RpdHV0ZSBvZiBQc3ljaGlhdHJ5LCBLaW5nJmFwb3M7

cyBDb2xsZWdlLCBMb25kb24sIFVLLiBjLmZlcnJpQGlvcC5rY2wuYWMudWs8L2F1dGgtYWRkcmVz

cz48dGl0bGVzPjx0aXRsZT5HbG9iYWwgcHJldmFsZW5jZSBvZiBkZW1lbnRpYTogYSBEZWxwaGkg

Y29uc2Vuc3VzIHN0dWR5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkxhbmNldDwvc2Vjb25kYXJ5

LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4yMTEyLTc8L3BhZ2VzPjx2b2x1bWU+MzY2PC92b2x1bWU+

PG51bWJlcj45NTAzPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvZWNvbm9taWNzLyplcGlkZW1pb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+Q29zdCBvZiBJbGxuZXNzPC9rZXl3b3JkPjxrZXl3b3JkPipEZWxwaGkgVGVjaG5p

cXVlPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD4qR2xvYmFsIEhl

YWx0aDwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5

d29yZD48a2V5d29yZD5NZXRhLUFuYWx5c2lzIGFzIFRvcGljPC9rZXl3b3JkPjxrZXl3b3JkPk1p

ZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlByZXZhbGVuY2U8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAwNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkRlYyAxNzwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0NzQtNTQ3WCAoRWxlY3Ryb25pYykmI3hEOzAxNDAt

NjczNiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTYzNjA3ODg8L2FjY2Vzc2lvbi1u

dW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3Yv

cHVibWVkLzE2MzYwNzg4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzI4

NTAyNjQ8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvUzAxNDAtNjcz

NigwNSk2Nzg4OS0wPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENp

dGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVjTnVtPjI3Mjwv

UmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MjcyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+

PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2

IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzEiPjI3Mjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlw

ZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRo

b3JzPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48YXV0aG9yPkFtb3V5ZWwsIFAuPC9hdXRo

b3I+PGF1dGhvcj5BbmRyaWV1LCBTLjwvYXV0aG9yPjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhv

cj48YXV0aG9yPkJyYXluZSwgQy48L2F1dGhvcj48YXV0aG9yPkJyb2RhdHksIEguPC9hdXRob3I+

PGF1dGhvcj5DZWRhem8tTWluZ3VleiwgQS48L2F1dGhvcj48YXV0aG9yPkR1Ym9pcywgQi48L2F1

dGhvcj48YXV0aG9yPkVkdmFyZHNzb24sIEQuPC9hdXRob3I+PGF1dGhvcj5GZWxkbWFuLCBILjwv

YXV0aG9yPjxhdXRob3I+RnJhdGlnbGlvbmksIEwuPC9hdXRob3I+PGF1dGhvcj5Gcmlzb25pLCBH

LiBCLjwvYXV0aG9yPjxhdXRob3I+R2F1dGhpZXIsIFMuPC9hdXRob3I+PGF1dGhvcj5HZW9yZ2Vz

LCBKLjwvYXV0aG9yPjxhdXRob3I+R3JhZmYsIEMuPC9hdXRob3I+PGF1dGhvcj5JcWJhbCwgSy48

L2F1dGhvcj48YXV0aG9yPkplc3NlbiwgRi48L2F1dGhvcj48YXV0aG9yPkpvaGFuc3NvbiwgRy48

L2F1dGhvcj48YXV0aG9yPkpvbnNzb24sIEwuPC9hdXRob3I+PGF1dGhvcj5LaXZpcGVsdG8sIE0u

PC9hdXRob3I+PGF1dGhvcj5LbmFwcCwgTS48L2F1dGhvcj48YXV0aG9yPk1hbmdpYWxhc2NoZSwg

Ri48L2F1dGhvcj48YXV0aG9yPk1lbGlzLCBSLjwvYXV0aG9yPjxhdXRob3I+Tm9yZGJlcmcsIEEu

PC9hdXRob3I+PGF1dGhvcj5SaWtrZXJ0LCBNLiBPLjwvYXV0aG9yPjxhdXRob3I+UWl1LCBDLjwv

YXV0aG9yPjxhdXRob3I+U2FrbWFyLCBULiBQLjwvYXV0aG9yPjxhdXRob3I+U2NoZWx0ZW5zLCBQ

LjwvYXV0aG9yPjxhdXRob3I+U2NobmVpZGVyLCBMLiBTLjwvYXV0aG9yPjxhdXRob3I+U3Blcmxp

bmcsIFIuPC9hdXRob3I+PGF1dGhvcj5UamVybmJlcmcsIEwuIE8uPC9hdXRob3I+PGF1dGhvcj5X

YWxkZW1hciwgRy48L2F1dGhvcj48YXV0aG9yPldpbW8sIEEuPC9hdXRob3I+PGF1dGhvcj5aZXR0

ZXJiZXJnLCBILjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNz

PkRlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBD

ZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2YgTmV1cm9nZXJpYXRyaWNz

LCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIEh1ZGRpbmdlLCBTd2VkZW47IERlcGFydG1lbnQgb2Yg

R2VyaWF0cmljIE1lZGljaW5lLCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRp

bmdlLCBTd2VkZW4uIEVsZWN0cm9uaWMgYWRkcmVzczogYmVuZ3Qtd2luYmxhZC1zd2VkaXNoYnJh

aW5wb3dlckBraS5zZS4mI3hEO0NlbnRyZSBIb3NwaXRhbGllciBSZWdpb25hbCBVbml2ZXJzaXRh

aXJlIGRlIExpbGxlLCBJbnN0aXR1dCBQYXN0ZXVyIGRlIExpbGxlLCBJTlNFUk0gVTExNjcgUklE

LUFHRSwgVW5pdGUgZCZhcG9zO0VwaWRlbWlvbG9naWUgZXQgZGUgU2FudGUgUHVibGlxdWUsIExh

YmV4IERJU1RBTFosIExpbGxlLCBGcmFuY2UuJiN4RDtEZXBhcnRtZW50IG9mIEVwaWRlbWlvbG9n

eSBhbmQgUHVibGljIEhlYWx0aCwgRmFjdWx0eSBvZiBNZWRpY2luZSwgVG91bG91c2UgVW5pdmVy

c2l0eSBIb3NwaXRhbCwgVG91bG91c2UsIEZyYW5jZS4mI3hEO1dvbGZzb24gQ2VudHJlIGZvciBB

Z2UtUmVsYXRlZCBEaXNlYXNlcywgS2luZyZhcG9zO3MgQ29sbGVnZSBMb25kb24sIExvbmRvbiwg

VUsuJiN4RDtDYW1icmlkZ2UgSW5zdGl0dXRlIG9mIFB1YmxpYyBIZWFsdGgsIFVuaXZlcnNpdHkg

b2YgQ2FtYnJpZGdlLCBDYW1icmlkZ2UsIFVLLiYjeEQ7Q2VudHJlIGZvciBIZWFsdGh5IEJyYWlu

IEFnZWluZyBhbmQgRGVtZW50aWEgQ29sbGFib3JhdGl2ZSBSZXNlYXJjaCBDZW50cmUsIFVuaXZl

cnNpdHkgb2YgTmV3IFNvdXRoIFdhbGVzLCBTeWRuZXksIE5TVywgQXVzdHJhbGlhLiYjeEQ7RGVw

YXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIENlbnRl

ciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEaXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIEth

cm9saW5za2EgSW5zdGl0dXRldCwgSHVkZGluZ2UsIFN3ZWRlbi4mI3hEO0luc3RpdHV0IGRlIGxh

IE1lbW9pcmUgZXQgZGUgbGEgTWFsYWRpZSBkJmFwb3M7QWx6aGVpbWVyLCBJTTJBLCBJTlNFUk0s

IEluc3RpdHV0IGR1IENlcnZlYXUgZXQgZGUgbGEgTW9lbGxlIEVwaW5pZXJlLCBVTVItUzk3NSwg

R3JvdXBlIEhvc3BpdGFsaWVyIFBpdGllLVNhbHBldHJpZXJlLCBVbml2ZXJzaXRlIFBpZXJyZSBl

dCBNYXJpZSBDdXJpZS1QYXJpcyA2LCBQYXJpcywgRnJhbmNlLiYjeEQ7U2Nob29sIG9mIE51cnNp

bmcgYW5kIE1pZHdpZmVyeSwgTGEgVHJvYmUgVW5pdmVyc2l0eSwgTWVsYm91cm5lLCBWSUMsIEF1

c3RyYWxpYTsgRGVwYXJ0bWVudCBvZiBOdXJzaW5nLCBVbWVhIFVuaXZlcnNpdHksIFVtZWEsIFN3

ZWRlbi4mI3hEO0RpdmlzaW9uIG9mIE5ldXJvbG9neSwgRmFjdWx0eSBvZiBNZWRpY2luZSwgVW5p

dmVyc2l0eSBvZiBCcml0aXNoIENvbHVtYmlhLCBWYW5jb3V2ZXIsIEJDLCBDYW5hZGEuJiN4RDtE

ZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgQ2Vu

dGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIEFnaW5nIFJlc2VhcmNoIENlbnRlciwgS2Fyb2xp

bnNrYSBJbnN0aXR1dGV0LCBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0dlbmV2YSBVbml2ZXJzaXR5

IEhvc3BpdGFscyBhbmQgVW5pdmVyc2l0eSBvZiBHZW5ldmEsIEdlbmV2YSwgU3dpdHplcmxhbmQ7

IElSQ0NTIENlbnRybyBTYW4gR2lvdmFubmkgZGkgRGlvIEZhdGViZW5lZnJhdGVsbGksIEJyZXNj

aWEsIEl0YWx5LiYjeEQ7TWNHaWxsIENlbnRlciBmb3IgU3R1ZGllcyBpbiBBZ2luZywgQWx6aGVp

bWVyJmFwb3M7cyBEaXNlYXNlIFJlc2VhcmNoIFVuaXQsIGFuZCBEb3VnbGFzIE1lbnRhbCBIZWFs

dGggVW5pdmVyc2l0eSBJbnN0aXR1dGUsIE1vbnRyZWFsLCBRQywgQ2FuYWRhLiYjeEQ7QWx6aGVp

bWVyIEV1cm9wZSwgTHV4ZW1ib3VyZyBDaXR5LCBMdXhlbWJvdXJnLiYjeEQ7RGVwYXJ0bWVudCBv

ZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6

aGVpbWVyIFJlc2VhcmNoLCBEaXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIEthcm9saW5za2Eg

SW5zdGl0dXRldCwgSHVkZGluZ2UsIFN3ZWRlbjsgRGVwYXJ0bWVudCBvZiBHZXJpYXRyaWMgTWVk

aWNpbmUsIEthcm9saW5za2EgVW5pdmVyc2l0eSBIb3NwaXRhbCwgSHVkZGluZ2UsIFN3ZWRlbi4m

I3hEO0RlcGFydG1lbnQgb2YgTmV1cm9jaGVtaXN0cnksIEluZ2UgR3J1bmRrZS1JcWJhbCBSZXNl

YXJjaCBGbG9vciwgTmV3IFlvcmsgU3RhdGUgSW5zdGl0dXRlIGZvciBCYXNpYyBSZXNlYXJjaCwg

U3RhdGVuIElzbGFuZCwgTlksIFVTQS4mI3hEO0RlcGFydG1lbnQgb2YgUHN5Y2hpYXRyeSwgVW5p

dmVyc2l0eSBvZiBDb2xvZ25lLCBDb2xvZ25lLCBHZXJtYW55OyBHZXJtYW4gQ2VudGVyIGZvciBO

ZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcyAoRFpORSksIEJvbm4sIEdlcm1hbnkuJiN4RDtEZXBh

cnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgQ2VudGVy

IGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0cmljcywgS2Fy

b2xpbnNrYSBJbnN0aXR1dGV0LCBIdWRkaW5nZSwgU3dlZGVuOyBEZXBhcnRtZW50IG9mIEdlcmlh

dHJpYyBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIdWRkaW5nZSwg

U3dlZGVuOyBEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29j

aWV0eSwgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIEFnaW5nIFJlc2VhcmNoIENlbnRl

ciwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO1BlcnNvbmFs

IFNvY2lhbCBTZXJ2aWNlcyBSZXNlYXJjaCBVbml0LCBMb25kb24gU2Nob29sIG9mIEVjb25vbWlj

cyBhbmQgUG9saXRpY2FsIFNjaWVuY2UsIExvbmRvbiwgVUsuJiN4RDtSYWRib3VkdW1jIEFsemhl

aW1lciBDZW50cmUgYW5kIERlcGFydG1lbnQgb2YgR2VyaWF0cmljIE1lZGljaW5lLCBSYWRib3Vk

IFVuaXZlcnNpdHkgTWVkaWNhbCBDZW50ZXIsIE5pam1lZ2VuLCBOZXRoZXJsYW5kcy4mI3hEO0Rl

cGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBDZW50

ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2YgVHJhbnNsYXRpb25hbCBBbHpo

ZWltZXIgQmlvbG9neSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBIdWRkaW5nZSwgU3dlZGVuOyBE

ZXBhcnRtZW50IG9mIEdlcmlhdHJpYyBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhv

c3BpdGFsLCBIdWRkaW5nZSwgU3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ks

IENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNo

LCBEaXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIEthcm9saW5za2EgSW5zdGl0dXRldCwgSHVk

ZGluZ2UsIFN3ZWRlbjsgTGFib3JhdG9yeSBvZiBDaGVtaWNhbCBCaW9sb2d5ICZhbXA7IFNpZ25h

bCBUcmFuc2R1Y3Rpb24sIFRoZSBSb2NrZWZlbGxlciBVbml2ZXJzaXR5LCBOZXcgWW9yaywgTlks

IFVTQS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9sb2d5IGFuZCBBbHpoZWltZXIgQ2VudGVyLCBW

VSBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBOZXVyb3NjaWVuY2UgQ2FtcHVzLCBBbXN0ZXJk

YW0sIE5ldGhlcmxhbmRzLiYjeEQ7RGVwYXJ0bWVudCBvZiBQc3ljaGlhdHJ5IGFuZCB0aGUgQmVo

YXZpb3JhbCBTY2llbmNlcyBhbmQgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIEtlY2sgU2Nob29s

IG9mIE1lZGljaW5lLCBMZW9uYXJkIERhdmlzIFNjaG9vbCBvZiBHZXJvbnRvbG9neSBvZiB0aGUg

VW5pdmVyc2l0eSBvZiBTb3V0aGVybiBDYWxpZm9ybmlhLCBMb3MgQW5nZWxlcywgQ0EsIFVTQS4m

I3hEO0NlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoIGFuZCBUcmVhdG1lbnQsIERlcGFydG1l

bnQgb2YgTmV1cm9sb2d5LCBCcmlnaGFtIGFuZCBXb21lbiZhcG9zO3MgSG9zcGl0YWwgYW5kIE1h

c3NhY2h1c2V0dHMgR2VuZXJhbCBIb3NwaXRhbCwgSGFydmFyZCBNZWRpY2FsIFNjaG9vbCwgQm9z

dG9uLCBNQSwgVVNBLiYjeEQ7RGFuaXNoIERlbWVudGlhIFJlc2VhcmNoIENlbnRyZSwgRGVwYXJ0

bWVudCBvZiBOZXVyb2xvZ3ksIFJpZ3Nob3NwaXRhbGV0LCBVbml2ZXJzaXR5IG9mIENvcGVuaGFn

ZW4sIENvcGVuaGFnZW4sIERlbm1hcmsuJiN4RDtDbGluaWNhbCBOZXVyb2NoZW1pc3RyeSBMYWJv

cmF0b3J5LCBEZXBhcnRtZW50IG9mIE5ldXJvc2NpZW5jZSBhbmQgUGh5c2lvbG9neSwgVGhlIFNh

aGxncmVuc2thIEFjYWRlbXkgYXQgdGhlIFVuaXZlcnNpdHkgb2YgR290aGVuYnVyZywgTW9sbmRh

bCwgU3dlZGVuOyBVQ0wgSW5zdGl0dXRlIG9mIE5ldXJvbG9neSwgUXVlZW4gU3F1YXJlLCBMb25k

b24sIFVLLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkRlZmVhdGluZyBBbHpoZWltZXIm

YXBvcztzIGRpc2Vhc2UgYW5kIG90aGVyIGRlbWVudGlhczogYSBwcmlvcml0eSBmb3IgRXVyb3Bl

YW4gc2NpZW5jZSBhbmQgc29jaWV0eTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5MYW5jZXQgTmV1

cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjQ1NS01MzI8L3BhZ2VzPjx2b2x1

bWU+MTU8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVp

bWVyIERpc2Vhc2UvKnRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QmlvbWVkaWNhbCBSZXNlYXJj

aC9lY29ub21pY3MvKm9yZ2FuaXphdGlvbiAmYW1wOyBhZG1pbmlzdHJhdGlvbjwva2V5d29yZD48

a2V5d29yZD5EZW1lbnRpYS8qdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5FdXJvcGU8L2tleXdv

cmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTY8

L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BcHI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNi

bj4xNDc0LTQ0NjUgKEVsZWN0cm9uaWMpJiN4RDsxNDc0LTQ0MjIgKExpbmtpbmcpPC9pc2JuPjxh

Y2Nlc3Npb24tbnVtPjI2OTg3NzAxPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI2OTg3NzAxPC91cmw+PHVy

bD5odHRwczovL2FjLmVscy1jZG4uY29tL1MxNDc0NDQyMjE2MDAwNjI0LzEtczIuMC1TMTQ3NDQ0

MjIxNjAwMDYyNC1tYWluLnBkZj9fdGlkPTA3N2YwODE1LWNiNTYtNDBjNS1hZGJmLWY4YmZhYTVi

YzlhNyZhbXA7YWNkbmF0PTE1MzQ0OTUyNjBfODFmMDJhM2RmYjhkYmNiMDFjY2NlYzEyZTI5ZjZj

ZWU8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEw

LjEwMTYvUzE0NzQtNDQyMigxNikwMDA2Mi00PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3Jl

Y29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 1-4. AD is a neurodegenerative disorder characterized mainly by the loss of memory functions and accompanied by other symptoms in a wide range of classes from mood, verbalization and even motor problems. The most striking outcome from this type of dementia is the incremental disability for performing everyday life routines and increasing dependence from others for care. Aging is the main risk factor for developing AD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb3BlejwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl

Y051bT4zMTAzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NSw2PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzEwMzwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1MzgwMDM5Ij4zMTAzPC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Mb3BleiwgQS4gRC48L2F1dGhvcj48YXV0

aG9yPk1hdGhlcnMsIEMuIEQuPC9hdXRob3I+PGF1dGhvcj5FenphdGksIE0uPC9hdXRob3I+PGF1

dGhvcj5KYW1pc29uLCBELiBULjwvYXV0aG9yPjxhdXRob3I+TXVycmF5LCBDLiBKLjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlNjaG9vbCBvZiBQb3B1bGF0

aW9uIEhlYWx0aCwgVW5pdmVyc2l0eSBvZiBRdWVlbnNsYW5kLCBCcmlzYmFuZSA0MDA2LCBBdXN0

cmFsaWEuIGEubG9wZXpAc3BoLnVxLmVkdS5hdTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxl

Pkdsb2JhbCBhbmQgcmVnaW9uYWwgYnVyZGVuIG9mIGRpc2Vhc2UgYW5kIHJpc2sgZmFjdG9ycywg

MjAwMTogc3lzdGVtYXRpYyBhbmFseXNpcyBvZiBwb3B1bGF0aW9uIGhlYWx0aCBkYXRhPC90aXRs

ZT48c2Vjb25kYXJ5LXRpdGxlPkxhbmNldDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdl

cz4xNzQ3LTU3PC9wYWdlcz48dm9sdW1lPjM2Nzwvdm9sdW1lPjxudW1iZXI+OTUyNDwvbnVtYmVy

PjxrZXl3b3Jkcz48a2V5d29yZD5BZG9sZXNjZW50PC9rZXl3b3JkPjxrZXl3b3JkPkFkdWx0PC9r

ZXl3b3JkPjxrZXl3b3JkPkFnZSBEaXN0cmlidXRpb248L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwv

a2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD4qQ2F1

c2Ugb2YgRGVhdGg8L2tleXdvcmQ+PGtleXdvcmQ+Q2hpbGQ8L2tleXdvcmQ+PGtleXdvcmQ+Q2hp

bGQsIFByZXNjaG9vbDwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+

Kkdsb2JhbCBIZWFsdGg8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3Jk

PkluY29tZTwva2V5d29yZD48a2V5d29yZD5JbmZhbnQ8L2tleXdvcmQ+PGtleXdvcmQ+SW5mYW50

LCBOZXdib3JuPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxl

IEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UG9wdWxhdGlvbiBTdXJ2ZWlsbGFuY2UvKm1ldGhvZHM8

L2tleXdvcmQ+PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlN0aWxsYmly

dGgvZXBpZGVtaW9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDY8L3ll

YXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXkgMjc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNi

bj4xNDc0LTU0N1ggKEVsZWN0cm9uaWMpJiN4RDswMTQwLTY3MzYgKExpbmtpbmcpPC9pc2JuPjxh

Y2Nlc3Npb24tbnVtPjE2NzMxMjcwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNjczMTI3MDwvdXJsPjwv

cmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMDE0

MC02NzM2KDA2KTY4NzcwLTk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0

ZT48Q2l0ZT48QXV0aG9yPkZhcnJlcjwvQXV0aG9yPjxZZWFyPjE5OTc8L1llYXI+PFJlY051bT4z

MTE5PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zMTE5PC9yZWMtbnVtYmVyPjxmb3JlaWdu

LWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpw

cnB0NWF2IiB0aW1lc3RhbXA9IjE1MzUzODAxMTMiPjMxMTk8L2tleT48L2ZvcmVpZ24ta2V5cz48

cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9y

cz48YXV0aG9ycz48YXV0aG9yPkZhcnJlciwgTC4gQS48L2F1dGhvcj48YXV0aG9yPkN1cHBsZXMs

IEwuIEEuPC9hdXRob3I+PGF1dGhvcj5IYWluZXMsIEouIEwuPC9hdXRob3I+PGF1dGhvcj5IeW1h

biwgQi48L2F1dGhvcj48YXV0aG9yPkt1a3VsbCwgVy4gQS48L2F1dGhvcj48YXV0aG9yPk1heWV1

eCwgUi48L2F1dGhvcj48YXV0aG9yPk15ZXJzLCBSLiBILjwvYXV0aG9yPjxhdXRob3I+UGVyaWNh

ay1WYW5jZSwgTS4gQS48L2F1dGhvcj48YXV0aG9yPlJpc2NoLCBOLjwvYXV0aG9yPjxhdXRob3I+

dmFuIER1aWpuLCBDLiBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1h

ZGRyZXNzPkRlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBCb3N0b24gVW5pdmVyc2l0eSBTY2hvb2wg

b2YgTWVkaWNpbmUsIE1hc3MgMDIxMTgsIFVTQS4gZmFycmVyQG5ldWdlbi5idS5lZHU8L2F1dGgt

YWRkcmVzcz48dGl0bGVzPjx0aXRsZT5FZmZlY3RzIG9mIGFnZSwgc2V4LCBhbmQgZXRobmljaXR5

IG9uIHRoZSBhc3NvY2lhdGlvbiBiZXR3ZWVuIGFwb2xpcG9wcm90ZWluIEUgZ2Vub3R5cGUgYW5k

IEFsemhlaW1lciBkaXNlYXNlLiBBIG1ldGEtYW5hbHlzaXMuIEFQT0UgYW5kIEFsemhlaW1lciBE

aXNlYXNlIE1ldGEgQW5hbHlzaXMgQ29uc29ydGl1bTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5K

QU1BPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEzNDktNTY8L3BhZ2VzPjx2b2x1

bWU+Mjc4PC92b2x1bWU+PG51bWJlcj4xNjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZHVs

dDwva2V5d29yZD48a2V5d29yZD5BZnJpY2FuIENvbnRpbmVudGFsIEFuY2VzdHJ5IEdyb3VwL2dl

bmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkFnZSBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPkFn

ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+

QWxsZWxlczwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9lcGlkZW1pb2xvZ3kv

KmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWlucyBFLypnZW5ldGljczwv

a2V5d29yZD48a2V5d29yZD5Bc2lhbiBDb250aW5lbnRhbCBBbmNlc3RyeSBHcm91cC9nZW5ldGlj

czwva2V5d29yZD48a2V5d29yZD5Db250aW5lbnRhbCBQb3B1bGF0aW9uIEdyb3Vwcy8qZ2VuZXRp

Y3M8L2tleXdvcmQ+PGtleXdvcmQ+RXVyb3BlYW4gQ29udGluZW50YWwgQW5jZXN0cnkgR3JvdXAv

Z2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkdlbm90

eXBlPC9rZXl3b3JkPjxrZXl3b3JkPkhpc3BhbmljIEFtZXJpY2Fucy9nZW5ldGljczwva2V5d29y

ZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TG9naXN0aWMgTW9kZWxzPC9rZXl3

b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+

PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5

OTc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5PY3QgMjItMjk8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4wMDk4LTc0ODQgKFByaW50KSYjeEQ7MDA5OC03NDg0IChMaW5raW5nKTwvaXNi

bj48YWNjZXNzaW9uLW51bT45MzQzNDY3PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC85MzQzNDY3PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb3BlejwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl

Y051bT4zMTAzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NSw2PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzEwMzwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1MzgwMDM5Ij4zMTAzPC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Mb3BleiwgQS4gRC48L2F1dGhvcj48YXV0

aG9yPk1hdGhlcnMsIEMuIEQuPC9hdXRob3I+PGF1dGhvcj5FenphdGksIE0uPC9hdXRob3I+PGF1

dGhvcj5KYW1pc29uLCBELiBULjwvYXV0aG9yPjxhdXRob3I+TXVycmF5LCBDLiBKLjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlNjaG9vbCBvZiBQb3B1bGF0

aW9uIEhlYWx0aCwgVW5pdmVyc2l0eSBvZiBRdWVlbnNsYW5kLCBCcmlzYmFuZSA0MDA2LCBBdXN0

cmFsaWEuIGEubG9wZXpAc3BoLnVxLmVkdS5hdTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxl

Pkdsb2JhbCBhbmQgcmVnaW9uYWwgYnVyZGVuIG9mIGRpc2Vhc2UgYW5kIHJpc2sgZmFjdG9ycywg

MjAwMTogc3lzdGVtYXRpYyBhbmFseXNpcyBvZiBwb3B1bGF0aW9uIGhlYWx0aCBkYXRhPC90aXRs

ZT48c2Vjb25kYXJ5LXRpdGxlPkxhbmNldDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdl

cz4xNzQ3LTU3PC9wYWdlcz48dm9sdW1lPjM2Nzwvdm9sdW1lPjxudW1iZXI+OTUyNDwvbnVtYmVy

PjxrZXl3b3Jkcz48a2V5d29yZD5BZG9sZXNjZW50PC9rZXl3b3JkPjxrZXl3b3JkPkFkdWx0PC9r

ZXl3b3JkPjxrZXl3b3JkPkFnZSBEaXN0cmlidXRpb248L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwv

a2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD4qQ2F1

c2Ugb2YgRGVhdGg8L2tleXdvcmQ+PGtleXdvcmQ+Q2hpbGQ8L2tleXdvcmQ+PGtleXdvcmQ+Q2hp

bGQsIFByZXNjaG9vbDwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+

Kkdsb2JhbCBIZWFsdGg8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3Jk

PkluY29tZTwva2V5d29yZD48a2V5d29yZD5JbmZhbnQ8L2tleXdvcmQ+PGtleXdvcmQ+SW5mYW50

LCBOZXdib3JuPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxl

IEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UG9wdWxhdGlvbiBTdXJ2ZWlsbGFuY2UvKm1ldGhvZHM8

L2tleXdvcmQ+PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlN0aWxsYmly

dGgvZXBpZGVtaW9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDY8L3ll

YXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXkgMjc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNi

bj4xNDc0LTU0N1ggKEVsZWN0cm9uaWMpJiN4RDswMTQwLTY3MzYgKExpbmtpbmcpPC9pc2JuPjxh

Y2Nlc3Npb24tbnVtPjE2NzMxMjcwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNjczMTI3MDwvdXJsPjwv

cmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMDE0

MC02NzM2KDA2KTY4NzcwLTk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0

ZT48Q2l0ZT48QXV0aG9yPkZhcnJlcjwvQXV0aG9yPjxZZWFyPjE5OTc8L1llYXI+PFJlY051bT4z

MTE5PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zMTE5PC9yZWMtbnVtYmVyPjxmb3JlaWdu

LWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpw

cnB0NWF2IiB0aW1lc3RhbXA9IjE1MzUzODAxMTMiPjMxMTk8L2tleT48L2ZvcmVpZ24ta2V5cz48

cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9y

cz48YXV0aG9ycz48YXV0aG9yPkZhcnJlciwgTC4gQS48L2F1dGhvcj48YXV0aG9yPkN1cHBsZXMs

IEwuIEEuPC9hdXRob3I+PGF1dGhvcj5IYWluZXMsIEouIEwuPC9hdXRob3I+PGF1dGhvcj5IeW1h

biwgQi48L2F1dGhvcj48YXV0aG9yPkt1a3VsbCwgVy4gQS48L2F1dGhvcj48YXV0aG9yPk1heWV1

eCwgUi48L2F1dGhvcj48YXV0aG9yPk15ZXJzLCBSLiBILjwvYXV0aG9yPjxhdXRob3I+UGVyaWNh

ay1WYW5jZSwgTS4gQS48L2F1dGhvcj48YXV0aG9yPlJpc2NoLCBOLjwvYXV0aG9yPjxhdXRob3I+

dmFuIER1aWpuLCBDLiBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1h

ZGRyZXNzPkRlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBCb3N0b24gVW5pdmVyc2l0eSBTY2hvb2wg

b2YgTWVkaWNpbmUsIE1hc3MgMDIxMTgsIFVTQS4gZmFycmVyQG5ldWdlbi5idS5lZHU8L2F1dGgt

YWRkcmVzcz48dGl0bGVzPjx0aXRsZT5FZmZlY3RzIG9mIGFnZSwgc2V4LCBhbmQgZXRobmljaXR5

IG9uIHRoZSBhc3NvY2lhdGlvbiBiZXR3ZWVuIGFwb2xpcG9wcm90ZWluIEUgZ2Vub3R5cGUgYW5k

IEFsemhlaW1lciBkaXNlYXNlLiBBIG1ldGEtYW5hbHlzaXMuIEFQT0UgYW5kIEFsemhlaW1lciBE

aXNlYXNlIE1ldGEgQW5hbHlzaXMgQ29uc29ydGl1bTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5K

QU1BPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEzNDktNTY8L3BhZ2VzPjx2b2x1

bWU+Mjc4PC92b2x1bWU+PG51bWJlcj4xNjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZHVs

dDwva2V5d29yZD48a2V5d29yZD5BZnJpY2FuIENvbnRpbmVudGFsIEFuY2VzdHJ5IEdyb3VwL2dl

bmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkFnZSBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPkFn

ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+

QWxsZWxlczwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9lcGlkZW1pb2xvZ3kv

KmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWlucyBFLypnZW5ldGljczwv

a2V5d29yZD48a2V5d29yZD5Bc2lhbiBDb250aW5lbnRhbCBBbmNlc3RyeSBHcm91cC9nZW5ldGlj

czwva2V5d29yZD48a2V5d29yZD5Db250aW5lbnRhbCBQb3B1bGF0aW9uIEdyb3Vwcy8qZ2VuZXRp

Y3M8L2tleXdvcmQ+PGtleXdvcmQ+RXVyb3BlYW4gQ29udGluZW50YWwgQW5jZXN0cnkgR3JvdXAv

Z2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkdlbm90

eXBlPC9rZXl3b3JkPjxrZXl3b3JkPkhpc3BhbmljIEFtZXJpY2Fucy9nZW5ldGljczwva2V5d29y

ZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TG9naXN0aWMgTW9kZWxzPC9rZXl3

b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+

PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5

OTc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5PY3QgMjItMjk8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4wMDk4LTc0ODQgKFByaW50KSYjeEQ7MDA5OC03NDg0IChMaW5raW5nKTwvaXNi

bj48YWNjZXNzaW9uLW51bT45MzQzNDY3PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC85MzQzNDY3PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 5,6. The risk of developing AD dementia becomes even higher as life expectancy increases and the world population becomes older, PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb3BlejwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl

Y051bT4zMTAzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NSw3PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzEwMzwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1MzgwMDM5Ij4zMTAzPC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Mb3BleiwgQS4gRC48L2F1dGhvcj48YXV0

aG9yPk1hdGhlcnMsIEMuIEQuPC9hdXRob3I+PGF1dGhvcj5FenphdGksIE0uPC9hdXRob3I+PGF1

dGhvcj5KYW1pc29uLCBELiBULjwvYXV0aG9yPjxhdXRob3I+TXVycmF5LCBDLiBKLjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlNjaG9vbCBvZiBQb3B1bGF0

aW9uIEhlYWx0aCwgVW5pdmVyc2l0eSBvZiBRdWVlbnNsYW5kLCBCcmlzYmFuZSA0MDA2LCBBdXN0

cmFsaWEuIGEubG9wZXpAc3BoLnVxLmVkdS5hdTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxl

Pkdsb2JhbCBhbmQgcmVnaW9uYWwgYnVyZGVuIG9mIGRpc2Vhc2UgYW5kIHJpc2sgZmFjdG9ycywg

MjAwMTogc3lzdGVtYXRpYyBhbmFseXNpcyBvZiBwb3B1bGF0aW9uIGhlYWx0aCBkYXRhPC90aXRs

ZT48c2Vjb25kYXJ5LXRpdGxlPkxhbmNldDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdl

cz4xNzQ3LTU3PC9wYWdlcz48dm9sdW1lPjM2Nzwvdm9sdW1lPjxudW1iZXI+OTUyNDwvbnVtYmVy

PjxrZXl3b3Jkcz48a2V5d29yZD5BZG9sZXNjZW50PC9rZXl3b3JkPjxrZXl3b3JkPkFkdWx0PC9r

ZXl3b3JkPjxrZXl3b3JkPkFnZSBEaXN0cmlidXRpb248L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwv

a2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD4qQ2F1

c2Ugb2YgRGVhdGg8L2tleXdvcmQ+PGtleXdvcmQ+Q2hpbGQ8L2tleXdvcmQ+PGtleXdvcmQ+Q2hp

bGQsIFByZXNjaG9vbDwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+

Kkdsb2JhbCBIZWFsdGg8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3Jk

PkluY29tZTwva2V5d29yZD48a2V5d29yZD5JbmZhbnQ8L2tleXdvcmQ+PGtleXdvcmQ+SW5mYW50

LCBOZXdib3JuPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxl

IEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UG9wdWxhdGlvbiBTdXJ2ZWlsbGFuY2UvKm1ldGhvZHM8

L2tleXdvcmQ+PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlN0aWxsYmly

dGgvZXBpZGVtaW9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDY8L3ll

YXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXkgMjc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNi

bj4xNDc0LTU0N1ggKEVsZWN0cm9uaWMpJiN4RDswMTQwLTY3MzYgKExpbmtpbmcpPC9pc2JuPjxh

Y2Nlc3Npb24tbnVtPjE2NzMxMjcwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNjczMTI3MDwvdXJsPjwv

cmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMDE0

MC02NzM2KDA2KTY4NzcwLTk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0

ZT48Q2l0ZT48QXV0aG9yPlByaW5jZTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJlY051bT4z

MjEyPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zMjEyPC9yZWMtbnVtYmVyPjxmb3JlaWdu

LWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpw

cnB0NWF2IiB0aW1lc3RhbXA9IjE1MzUzODEzNjQiPjMyMTI8L2tleT48L2ZvcmVpZ24ta2V5cz48

cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9y

cz48YXV0aG9ycz48YXV0aG9yPlByaW5jZSwgTS48L2F1dGhvcj48YXV0aG9yPkJyeWNlLCBSLjwv

YXV0aG9yPjxhdXRob3I+QWxiYW5lc2UsIEUuPC9hdXRob3I+PGF1dGhvcj5XaW1vLCBBLjwvYXV0

aG9yPjxhdXRob3I+UmliZWlybywgVy48L2F1dGhvcj48YXV0aG9yPkZlcnJpLCBDLiBQLjwvYXV0

aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkluc3RpdHV0ZSBvZiBQ

c3ljaGlhdHJ5LCBLaW5nJmFwb3M7cyBDb2xsZWdlIExvbmRvbiwgTG9uZG9uLCBVSy4gTWFydGlu

LlByaW5jZUBrY2wuYWMudWs8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5UaGUgZ2xvYmFs

IHByZXZhbGVuY2Ugb2YgZGVtZW50aWE6IGEgc3lzdGVtYXRpYyByZXZpZXcgYW5kIG1ldGFhbmFs

eXNpczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbHpoZWltZXJzIERlbWVudDwvc2Vjb25kYXJ5

LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz42My03NSBlMjwvcGFnZXM+PHZvbHVtZT45PC92b2x1bWU+

PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdv

cmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+RGVtZW50aWEvKmVwaWRlbWlv

bG9neTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+R2xvYmFsIEhl

YWx0aC8qdHJlbmRzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5M

aWZlIEV4cGVjdGFuY3kvdHJlbmRzPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtl

eXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UHJldmFsZW5jZTwva2V5d29yZD48

L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SmFuPC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU1Mi01Mjc5IChFbGVjdHJvbmljKSYjeEQ7

MTU1Mi01MjYwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzMwNTgyMzwvYWNjZXNz

aW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmlo

Lmdvdi9wdWJtZWQvMjMzMDU4MjM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5qYWx6LjIwMTIuMTEuMDA3PC9lbGVjdHJvbmljLXJl

c291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb3BlejwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl

Y051bT4zMTAzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NSw3PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzEwMzwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1MzgwMDM5Ij4zMTAzPC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Mb3BleiwgQS4gRC48L2F1dGhvcj48YXV0

aG9yPk1hdGhlcnMsIEMuIEQuPC9hdXRob3I+PGF1dGhvcj5FenphdGksIE0uPC9hdXRob3I+PGF1

dGhvcj5KYW1pc29uLCBELiBULjwvYXV0aG9yPjxhdXRob3I+TXVycmF5LCBDLiBKLjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlNjaG9vbCBvZiBQb3B1bGF0

aW9uIEhlYWx0aCwgVW5pdmVyc2l0eSBvZiBRdWVlbnNsYW5kLCBCcmlzYmFuZSA0MDA2LCBBdXN0

cmFsaWEuIGEubG9wZXpAc3BoLnVxLmVkdS5hdTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxl

Pkdsb2JhbCBhbmQgcmVnaW9uYWwgYnVyZGVuIG9mIGRpc2Vhc2UgYW5kIHJpc2sgZmFjdG9ycywg

MjAwMTogc3lzdGVtYXRpYyBhbmFseXNpcyBvZiBwb3B1bGF0aW9uIGhlYWx0aCBkYXRhPC90aXRs

ZT48c2Vjb25kYXJ5LXRpdGxlPkxhbmNldDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdl

cz4xNzQ3LTU3PC9wYWdlcz48dm9sdW1lPjM2Nzwvdm9sdW1lPjxudW1iZXI+OTUyNDwvbnVtYmVy

PjxrZXl3b3Jkcz48a2V5d29yZD5BZG9sZXNjZW50PC9rZXl3b3JkPjxrZXl3b3JkPkFkdWx0PC9r

ZXl3b3JkPjxrZXl3b3JkPkFnZSBEaXN0cmlidXRpb248L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwv

a2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD4qQ2F1

c2Ugb2YgRGVhdGg8L2tleXdvcmQ+PGtleXdvcmQ+Q2hpbGQ8L2tleXdvcmQ+PGtleXdvcmQ+Q2hp

bGQsIFByZXNjaG9vbDwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+

Kkdsb2JhbCBIZWFsdGg8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3Jk

PkluY29tZTwva2V5d29yZD48a2V5d29yZD5JbmZhbnQ8L2tleXdvcmQ+PGtleXdvcmQ+SW5mYW50

LCBOZXdib3JuPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxl

IEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UG9wdWxhdGlvbiBTdXJ2ZWlsbGFuY2UvKm1ldGhvZHM8

L2tleXdvcmQ+PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlN0aWxsYmly

dGgvZXBpZGVtaW9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDY8L3ll

YXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXkgMjc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNi

bj4xNDc0LTU0N1ggKEVsZWN0cm9uaWMpJiN4RDswMTQwLTY3MzYgKExpbmtpbmcpPC9pc2JuPjxh

Y2Nlc3Npb24tbnVtPjE2NzMxMjcwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNjczMTI3MDwvdXJsPjwv

cmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMDE0

MC02NzM2KDA2KTY4NzcwLTk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0

ZT48Q2l0ZT48QXV0aG9yPlByaW5jZTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJlY051bT4z

MjEyPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zMjEyPC9yZWMtbnVtYmVyPjxmb3JlaWdu

LWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpw

cnB0NWF2IiB0aW1lc3RhbXA9IjE1MzUzODEzNjQiPjMyMTI8L2tleT48L2ZvcmVpZ24ta2V5cz48

cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9y

cz48YXV0aG9ycz48YXV0aG9yPlByaW5jZSwgTS48L2F1dGhvcj48YXV0aG9yPkJyeWNlLCBSLjwv

YXV0aG9yPjxhdXRob3I+QWxiYW5lc2UsIEUuPC9hdXRob3I+PGF1dGhvcj5XaW1vLCBBLjwvYXV0

aG9yPjxhdXRob3I+UmliZWlybywgVy48L2F1dGhvcj48YXV0aG9yPkZlcnJpLCBDLiBQLjwvYXV0

aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkluc3RpdHV0ZSBvZiBQ

c3ljaGlhdHJ5LCBLaW5nJmFwb3M7cyBDb2xsZWdlIExvbmRvbiwgTG9uZG9uLCBVSy4gTWFydGlu

LlByaW5jZUBrY2wuYWMudWs8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5UaGUgZ2xvYmFs

IHByZXZhbGVuY2Ugb2YgZGVtZW50aWE6IGEgc3lzdGVtYXRpYyByZXZpZXcgYW5kIG1ldGFhbmFs

eXNpczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbHpoZWltZXJzIERlbWVudDwvc2Vjb25kYXJ5

LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz42My03NSBlMjwvcGFnZXM+PHZvbHVtZT45PC92b2x1bWU+

PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdv

cmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+RGVtZW50aWEvKmVwaWRlbWlv

bG9neTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+R2xvYmFsIEhl

YWx0aC8qdHJlbmRzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5M

aWZlIEV4cGVjdGFuY3kvdHJlbmRzPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtl

eXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UHJldmFsZW5jZTwva2V5d29yZD48

L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SmFuPC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU1Mi01Mjc5IChFbGVjdHJvbmljKSYjeEQ7

MTU1Mi01MjYwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzMwNTgyMzwvYWNjZXNz

aW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmlo

Lmdvdi9wdWJtZWQvMjMzMDU4MjM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5qYWx6LjIwMTIuMTEuMDA3PC9lbGVjdHJvbmljLXJl

c291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 5,7. Other reviews have dealt extensively with the economic burden this disease represent for countries PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjI3MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjEsNDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI3MjwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMxNzc1MjcxIj4yNzI8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhv

cj5BbW91eWVsLCBQLjwvYXV0aG9yPjxhdXRob3I+QW5kcmlldSwgUy48L2F1dGhvcj48YXV0aG9y

PkJhbGxhcmQsIEMuPC9hdXRob3I+PGF1dGhvcj5CcmF5bmUsIEMuPC9hdXRob3I+PGF1dGhvcj5C

cm9kYXR5LCBILjwvYXV0aG9yPjxhdXRob3I+Q2VkYXpvLU1pbmd1ZXosIEEuPC9hdXRob3I+PGF1

dGhvcj5EdWJvaXMsIEIuPC9hdXRob3I+PGF1dGhvcj5FZHZhcmRzc29uLCBELjwvYXV0aG9yPjxh

dXRob3I+RmVsZG1hbiwgSC48L2F1dGhvcj48YXV0aG9yPkZyYXRpZ2xpb25pLCBMLjwvYXV0aG9y

PjxhdXRob3I+RnJpc29uaSwgRy4gQi48L2F1dGhvcj48YXV0aG9yPkdhdXRoaWVyLCBTLjwvYXV0

aG9yPjxhdXRob3I+R2VvcmdlcywgSi48L2F1dGhvcj48YXV0aG9yPkdyYWZmLCBDLjwvYXV0aG9y

PjxhdXRob3I+SXFiYWwsIEsuPC9hdXRob3I+PGF1dGhvcj5KZXNzZW4sIEYuPC9hdXRob3I+PGF1

dGhvcj5Kb2hhbnNzb24sIEcuPC9hdXRob3I+PGF1dGhvcj5Kb25zc29uLCBMLjwvYXV0aG9yPjxh

dXRob3I+S2l2aXBlbHRvLCBNLjwvYXV0aG9yPjxhdXRob3I+S25hcHAsIE0uPC9hdXRob3I+PGF1

dGhvcj5NYW5naWFsYXNjaGUsIEYuPC9hdXRob3I+PGF1dGhvcj5NZWxpcywgUi48L2F1dGhvcj48

YXV0aG9yPk5vcmRiZXJnLCBBLjwvYXV0aG9yPjxhdXRob3I+Umlra2VydCwgTS4gTy48L2F1dGhv

cj48YXV0aG9yPlFpdSwgQy48L2F1dGhvcj48YXV0aG9yPlNha21hciwgVC4gUC48L2F1dGhvcj48

YXV0aG9yPlNjaGVsdGVucywgUC48L2F1dGhvcj48YXV0aG9yPlNjaG5laWRlciwgTC4gUy48L2F1

dGhvcj48YXV0aG9yPlNwZXJsaW5nLCBSLjwvYXV0aG9yPjxhdXRob3I+VGplcm5iZXJnLCBMLiBP

LjwvYXV0aG9yPjxhdXRob3I+V2FsZGVtYXIsIEcuPC9hdXRob3I+PGF1dGhvcj5XaW1vLCBBLjwv

YXV0aG9yPjxhdXRob3I+WmV0dGVyYmVyZywgSC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli

dXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2ll

bmNlcyBhbmQgU29jaWV0eSwgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9u

IG9mIE5ldXJvZ2VyaWF0cmljcywgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBIdWRkaW5nZSwgU3dl

ZGVuOyBEZXBhcnRtZW50IG9mIEdlcmlhdHJpYyBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJz

aXR5IEhvc3BpdGFsLCBIdWRkaW5nZSwgU3dlZGVuLiBFbGVjdHJvbmljIGFkZHJlc3M6IGJlbmd0

LXdpbmJsYWQtc3dlZGlzaGJyYWlucG93ZXJAa2kuc2UuJiN4RDtDZW50cmUgSG9zcGl0YWxpZXIg

UmVnaW9uYWwgVW5pdmVyc2l0YWlyZSBkZSBMaWxsZSwgSW5zdGl0dXQgUGFzdGV1ciBkZSBMaWxs

ZSwgSU5TRVJNIFUxMTY3IFJJRC1BR0UsIFVuaXRlIGQmYXBvcztFcGlkZW1pb2xvZ2llIGV0IGRl

IFNhbnRlIFB1YmxpcXVlLCBMYWJleCBESVNUQUxaLCBMaWxsZSwgRnJhbmNlLiYjeEQ7RGVwYXJ0

bWVudCBvZiBFcGlkZW1pb2xvZ3kgYW5kIFB1YmxpYyBIZWFsdGgsIEZhY3VsdHkgb2YgTWVkaWNp

bmUsIFRvdWxvdXNlIFVuaXZlcnNpdHkgSG9zcGl0YWwsIFRvdWxvdXNlLCBGcmFuY2UuJiN4RDtX

b2xmc29uIENlbnRyZSBmb3IgQWdlLVJlbGF0ZWQgRGlzZWFzZXMsIEtpbmcmYXBvcztzIENvbGxl

Z2UgTG9uZG9uLCBMb25kb24sIFVLLiYjeEQ7Q2FtYnJpZGdlIEluc3RpdHV0ZSBvZiBQdWJsaWMg

SGVhbHRoLCBVbml2ZXJzaXR5IG9mIENhbWJyaWRnZSwgQ2FtYnJpZGdlLCBVSy4mI3hEO0NlbnRy

ZSBmb3IgSGVhbHRoeSBCcmFpbiBBZ2VpbmcgYW5kIERlbWVudGlhIENvbGxhYm9yYXRpdmUgUmVz

ZWFyY2ggQ2VudHJlLCBVbml2ZXJzaXR5IG9mIE5ldyBTb3V0aCBXYWxlcywgU3lkbmV5LCBOU1cs

IEF1c3RyYWxpYS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2Vz

IGFuZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2Yg

TmV1cm9nZXJpYXRyaWNzLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIEh1ZGRpbmdlLCBTd2VkZW4u

JiN4RDtJbnN0aXR1dCBkZSBsYSBNZW1vaXJlIGV0IGRlIGxhIE1hbGFkaWUgZCZhcG9zO0Fsemhl

aW1lciwgSU0yQSwgSU5TRVJNLCBJbnN0aXR1dCBkdSBDZXJ2ZWF1IGV0IGRlIGxhIE1vZWxsZSBF

cGluaWVyZSwgVU1SLVM5NzUsIEdyb3VwZSBIb3NwaXRhbGllciBQaXRpZS1TYWxwZXRyaWVyZSwg

VW5pdmVyc2l0ZSBQaWVycmUgZXQgTWFyaWUgQ3VyaWUtUGFyaXMgNiwgUGFyaXMsIEZyYW5jZS4m

I3hEO1NjaG9vbCBvZiBOdXJzaW5nIGFuZCBNaWR3aWZlcnksIExhIFRyb2JlIFVuaXZlcnNpdHks

IE1lbGJvdXJuZSwgVklDLCBBdXN0cmFsaWE7IERlcGFydG1lbnQgb2YgTnVyc2luZywgVW1lYSBV

bml2ZXJzaXR5LCBVbWVhLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBOZXVyb2xvZ3ksIEZhY3Vs

dHkgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQnJpdGlzaCBDb2x1bWJpYSwgVmFuY291dmVy

LCBCQywgQ2FuYWRhLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5j

ZXMgYW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBBZ2luZyBSZXNl

YXJjaCBDZW50ZXIsIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW4uJiN4

RDtHZW5ldmEgVW5pdmVyc2l0eSBIb3NwaXRhbHMgYW5kIFVuaXZlcnNpdHkgb2YgR2VuZXZhLCBH

ZW5ldmEsIFN3aXR6ZXJsYW5kOyBJUkNDUyBDZW50cm8gU2FuIEdpb3Zhbm5pIGRpIERpbyBGYXRl

YmVuZWZyYXRlbGxpLCBCcmVzY2lhLCBJdGFseS4mI3hEO01jR2lsbCBDZW50ZXIgZm9yIFN0dWRp

ZXMgaW4gQWdpbmcsIEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZSBSZXNlYXJjaCBVbml0LCBhbmQg

RG91Z2xhcyBNZW50YWwgSGVhbHRoIFVuaXZlcnNpdHkgSW5zdGl0dXRlLCBNb250cmVhbCwgUUMs

IENhbmFkYS4mI3hEO0FsemhlaW1lciBFdXJvcGUsIEx1eGVtYm91cmcgQ2l0eSwgTHV4ZW1ib3Vy

Zy4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2Np

ZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2YgTmV1cm9nZXJp

YXRyaWNzLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIEh1ZGRpbmdlLCBTd2VkZW47IERlcGFydG1l

bnQgb2YgR2VyaWF0cmljIE1lZGljaW5lLCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWws

IEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvY2hlbWlzdHJ5LCBJbmdl

IEdydW5ka2UtSXFiYWwgUmVzZWFyY2ggRmxvb3IsIE5ldyBZb3JrIFN0YXRlIEluc3RpdHV0ZSBm

b3IgQmFzaWMgUmVzZWFyY2gsIFN0YXRlbiBJc2xhbmQsIE5ZLCBVU0EuJiN4RDtEZXBhcnRtZW50

IG9mIFBzeWNoaWF0cnksIFVuaXZlcnNpdHkgb2YgQ29sb2duZSwgQ29sb2duZSwgR2VybWFueTsg

R2VybWFuIENlbnRlciBmb3IgTmV1cm9kZWdlbmVyYXRpdmUgRGlzZWFzZXMgKERaTkUpLCBCb25u

LCBHZXJtYW55LiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMg

YW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEaXZpc2lvbiBvZiBO

ZXVyb2dlcmlhdHJpY3MsIEthcm9saW5za2EgSW5zdGl0dXRldCwgSHVkZGluZ2UsIFN3ZWRlbjsg

RGVwYXJ0bWVudCBvZiBHZXJpYXRyaWMgTWVkaWNpbmUsIEthcm9saW5za2EgVW5pdmVyc2l0eSBI

b3NwaXRhbCwgSHVkZGluZ2UsIFN3ZWRlbjsgRGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENh

cmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBB

Z2luZyBSZXNlYXJjaCBDZW50ZXIsIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBT

d2VkZW4uJiN4RDtQZXJzb25hbCBTb2NpYWwgU2VydmljZXMgUmVzZWFyY2ggVW5pdCwgTG9uZG9u

IFNjaG9vbCBvZiBFY29ub21pY3MgYW5kIFBvbGl0aWNhbCBTY2llbmNlLCBMb25kb24sIFVLLiYj

eEQ7UmFkYm91ZHVtYyBBbHpoZWltZXIgQ2VudHJlIGFuZCBEZXBhcnRtZW50IG9mIEdlcmlhdHJp

YyBNZWRpY2luZSwgUmFkYm91ZCBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBOaWptZWdlbiwg

TmV0aGVybGFuZHMuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNl

cyBhbmQgU29jaWV0eSwgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9m

IFRyYW5zbGF0aW9uYWwgQWx6aGVpbWVyIEJpb2xvZ3ksIEthcm9saW5za2EgSW5zdGl0dXRldCwg

SHVkZGluZ2UsIFN3ZWRlbjsgRGVwYXJ0bWVudCBvZiBHZXJpYXRyaWMgTWVkaWNpbmUsIEthcm9s

aW5za2EgVW5pdmVyc2l0eSBIb3NwaXRhbCwgSHVkZGluZ2UsIFN3ZWRlbi4mI3hEO0RlcGFydG1l

bnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBDZW50ZXIgZm9y

IEFsemhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2YgTmV1cm9nZXJpYXRyaWNzLCBLYXJvbGlu

c2thIEluc3RpdHV0ZXQsIEh1ZGRpbmdlLCBTd2VkZW47IExhYm9yYXRvcnkgb2YgQ2hlbWljYWwg

QmlvbG9neSAmYW1wOyBTaWduYWwgVHJhbnNkdWN0aW9uLCBUaGUgUm9ja2VmZWxsZXIgVW5pdmVy

c2l0eSwgTmV3IFlvcmssIE5ZLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvbG9neSBhbmQg

QWx6aGVpbWVyIENlbnRlciwgVlUgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRlciwgTmV1cm9zY2ll

bmNlIENhbXB1cywgQW1zdGVyZGFtLCBOZXRoZXJsYW5kcy4mI3hEO0RlcGFydG1lbnQgb2YgUHN5

Y2hpYXRyeSBhbmQgdGhlIEJlaGF2aW9yYWwgU2NpZW5jZXMgYW5kIERlcGFydG1lbnQgb2YgTmV1

cm9sb2d5LCBLZWNrIFNjaG9vbCBvZiBNZWRpY2luZSwgTGVvbmFyZCBEYXZpcyBTY2hvb2wgb2Yg

R2Vyb250b2xvZ3kgb2YgdGhlIFVuaXZlcnNpdHkgb2YgU291dGhlcm4gQ2FsaWZvcm5pYSwgTG9z

IEFuZ2VsZXMsIENBLCBVU0EuJiN4RDtDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCBhbmQg

VHJlYXRtZW50LCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgQnJpZ2hhbSBhbmQgV29tZW4mYXBv

cztzIEhvc3BpdGFsIGFuZCBNYXNzYWNodXNldHRzIEdlbmVyYWwgSG9zcGl0YWwsIEhhcnZhcmQg

TWVkaWNhbCBTY2hvb2wsIEJvc3RvbiwgTUEsIFVTQS4mI3hEO0RhbmlzaCBEZW1lbnRpYSBSZXNl

YXJjaCBDZW50cmUsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBSaWdzaG9zcGl0YWxldCwgVW5p

dmVyc2l0eSBvZiBDb3BlbmhhZ2VuLCBDb3BlbmhhZ2VuLCBEZW5tYXJrLiYjeEQ7Q2xpbmljYWwg

TmV1cm9jaGVtaXN0cnkgTGFib3JhdG9yeSwgRGVwYXJ0bWVudCBvZiBOZXVyb3NjaWVuY2UgYW5k

IFBoeXNpb2xvZ3ksIFRoZSBTYWhsZ3JlbnNrYSBBY2FkZW15IGF0IHRoZSBVbml2ZXJzaXR5IG9m

IEdvdGhlbmJ1cmcsIE1vbG5kYWwsIFN3ZWRlbjsgVUNMIEluc3RpdHV0ZSBvZiBOZXVyb2xvZ3ks

IFF1ZWVuIFNxdWFyZSwgTG9uZG9uLCBVSy48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5E

ZWZlYXRpbmcgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGFuZCBvdGhlciBkZW1lbnRpYXM6IGEg

cHJpb3JpdHkgZm9yIEV1cm9wZWFuIHNjaWVuY2UgYW5kIHNvY2lldHk8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+TGFuY2V0IE5ldXJvbDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz40

NTUtNTMyPC9wYWdlcz48dm9sdW1lPjE1PC92b2x1bWU+PG51bWJlcj41PC9udW1iZXI+PGtleXdv

cmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLyp0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3Jk

PkJpb21lZGljYWwgUmVzZWFyY2gvZWNvbm9taWNzLypvcmdhbml6YXRpb24gJmFtcDsgYWRtaW5p

c3RyYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+RGVtZW50aWEvKnRoZXJhcHk8L2tleXdvcmQ+PGtl

eXdvcmQ+RXVyb3BlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48L2tleXdvcmRz

PjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXByPC9kYXRlPjwvcHVi

LWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ3NC00NDY1IChFbGVjdHJvbmljKSYjeEQ7MTQ3NC00NDIy

IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNjk4NzcwMTwvYWNjZXNzaW9uLW51bT48

dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1l

ZC8yNjk4NzcwMTwvdXJsPjx1cmw+aHR0cHM6Ly9hYy5lbHMtY2RuLmNvbS9TMTQ3NDQ0MjIxNjAw

MDYyNC8xLXMyLjAtUzE0NzQ0NDIyMTYwMDA2MjQtbWFpbi5wZGY/X3RpZD0wNzdmMDgxNS1jYjU2

LTQwYzUtYWRiZi1mOGJmYWE1YmM5YTcmYW1wO2FjZG5hdD0xNTM0NDk1MjYwXzgxZjAyYTNkZmI4

ZGJjYjAxY2NjZWMxMmUyOWY2Y2VlPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJv

bmljLXJlc291cmNlLW51bT4xMC4xMDE2L1MxNDc0LTQ0MjIoMTYpMDAwNjItNDwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+QnJvb2ttZXllcjwv

QXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJlY051bT4zMTI2PC9SZWNOdW0+PHJlY29yZD48cmVj

LW51bWJlcj4zMTI2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1p

ZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzUz

ODA1NjkiPjMxMjY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBB

cnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJyb29r

bWV5ZXIsIFIuPC9hdXRob3I+PGF1dGhvcj5Kb2huc29uLCBFLjwvYXV0aG9yPjxhdXRob3I+Wmll

Z2xlci1HcmFoYW0sIEsuPC9hdXRob3I+PGF1dGhvcj5BcnJpZ2hpLCBILiBNLjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgQmlvc3Rh

dGlzdGljcywgSm9obnMgSG9wa2lucyBCbG9vbWJlcmcgU2Nob29sIG9mIFB1YmxpYyBIZWFsdGgs

IEpvaG5zIEhvcGtpbnMgVW5pdmVyc2l0eSwgQmFsdGltb3JlLCBNRCwgVVNBLiByYnJvb2tAamhz

cGguZWR1PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Rm9yZWNhc3RpbmcgdGhlIGdsb2Jh

bCBidXJkZW4gb2YgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPkFsemhlaW1lcnMgRGVtZW50PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjE4

Ni05MTwvcGFnZXM+PHZvbHVtZT4zPC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGRhdGVzPjx5

ZWFyPjIwMDc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWw8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4xNTUyLTUyNzkgKEVsZWN0cm9uaWMpJiN4RDsxNTUyLTUyNjAgKExpbmtpbmcp

PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjE5NTk1OTM3PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh

dGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xOTU5NTkz

NzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu

MTAxNi9qLmphbHouMjAwNy4wNC4zODE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3Jk

PjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjI3MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjEsNDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI3MjwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMxNzc1MjcxIj4yNzI8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhv

cj5BbW91eWVsLCBQLjwvYXV0aG9yPjxhdXRob3I+QW5kcmlldSwgUy48L2F1dGhvcj48YXV0aG9y

PkJhbGxhcmQsIEMuPC9hdXRob3I+PGF1dGhvcj5CcmF5bmUsIEMuPC9hdXRob3I+PGF1dGhvcj5C

cm9kYXR5LCBILjwvYXV0aG9yPjxhdXRob3I+Q2VkYXpvLU1pbmd1ZXosIEEuPC9hdXRob3I+PGF1

dGhvcj5EdWJvaXMsIEIuPC9hdXRob3I+PGF1dGhvcj5FZHZhcmRzc29uLCBELjwvYXV0aG9yPjxh

dXRob3I+RmVsZG1hbiwgSC48L2F1dGhvcj48YXV0aG9yPkZyYXRpZ2xpb25pLCBMLjwvYXV0aG9y

PjxhdXRob3I+RnJpc29uaSwgRy4gQi48L2F1dGhvcj48YXV0aG9yPkdhdXRoaWVyLCBTLjwvYXV0

aG9yPjxhdXRob3I+R2VvcmdlcywgSi48L2F1dGhvcj48YXV0aG9yPkdyYWZmLCBDLjwvYXV0aG9y

PjxhdXRob3I+SXFiYWwsIEsuPC9hdXRob3I+PGF1dGhvcj5KZXNzZW4sIEYuPC9hdXRob3I+PGF1

dGhvcj5Kb2hhbnNzb24sIEcuPC9hdXRob3I+PGF1dGhvcj5Kb25zc29uLCBMLjwvYXV0aG9yPjxh

dXRob3I+S2l2aXBlbHRvLCBNLjwvYXV0aG9yPjxhdXRob3I+S25hcHAsIE0uPC9hdXRob3I+PGF1

dGhvcj5NYW5naWFsYXNjaGUsIEYuPC9hdXRob3I+PGF1dGhvcj5NZWxpcywgUi48L2F1dGhvcj48

YXV0aG9yPk5vcmRiZXJnLCBBLjwvYXV0aG9yPjxhdXRob3I+Umlra2VydCwgTS4gTy48L2F1dGhv

cj48YXV0aG9yPlFpdSwgQy48L2F1dGhvcj48YXV0aG9yPlNha21hciwgVC4gUC48L2F1dGhvcj48

YXV0aG9yPlNjaGVsdGVucywgUC48L2F1dGhvcj48YXV0aG9yPlNjaG5laWRlciwgTC4gUy48L2F1

dGhvcj48YXV0aG9yPlNwZXJsaW5nLCBSLjwvYXV0aG9yPjxhdXRob3I+VGplcm5iZXJnLCBMLiBP

LjwvYXV0aG9yPjxhdXRob3I+V2FsZGVtYXIsIEcuPC9hdXRob3I+PGF1dGhvcj5XaW1vLCBBLjwv

YXV0aG9yPjxhdXRob3I+WmV0dGVyYmVyZywgSC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli

dXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2ll

bmNlcyBhbmQgU29jaWV0eSwgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9u

IG9mIE5ldXJvZ2VyaWF0cmljcywgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBIdWRkaW5nZSwgU3dl

ZGVuOyBEZXBhcnRtZW50IG9mIEdlcmlhdHJpYyBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJz

aXR5IEhvc3BpdGFsLCBIdWRkaW5nZSwgU3dlZGVuLiBFbGVjdHJvbmljIGFkZHJlc3M6IGJlbmd0

LXdpbmJsYWQtc3dlZGlzaGJyYWlucG93ZXJAa2kuc2UuJiN4RDtDZW50cmUgSG9zcGl0YWxpZXIg

UmVnaW9uYWwgVW5pdmVyc2l0YWlyZSBkZSBMaWxsZSwgSW5zdGl0dXQgUGFzdGV1ciBkZSBMaWxs

ZSwgSU5TRVJNIFUxMTY3IFJJRC1BR0UsIFVuaXRlIGQmYXBvcztFcGlkZW1pb2xvZ2llIGV0IGRl

IFNhbnRlIFB1YmxpcXVlLCBMYWJleCBESVNUQUxaLCBMaWxsZSwgRnJhbmNlLiYjeEQ7RGVwYXJ0

bWVudCBvZiBFcGlkZW1pb2xvZ3kgYW5kIFB1YmxpYyBIZWFsdGgsIEZhY3VsdHkgb2YgTWVkaWNp

bmUsIFRvdWxvdXNlIFVuaXZlcnNpdHkgSG9zcGl0YWwsIFRvdWxvdXNlLCBGcmFuY2UuJiN4RDtX

b2xmc29uIENlbnRyZSBmb3IgQWdlLVJlbGF0ZWQgRGlzZWFzZXMsIEtpbmcmYXBvcztzIENvbGxl

Z2UgTG9uZG9uLCBMb25kb24sIFVLLiYjeEQ7Q2FtYnJpZGdlIEluc3RpdHV0ZSBvZiBQdWJsaWMg

SGVhbHRoLCBVbml2ZXJzaXR5IG9mIENhbWJyaWRnZSwgQ2FtYnJpZGdlLCBVSy4mI3hEO0NlbnRy

ZSBmb3IgSGVhbHRoeSBCcmFpbiBBZ2VpbmcgYW5kIERlbWVudGlhIENvbGxhYm9yYXRpdmUgUmVz

ZWFyY2ggQ2VudHJlLCBVbml2ZXJzaXR5IG9mIE5ldyBTb3V0aCBXYWxlcywgU3lkbmV5LCBOU1cs

IEF1c3RyYWxpYS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2Vz

IGFuZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2Yg

TmV1cm9nZXJpYXRyaWNzLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIEh1ZGRpbmdlLCBTd2VkZW4u

JiN4RDtJbnN0aXR1dCBkZSBsYSBNZW1vaXJlIGV0IGRlIGxhIE1hbGFkaWUgZCZhcG9zO0Fsemhl

aW1lciwgSU0yQSwgSU5TRVJNLCBJbnN0aXR1dCBkdSBDZXJ2ZWF1IGV0IGRlIGxhIE1vZWxsZSBF

cGluaWVyZSwgVU1SLVM5NzUsIEdyb3VwZSBIb3NwaXRhbGllciBQaXRpZS1TYWxwZXRyaWVyZSwg

VW5pdmVyc2l0ZSBQaWVycmUgZXQgTWFyaWUgQ3VyaWUtUGFyaXMgNiwgUGFyaXMsIEZyYW5jZS4m

I3hEO1NjaG9vbCBvZiBOdXJzaW5nIGFuZCBNaWR3aWZlcnksIExhIFRyb2JlIFVuaXZlcnNpdHks

IE1lbGJvdXJuZSwgVklDLCBBdXN0cmFsaWE7IERlcGFydG1lbnQgb2YgTnVyc2luZywgVW1lYSBV

bml2ZXJzaXR5LCBVbWVhLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBOZXVyb2xvZ3ksIEZhY3Vs

dHkgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQnJpdGlzaCBDb2x1bWJpYSwgVmFuY291dmVy

LCBCQywgQ2FuYWRhLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5j

ZXMgYW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBBZ2luZyBSZXNl

YXJjaCBDZW50ZXIsIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW4uJiN4

RDtHZW5ldmEgVW5pdmVyc2l0eSBIb3NwaXRhbHMgYW5kIFVuaXZlcnNpdHkgb2YgR2VuZXZhLCBH

ZW5ldmEsIFN3aXR6ZXJsYW5kOyBJUkNDUyBDZW50cm8gU2FuIEdpb3Zhbm5pIGRpIERpbyBGYXRl

YmVuZWZyYXRlbGxpLCBCcmVzY2lhLCBJdGFseS4mI3hEO01jR2lsbCBDZW50ZXIgZm9yIFN0dWRp

ZXMgaW4gQWdpbmcsIEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZSBSZXNlYXJjaCBVbml0LCBhbmQg

RG91Z2xhcyBNZW50YWwgSGVhbHRoIFVuaXZlcnNpdHkgSW5zdGl0dXRlLCBNb250cmVhbCwgUUMs

IENhbmFkYS4mI3hEO0FsemhlaW1lciBFdXJvcGUsIEx1eGVtYm91cmcgQ2l0eSwgTHV4ZW1ib3Vy

Zy4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2Np

ZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2YgTmV1cm9nZXJp

YXRyaWNzLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIEh1ZGRpbmdlLCBTd2VkZW47IERlcGFydG1l

bnQgb2YgR2VyaWF0cmljIE1lZGljaW5lLCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWws

IEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvY2hlbWlzdHJ5LCBJbmdl

IEdydW5ka2UtSXFiYWwgUmVzZWFyY2ggRmxvb3IsIE5ldyBZb3JrIFN0YXRlIEluc3RpdHV0ZSBm

b3IgQmFzaWMgUmVzZWFyY2gsIFN0YXRlbiBJc2xhbmQsIE5ZLCBVU0EuJiN4RDtEZXBhcnRtZW50

IG9mIFBzeWNoaWF0cnksIFVuaXZlcnNpdHkgb2YgQ29sb2duZSwgQ29sb2duZSwgR2VybWFueTsg

R2VybWFuIENlbnRlciBmb3IgTmV1cm9kZWdlbmVyYXRpdmUgRGlzZWFzZXMgKERaTkUpLCBCb25u

LCBHZXJtYW55LiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMg

YW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEaXZpc2lvbiBvZiBO

ZXVyb2dlcmlhdHJpY3MsIEthcm9saW5za2EgSW5zdGl0dXRldCwgSHVkZGluZ2UsIFN3ZWRlbjsg

RGVwYXJ0bWVudCBvZiBHZXJpYXRyaWMgTWVkaWNpbmUsIEthcm9saW5za2EgVW5pdmVyc2l0eSBI

b3NwaXRhbCwgSHVkZGluZ2UsIFN3ZWRlbjsgRGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENh

cmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBB

Z2luZyBSZXNlYXJjaCBDZW50ZXIsIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBT

d2VkZW4uJiN4RDtQZXJzb25hbCBTb2NpYWwgU2VydmljZXMgUmVzZWFyY2ggVW5pdCwgTG9uZG9u

IFNjaG9vbCBvZiBFY29ub21pY3MgYW5kIFBvbGl0aWNhbCBTY2llbmNlLCBMb25kb24sIFVLLiYj

eEQ7UmFkYm91ZHVtYyBBbHpoZWltZXIgQ2VudHJlIGFuZCBEZXBhcnRtZW50IG9mIEdlcmlhdHJp

YyBNZWRpY2luZSwgUmFkYm91ZCBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBOaWptZWdlbiwg

TmV0aGVybGFuZHMuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNl

cyBhbmQgU29jaWV0eSwgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9m

IFRyYW5zbGF0aW9uYWwgQWx6aGVpbWVyIEJpb2xvZ3ksIEthcm9saW5za2EgSW5zdGl0dXRldCwg

SHVkZGluZ2UsIFN3ZWRlbjsgRGVwYXJ0bWVudCBvZiBHZXJpYXRyaWMgTWVkaWNpbmUsIEthcm9s

aW5za2EgVW5pdmVyc2l0eSBIb3NwaXRhbCwgSHVkZGluZ2UsIFN3ZWRlbi4mI3hEO0RlcGFydG1l

bnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBDZW50ZXIgZm9y

IEFsemhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2YgTmV1cm9nZXJpYXRyaWNzLCBLYXJvbGlu

c2thIEluc3RpdHV0ZXQsIEh1ZGRpbmdlLCBTd2VkZW47IExhYm9yYXRvcnkgb2YgQ2hlbWljYWwg

QmlvbG9neSAmYW1wOyBTaWduYWwgVHJhbnNkdWN0aW9uLCBUaGUgUm9ja2VmZWxsZXIgVW5pdmVy

c2l0eSwgTmV3IFlvcmssIE5ZLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvbG9neSBhbmQg

QWx6aGVpbWVyIENlbnRlciwgVlUgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRlciwgTmV1cm9zY2ll

bmNlIENhbXB1cywgQW1zdGVyZGFtLCBOZXRoZXJsYW5kcy4mI3hEO0RlcGFydG1lbnQgb2YgUHN5

Y2hpYXRyeSBhbmQgdGhlIEJlaGF2aW9yYWwgU2NpZW5jZXMgYW5kIERlcGFydG1lbnQgb2YgTmV1

cm9sb2d5LCBLZWNrIFNjaG9vbCBvZiBNZWRpY2luZSwgTGVvbmFyZCBEYXZpcyBTY2hvb2wgb2Yg

R2Vyb250b2xvZ3kgb2YgdGhlIFVuaXZlcnNpdHkgb2YgU291dGhlcm4gQ2FsaWZvcm5pYSwgTG9z

IEFuZ2VsZXMsIENBLCBVU0EuJiN4RDtDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCBhbmQg

VHJlYXRtZW50LCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgQnJpZ2hhbSBhbmQgV29tZW4mYXBv

cztzIEhvc3BpdGFsIGFuZCBNYXNzYWNodXNldHRzIEdlbmVyYWwgSG9zcGl0YWwsIEhhcnZhcmQg

TWVkaWNhbCBTY2hvb2wsIEJvc3RvbiwgTUEsIFVTQS4mI3hEO0RhbmlzaCBEZW1lbnRpYSBSZXNl

YXJjaCBDZW50cmUsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBSaWdzaG9zcGl0YWxldCwgVW5p

dmVyc2l0eSBvZiBDb3BlbmhhZ2VuLCBDb3BlbmhhZ2VuLCBEZW5tYXJrLiYjeEQ7Q2xpbmljYWwg

TmV1cm9jaGVtaXN0cnkgTGFib3JhdG9yeSwgRGVwYXJ0bWVudCBvZiBOZXVyb3NjaWVuY2UgYW5k

IFBoeXNpb2xvZ3ksIFRoZSBTYWhsZ3JlbnNrYSBBY2FkZW15IGF0IHRoZSBVbml2ZXJzaXR5IG9m

IEdvdGhlbmJ1cmcsIE1vbG5kYWwsIFN3ZWRlbjsgVUNMIEluc3RpdHV0ZSBvZiBOZXVyb2xvZ3ks

IFF1ZWVuIFNxdWFyZSwgTG9uZG9uLCBVSy48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5E

ZWZlYXRpbmcgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGFuZCBvdGhlciBkZW1lbnRpYXM6IGEg

cHJpb3JpdHkgZm9yIEV1cm9wZWFuIHNjaWVuY2UgYW5kIHNvY2lldHk8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+TGFuY2V0IE5ldXJvbDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz40

NTUtNTMyPC9wYWdlcz48dm9sdW1lPjE1PC92b2x1bWU+PG51bWJlcj41PC9udW1iZXI+PGtleXdv

cmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLyp0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3Jk

PkJpb21lZGljYWwgUmVzZWFyY2gvZWNvbm9taWNzLypvcmdhbml6YXRpb24gJmFtcDsgYWRtaW5p

c3RyYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+RGVtZW50aWEvKnRoZXJhcHk8L2tleXdvcmQ+PGtl

eXdvcmQ+RXVyb3BlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48L2tleXdvcmRz

PjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXByPC9kYXRlPjwvcHVi

LWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ3NC00NDY1IChFbGVjdHJvbmljKSYjeEQ7MTQ3NC00NDIy

IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNjk4NzcwMTwvYWNjZXNzaW9uLW51bT48

dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1l

ZC8yNjk4NzcwMTwvdXJsPjx1cmw+aHR0cHM6Ly9hYy5lbHMtY2RuLmNvbS9TMTQ3NDQ0MjIxNjAw

MDYyNC8xLXMyLjAtUzE0NzQ0NDIyMTYwMDA2MjQtbWFpbi5wZGY/X3RpZD0wNzdmMDgxNS1jYjU2

LTQwYzUtYWRiZi1mOGJmYWE1YmM5YTcmYW1wO2FjZG5hdD0xNTM0NDk1MjYwXzgxZjAyYTNkZmI4

ZGJjYjAxY2NjZWMxMmUyOWY2Y2VlPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJv

bmljLXJlc291cmNlLW51bT4xMC4xMDE2L1MxNDc0LTQ0MjIoMTYpMDAwNjItNDwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+QnJvb2ttZXllcjwv

QXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJlY051bT4zMTI2PC9SZWNOdW0+PHJlY29yZD48cmVj

LW51bWJlcj4zMTI2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1p

ZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzUz

ODA1NjkiPjMxMjY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBB

cnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJyb29r

bWV5ZXIsIFIuPC9hdXRob3I+PGF1dGhvcj5Kb2huc29uLCBFLjwvYXV0aG9yPjxhdXRob3I+Wmll

Z2xlci1HcmFoYW0sIEsuPC9hdXRob3I+PGF1dGhvcj5BcnJpZ2hpLCBILiBNLjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgQmlvc3Rh

dGlzdGljcywgSm9obnMgSG9wa2lucyBCbG9vbWJlcmcgU2Nob29sIG9mIFB1YmxpYyBIZWFsdGgs

IEpvaG5zIEhvcGtpbnMgVW5pdmVyc2l0eSwgQmFsdGltb3JlLCBNRCwgVVNBLiByYnJvb2tAamhz

cGguZWR1PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Rm9yZWNhc3RpbmcgdGhlIGdsb2Jh

bCBidXJkZW4gb2YgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPkFsemhlaW1lcnMgRGVtZW50PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjE4

Ni05MTwvcGFnZXM+PHZvbHVtZT4zPC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGRhdGVzPjx5

ZWFyPjIwMDc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWw8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4xNTUyLTUyNzkgKEVsZWN0cm9uaWMpJiN4RDsxNTUyLTUyNjAgKExpbmtpbmcp

PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjE5NTk1OTM3PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh

dGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xOTU5NTkz

NzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu

MTAxNi9qLmphbHouMjAwNy4wNC4zODE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3Jk

PjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 1,4, estimating it at 0.65% of the world gross domestic product, a cipher rarely seen for a single disease PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW1vPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48UmVj

TnVtPjMyMTU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij44

PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzIxNTwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhw

Znd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1MzgyMTI0Ij4zMjE1PC9rZXk+PC9mb3Jl

aWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxj

b250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XaW1vLCBBLjwvYXV0aG9yPjxhdXRob3I+R3Vl

cmNoZXQsIE0uPC9hdXRob3I+PGF1dGhvcj5BbGksIEcuIEMuPC9hdXRob3I+PGF1dGhvcj5XdSwg

WS4gVC48L2F1dGhvcj48YXV0aG9yPlByaW5hLCBBLiBNLjwvYXV0aG9yPjxhdXRob3I+V2luYmxh

ZCwgQi48L2F1dGhvcj48YXV0aG9yPkpvbnNzb24sIEwuPC9hdXRob3I+PGF1dGhvcj5MaXUsIFou

PC9hdXRob3I+PGF1dGhvcj5QcmluY2UsIE0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjxhdXRoLWFkZHJlc3M+QWdpbmcgUmVzZWFyY2ggQ2VudGVyLCBEZXBhcnRtZW50IG9mIE5l

dXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSAoTlZTKSwgS2Fyb2xpbnNrYSBJ

bnN0aXR1dGV0IGFuZCBTdG9ja2hvbG0gVW5pdmVyc2l0eSwgU3RvY2tob2xtLCBTd2VkZW47IERp

dmlzaW9uIG9mIE5ldXJvZ2VyaWF0cmljcywgRGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENh

cmUgU2NpZW5jZXMgYW5kIFNvY2lldHkgKE5WUyksIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3Rv

Y2tob2xtLCBTd2VkZW47IENlbnRyZSBmb3IgUmVzZWFyY2ggYW5kIERldmVsb3BtZW50LCBVcHBz

YWxhIFVuaXZlcnNpdHkvQ291bnR5IENvdW5jaWwgb2YgR2F2bGVib3JnLCBHYXZsZSwgU3dlZGVu

LiBFbGVjdHJvbmljIGFkZHJlc3M6IEFuZGVycy5XaW1vQGtpLnNlLiYjeEQ7S2luZyZhcG9zO3Mg

Q29sbGVnZSBMb25kb24sIFRoZSBHbG9iYWwgT2JzZXJ2YXRvcnkgZm9yIEFnZWluZyBhbmQgRGVt

ZW50aWEgQ2FyZSwgSW5zdGl0dXRlIG9mIFBzeWNoaWF0cnksIFBzeWNob2xvZ3kgYW5kIE5ldXJv

c2NpZW5jZSwgSGVhbHRoIFNlcnZpY2UgYW5kIFBvcHVsYXRpb24gUmVzZWFyY2ggRGVwYXJ0bWVu

dCwgTG9uZG9uLCBVSy4mI3hEO1JFQUNIOiBUaGUgQ2VudHJlIGZvciBSZXNlYXJjaCBpbiBBZ2Vp

bmcgYW5kIENvZ25pdGl2ZSBIZWFsdGgsIENvbGxlZ2Ugb2YgTGlmZSBhbmQgRW52aXJvbm1lbnQg

U2NpZW5jZXMsIERlcGFydG1lbnQgb2YgUHN5Y2hvbG9neSwgVW5pdmVyc2l0eSBvZiBFeGV0ZXIs

IEV4ZXRlciwgVUsuJiN4RDtEaXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIERlcGFydG1lbnQg

b2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5IChOVlMpLCBLYXJvbGlu

c2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7SW5zdGl0dXRlIG9mIE1lbnRh

bCBIZWFsdGgsIFBla2luZyBVbml2ZXJzaXR5LCBCZWlqaW5nLCBDaGluYS48L2F1dGgtYWRkcmVz

cz48dGl0bGVzPjx0aXRsZT5UaGUgd29ybGR3aWRlIGNvc3RzIG9mIGRlbWVudGlhIDIwMTUgYW5k

IGNvbXBhcmlzb25zIHdpdGggMjAxMDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbHpoZWltZXJz

IERlbWVudDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xLTc8L3BhZ2VzPjx2b2x1

bWU+MTM8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+KkNvc3Qg

b2YgSWxsbmVzczwva2V5d29yZD48a2V5d29yZD5Dcm9zcy1TZWN0aW9uYWwgU3R1ZGllczwva2V5

d29yZD48a2V5d29yZD5EZW1lbnRpYS9kaWFnbm9zaXMvKmVjb25vbWljcy8qZXBpZGVtaW9sb2d5

L3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkdsb2Jh

bCBIZWFsdGgvKmVjb25vbWljczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtl

eXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5SZXRyb3NwZWN0aXZlIFN0dWRpZXM8L2tleXdv

cmQ+PGtleXdvcmQ+U2Vuc2l0aXZpdHkgYW5kIFNwZWNpZmljaXR5PC9rZXl3b3JkPjxrZXl3b3Jk

PipBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+KkNvc3Q8L2tleXdv

cmQ+PGtleXdvcmQ+KkNvc3RzIG9mIGlsbG5lc3M8L2tleXdvcmQ+PGtleXdvcmQ+KkRlbWVudGlh

PC9rZXl3b3JkPjxrZXl3b3JkPipFY29ub21pY3M8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjE1NTItNTI3OSAoRWxlY3Ryb25pYykmI3hEOzE1NTItNTI2MCAoTGlua2lu

Zyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjc1ODM2NTI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJl

bGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI3NTgz

NjUyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzUyMzI0MTc8L2N1c3Rv

bTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5qYWx6LjIwMTYuMDcuMTUwPC9l

bGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW1vPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48UmVj

TnVtPjMyMTU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij44

PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzIxNTwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhw

Znd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1MzgyMTI0Ij4zMjE1PC9rZXk+PC9mb3Jl

aWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxj

b250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XaW1vLCBBLjwvYXV0aG9yPjxhdXRob3I+R3Vl

cmNoZXQsIE0uPC9hdXRob3I+PGF1dGhvcj5BbGksIEcuIEMuPC9hdXRob3I+PGF1dGhvcj5XdSwg

WS4gVC48L2F1dGhvcj48YXV0aG9yPlByaW5hLCBBLiBNLjwvYXV0aG9yPjxhdXRob3I+V2luYmxh

ZCwgQi48L2F1dGhvcj48YXV0aG9yPkpvbnNzb24sIEwuPC9hdXRob3I+PGF1dGhvcj5MaXUsIFou

PC9hdXRob3I+PGF1dGhvcj5QcmluY2UsIE0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjxhdXRoLWFkZHJlc3M+QWdpbmcgUmVzZWFyY2ggQ2VudGVyLCBEZXBhcnRtZW50IG9mIE5l

dXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSAoTlZTKSwgS2Fyb2xpbnNrYSBJ

bnN0aXR1dGV0IGFuZCBTdG9ja2hvbG0gVW5pdmVyc2l0eSwgU3RvY2tob2xtLCBTd2VkZW47IERp

dmlzaW9uIG9mIE5ldXJvZ2VyaWF0cmljcywgRGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENh

cmUgU2NpZW5jZXMgYW5kIFNvY2lldHkgKE5WUyksIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3Rv

Y2tob2xtLCBTd2VkZW47IENlbnRyZSBmb3IgUmVzZWFyY2ggYW5kIERldmVsb3BtZW50LCBVcHBz

YWxhIFVuaXZlcnNpdHkvQ291bnR5IENvdW5jaWwgb2YgR2F2bGVib3JnLCBHYXZsZSwgU3dlZGVu

LiBFbGVjdHJvbmljIGFkZHJlc3M6IEFuZGVycy5XaW1vQGtpLnNlLiYjeEQ7S2luZyZhcG9zO3Mg

Q29sbGVnZSBMb25kb24sIFRoZSBHbG9iYWwgT2JzZXJ2YXRvcnkgZm9yIEFnZWluZyBhbmQgRGVt

ZW50aWEgQ2FyZSwgSW5zdGl0dXRlIG9mIFBzeWNoaWF0cnksIFBzeWNob2xvZ3kgYW5kIE5ldXJv

c2NpZW5jZSwgSGVhbHRoIFNlcnZpY2UgYW5kIFBvcHVsYXRpb24gUmVzZWFyY2ggRGVwYXJ0bWVu

dCwgTG9uZG9uLCBVSy4mI3hEO1JFQUNIOiBUaGUgQ2VudHJlIGZvciBSZXNlYXJjaCBpbiBBZ2Vp

bmcgYW5kIENvZ25pdGl2ZSBIZWFsdGgsIENvbGxlZ2Ugb2YgTGlmZSBhbmQgRW52aXJvbm1lbnQg

U2NpZW5jZXMsIERlcGFydG1lbnQgb2YgUHN5Y2hvbG9neSwgVW5pdmVyc2l0eSBvZiBFeGV0ZXIs

IEV4ZXRlciwgVUsuJiN4RDtEaXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIERlcGFydG1lbnQg

b2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5IChOVlMpLCBLYXJvbGlu

c2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7SW5zdGl0dXRlIG9mIE1lbnRh

bCBIZWFsdGgsIFBla2luZyBVbml2ZXJzaXR5LCBCZWlqaW5nLCBDaGluYS48L2F1dGgtYWRkcmVz

cz48dGl0bGVzPjx0aXRsZT5UaGUgd29ybGR3aWRlIGNvc3RzIG9mIGRlbWVudGlhIDIwMTUgYW5k

IGNvbXBhcmlzb25zIHdpdGggMjAxMDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbHpoZWltZXJz

IERlbWVudDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xLTc8L3BhZ2VzPjx2b2x1

bWU+MTM8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+KkNvc3Qg

b2YgSWxsbmVzczwva2V5d29yZD48a2V5d29yZD5Dcm9zcy1TZWN0aW9uYWwgU3R1ZGllczwva2V5

d29yZD48a2V5d29yZD5EZW1lbnRpYS9kaWFnbm9zaXMvKmVjb25vbWljcy8qZXBpZGVtaW9sb2d5

L3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkdsb2Jh

bCBIZWFsdGgvKmVjb25vbWljczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtl

eXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5SZXRyb3NwZWN0aXZlIFN0dWRpZXM8L2tleXdv

cmQ+PGtleXdvcmQ+U2Vuc2l0aXZpdHkgYW5kIFNwZWNpZmljaXR5PC9rZXl3b3JkPjxrZXl3b3Jk

PipBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+KkNvc3Q8L2tleXdv

cmQ+PGtleXdvcmQ+KkNvc3RzIG9mIGlsbG5lc3M8L2tleXdvcmQ+PGtleXdvcmQ+KkRlbWVudGlh

PC9rZXl3b3JkPjxrZXl3b3JkPipFY29ub21pY3M8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjE1NTItNTI3OSAoRWxlY3Ryb25pYykmI3hEOzE1NTItNTI2MCAoTGlua2lu

Zyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjc1ODM2NTI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJl

bGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI3NTgz

NjUyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzUyMzI0MTc8L2N1c3Rv

bTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5qYWx6LjIwMTYuMDcuMTUwPC9l

bGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 8. Moreover, it is likely that the economic burden for AD is largely underestimated, since it is difficult to account for the expenditure from family members paying for nursing or stopping working to take care of their relatives PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QcmluY2U8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

ZWNOdW0+MzIxMTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjcsOSwxMDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjMyMTE8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTM4MTM2NCI+MzIxMTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+UHJpbmNlLCBNLjwvYXV0aG9yPjxh

dXRob3I+QWxpLCBHLiBDLjwvYXV0aG9yPjxhdXRob3I+R3VlcmNoZXQsIE0uPC9hdXRob3I+PGF1

dGhvcj5QcmluYSwgQS4gTS48L2F1dGhvcj48YXV0aG9yPkFsYmFuZXNlLCBFLjwvYXV0aG9yPjxh

dXRob3I+V3UsIFkuIFQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk

ZHJlc3M+VGhlIEdsb2JhbCBPYnNlcnZhdG9yeSBmb3IgQWdlaW5nIGFuZCBEZW1lbnRpYSBDYXJl

LCBIZWFsdGggU2VydmljZSAmYW1wOyBQb3B1bGF0aW9uIFJlc2VhcmNoIERlcGFydG1lbnQsIElu

c3RpdHV0ZSBvZiBQc3ljaGlhdHJ5LCBQc3ljaG9sb2d5IGFuZCBOZXVyb3NjaWVuY2UsIEtpbmcm

YXBvcztzIENvbGxlZ2UgTG9uZG9uLCBQTyAzNiwgRGF2aWQgR29sZGJlcmcgQ2VudHJlLCBEZSBD

cmVzcGlnbnkgUGFyaywgTG9uZG9uLCBTRTUgOEFGLCBVSy4gbWFydGluLnByaW5jZUBrY2wuYWMu

dWsuJiN4RDtUaGUgR2xvYmFsIE9ic2VydmF0b3J5IGZvciBBZ2VpbmcgYW5kIERlbWVudGlhIENh

cmUsIEhlYWx0aCBTZXJ2aWNlICZhbXA7IFBvcHVsYXRpb24gUmVzZWFyY2ggRGVwYXJ0bWVudCwg

SW5zdGl0dXRlIG9mIFBzeWNoaWF0cnksIFBzeWNob2xvZ3kgYW5kIE5ldXJvc2NpZW5jZSwgS2lu

ZyZhcG9zO3MgQ29sbGVnZSBMb25kb24sIFBPIDM2LCBEYXZpZCBHb2xkYmVyZyBDZW50cmUsIERl

IENyZXNwaWdueSBQYXJrLCBMb25kb24sIFNFNSA4QUYsIFVLLiYjeEQ7RGVwYXJ0bWVudCBvZiBQ

dWJsaWMgSGVhbHRoIGFuZCBQcmltYXJ5IENhcmUsIFNjaG9vbCBvZiBDbGluaWNhbCBNZWRpY2lu

ZSwgVW5pdmVyc2l0eSBvZiBDYW1icmlkZ2UsIENhbWJyaWRnZSwgVUsuJiN4RDtEZXBhcnRtZW50

IG9mIFBzeWNoaWF0cnksIFVuaXZlcnNpdHkgb2YgR2VuZXZhLCBHZW5ldmEsIFN3aXR6ZXJsYW5k

LiYjeEQ7Q2FtYnJpZGdlIEluc3RpdHV0ZSBvZiBQdWJsaWMgSGVhbHRoLCBVbml2ZXJzaXR5IG9m

IENhbWJyaWRnZSwgQ2FtYnJpZGdlLCBVSy48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5S

ZWNlbnQgZ2xvYmFsIHRyZW5kcyBpbiB0aGUgcHJldmFsZW5jZSBhbmQgaW5jaWRlbmNlIG9mIGRl

bWVudGlhLCBhbmQgc3Vydml2YWwgd2l0aCBkZW1lbnRpYTwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5BbHpoZWltZXJzIFJlcyBUaGVyPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+QWx6aGVpbWVycyBSZXMgVGhlcjwvZnVsbC10aXRsZT48L3BlcmlvZGlj

YWw+PHBhZ2VzPjIzPC9wYWdlcz48dm9sdW1lPjg8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48

a2V5d29yZHM+PGtleXdvcmQ+RGVtZW50aWEvKmVwaWRlbWlvbG9neS8qbW9ydGFsaXR5PC9rZXl3

b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5HbG9iYWwgSGVhbHRoL3N0YXRp

c3RpY3MgJmFtcDsgbnVtZXJpY2FsIGRhdGEvKnRyZW5kczwva2V5d29yZD48a2V5d29yZD5IdW1h

bnM8L2tleXdvcmQ+PGtleXdvcmQ+SW5jaWRlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPkxvbmdpdHVk

aW5hbCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWV0

YS1BbmFseXNpcyBhcyBUb3BpYzwva2V5d29yZD48a2V5d29yZD5QcmV2YWxlbmNlPC9rZXl3b3Jk

PjxrZXl3b3JkPlJldHJvc3BlY3RpdmUgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD4qRGVtZW50

aWE8L2tleXdvcmQ+PGtleXdvcmQ+KkVwaWRlbWlvbG9neTwva2V5d29yZD48a2V5d29yZD4qR2xv

YmFsIGhlYWx0aDwva2V5d29yZD48a2V5d29yZD4qTWV0YS1hbmFseXNpczwva2V5d29yZD48a2V5

d29yZD4qUHJvamVjdGlvbjwva2V5d29yZD48a2V5d29yZD4qU3lzdGVtYXRpYyByZXZpZXc8L2tl

eXdvcmQ+PGtleXdvcmQ+KlRyZW5kczwva2V5d29yZD48a2V5d29yZD4qV29ybGR3aWRlPC9rZXl3

b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5K

dWwgMzA8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNzU4LTkxOTMgKEVsZWN0cm9u

aWMpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3NDczNjgxPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxy

ZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNzQ3

MzY4MTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0OTY3Mjk5PC9jdXN0

b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTg2L3MxMzE5NS0wMTYtMDE4OC04PC9l

bGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5Qcmlu

Y2U8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNOdW0+MzIxMjwvUmVjTnVtPjxyZWNvcmQ+

PHJlYy1udW1iZXI+MzIxMjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIg

ZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIx

NTM1MzgxMzY0Ij4zMjEyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Q

cmluY2UsIE0uPC9hdXRob3I+PGF1dGhvcj5CcnljZSwgUi48L2F1dGhvcj48YXV0aG9yPkFsYmFu

ZXNlLCBFLjwvYXV0aG9yPjxhdXRob3I+V2ltbywgQS48L2F1dGhvcj48YXV0aG9yPlJpYmVpcm8s

IFcuPC9hdXRob3I+PGF1dGhvcj5GZXJyaSwgQy4gUC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5JbnN0aXR1dGUgb2YgUHN5Y2hpYXRyeSwgS2luZyZhcG9z

O3MgQ29sbGVnZSBMb25kb24sIExvbmRvbiwgVUsuIE1hcnRpbi5QcmluY2VAa2NsLmFjLnVrPC9h

dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGhlIGdsb2JhbCBwcmV2YWxlbmNlIG9mIGRlbWVu

dGlhOiBhIHN5c3RlbWF0aWMgcmV2aWV3IGFuZCBtZXRhYW5hbHlzaXM8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+QWx6aGVpbWVycyBEZW1lbnQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFn

ZXM+NjMtNzUgZTI8L3BhZ2VzPjx2b2x1bWU+OTwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxr

ZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVy

PC9rZXl3b3JkPjxrZXl3b3JkPkRlbWVudGlhLyplcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkdsb2JhbCBIZWFsdGgvKnRyZW5kczwva2V5d29y

ZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TGlmZSBFeHBlY3RhbmN5L3RyZW5k

czwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9r

ZXl3b3JkPjxrZXl3b3JkPlByZXZhbGVuY2U8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxpc2JuPjE1NTItNTI3OSAoRWxlY3Ryb25pYykmI3hEOzE1NTItNTI2MCAoTGlua2luZyk8

L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjMzMDU4MjM8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0

ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzMzA1ODIz

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4x

MDE2L2ouamFsei4yMDEyLjExLjAwNzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+

PC9DaXRlPjxDaXRlPjxBdXRob3I+V2ltbzwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJlY051

bT4zMjE0PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zMjE0PC9yZWMtbnVtYmVyPjxmb3Jl

aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRz

enpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzUzODE3MTUiPjMyMTQ8L2tleT48L2ZvcmVpZ24ta2V5

cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1

dG9ycz48YXV0aG9ycz48YXV0aG9yPldpbW8sIEEuPC9hdXRob3I+PGF1dGhvcj5Kb25zc29uLCBM

LjwvYXV0aG9yPjxhdXRob3I+Qm9uZCwgSi48L2F1dGhvcj48YXV0aG9yPlByaW5jZSwgTS48L2F1

dGhvcj48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5BbHpoZWltZXIgRGlzZWFz

ZSwgSW50ZXJuYXRpb25hbDwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1h

ZGRyZXNzPktJLUFsemhlaW1lciBEaXNlYXNlIFJlc2VhcmNoIENlbnRyZSwgS2Fyb2xpbnNrYSBJ

bnN0aXR1dGV0LCBTdG9ja2hvbG0sIFN3ZWRlbi4gV2ltb0BraS5zZTwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPlRoZSB3b3JsZHdpZGUgZWNvbm9taWMgaW1wYWN0IG9mIGRlbWVudGlhIDIw

MTA8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWx6aGVpbWVycyBEZW1lbnQ8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+MS0xMSBlMzwvcGFnZXM+PHZvbHVtZT45PC92b2x1bWU+PG51

bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPipDb3N0IG9mIElsbG5lc3M8L2tleXdv

cmQ+PGtleXdvcmQ+RGVtZW50aWEvKmVjb25vbWljczwva2V5d29yZD48a2V5d29yZD5HbG9iYWwg

SGVhbHRoLyplY29ub21pY3M8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjwva2V5

d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KYW48L2RhdGU+

PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTUyLTUyNzkgKEVsZWN0cm9uaWMpJiN4RDsxNTUy

LTUyNjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIzMzA1ODIxPC9hY2Nlc3Npb24t

bnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292

L3B1Ym1lZC8yMzMwNTgyMTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+MTAuMTAxNi9qLmphbHouMjAxMi4xMS4wMDY8L2VsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QcmluY2U8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

ZWNOdW0+MzIxMTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjcsOSwxMDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjMyMTE8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTM4MTM2NCI+MzIxMTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+UHJpbmNlLCBNLjwvYXV0aG9yPjxh

dXRob3I+QWxpLCBHLiBDLjwvYXV0aG9yPjxhdXRob3I+R3VlcmNoZXQsIE0uPC9hdXRob3I+PGF1

dGhvcj5QcmluYSwgQS4gTS48L2F1dGhvcj48YXV0aG9yPkFsYmFuZXNlLCBFLjwvYXV0aG9yPjxh

dXRob3I+V3UsIFkuIFQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk

ZHJlc3M+VGhlIEdsb2JhbCBPYnNlcnZhdG9yeSBmb3IgQWdlaW5nIGFuZCBEZW1lbnRpYSBDYXJl

LCBIZWFsdGggU2VydmljZSAmYW1wOyBQb3B1bGF0aW9uIFJlc2VhcmNoIERlcGFydG1lbnQsIElu

c3RpdHV0ZSBvZiBQc3ljaGlhdHJ5LCBQc3ljaG9sb2d5IGFuZCBOZXVyb3NjaWVuY2UsIEtpbmcm

YXBvcztzIENvbGxlZ2UgTG9uZG9uLCBQTyAzNiwgRGF2aWQgR29sZGJlcmcgQ2VudHJlLCBEZSBD

cmVzcGlnbnkgUGFyaywgTG9uZG9uLCBTRTUgOEFGLCBVSy4gbWFydGluLnByaW5jZUBrY2wuYWMu

dWsuJiN4RDtUaGUgR2xvYmFsIE9ic2VydmF0b3J5IGZvciBBZ2VpbmcgYW5kIERlbWVudGlhIENh

cmUsIEhlYWx0aCBTZXJ2aWNlICZhbXA7IFBvcHVsYXRpb24gUmVzZWFyY2ggRGVwYXJ0bWVudCwg

SW5zdGl0dXRlIG9mIFBzeWNoaWF0cnksIFBzeWNob2xvZ3kgYW5kIE5ldXJvc2NpZW5jZSwgS2lu

ZyZhcG9zO3MgQ29sbGVnZSBMb25kb24sIFBPIDM2LCBEYXZpZCBHb2xkYmVyZyBDZW50cmUsIERl

IENyZXNwaWdueSBQYXJrLCBMb25kb24sIFNFNSA4QUYsIFVLLiYjeEQ7RGVwYXJ0bWVudCBvZiBQ

dWJsaWMgSGVhbHRoIGFuZCBQcmltYXJ5IENhcmUsIFNjaG9vbCBvZiBDbGluaWNhbCBNZWRpY2lu

ZSwgVW5pdmVyc2l0eSBvZiBDYW1icmlkZ2UsIENhbWJyaWRnZSwgVUsuJiN4RDtEZXBhcnRtZW50

IG9mIFBzeWNoaWF0cnksIFVuaXZlcnNpdHkgb2YgR2VuZXZhLCBHZW5ldmEsIFN3aXR6ZXJsYW5k

LiYjeEQ7Q2FtYnJpZGdlIEluc3RpdHV0ZSBvZiBQdWJsaWMgSGVhbHRoLCBVbml2ZXJzaXR5IG9m

IENhbWJyaWRnZSwgQ2FtYnJpZGdlLCBVSy48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5S

ZWNlbnQgZ2xvYmFsIHRyZW5kcyBpbiB0aGUgcHJldmFsZW5jZSBhbmQgaW5jaWRlbmNlIG9mIGRl

bWVudGlhLCBhbmQgc3Vydml2YWwgd2l0aCBkZW1lbnRpYTwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5BbHpoZWltZXJzIFJlcyBUaGVyPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+QWx6aGVpbWVycyBSZXMgVGhlcjwvZnVsbC10aXRsZT48L3BlcmlvZGlj

YWw+PHBhZ2VzPjIzPC9wYWdlcz48dm9sdW1lPjg8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48

a2V5d29yZHM+PGtleXdvcmQ+RGVtZW50aWEvKmVwaWRlbWlvbG9neS8qbW9ydGFsaXR5PC9rZXl3

b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5HbG9iYWwgSGVhbHRoL3N0YXRp

c3RpY3MgJmFtcDsgbnVtZXJpY2FsIGRhdGEvKnRyZW5kczwva2V5d29yZD48a2V5d29yZD5IdW1h

bnM8L2tleXdvcmQ+PGtleXdvcmQ+SW5jaWRlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPkxvbmdpdHVk

aW5hbCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWV0

YS1BbmFseXNpcyBhcyBUb3BpYzwva2V5d29yZD48a2V5d29yZD5QcmV2YWxlbmNlPC9rZXl3b3Jk

PjxrZXl3b3JkPlJldHJvc3BlY3RpdmUgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD4qRGVtZW50

aWE8L2tleXdvcmQ+PGtleXdvcmQ+KkVwaWRlbWlvbG9neTwva2V5d29yZD48a2V5d29yZD4qR2xv

YmFsIGhlYWx0aDwva2V5d29yZD48a2V5d29yZD4qTWV0YS1hbmFseXNpczwva2V5d29yZD48a2V5

d29yZD4qUHJvamVjdGlvbjwva2V5d29yZD48a2V5d29yZD4qU3lzdGVtYXRpYyByZXZpZXc8L2tl

eXdvcmQ+PGtleXdvcmQ+KlRyZW5kczwva2V5d29yZD48a2V5d29yZD4qV29ybGR3aWRlPC9rZXl3

b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5K

dWwgMzA8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNzU4LTkxOTMgKEVsZWN0cm9u

aWMpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3NDczNjgxPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxy

ZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNzQ3

MzY4MTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0OTY3Mjk5PC9jdXN0

b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTg2L3MxMzE5NS0wMTYtMDE4OC04PC9l

bGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5Qcmlu

Y2U8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNOdW0+MzIxMjwvUmVjTnVtPjxyZWNvcmQ+

PHJlYy1udW1iZXI+MzIxMjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIg

ZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIx

NTM1MzgxMzY0Ij4zMjEyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Q

cmluY2UsIE0uPC9hdXRob3I+PGF1dGhvcj5CcnljZSwgUi48L2F1dGhvcj48YXV0aG9yPkFsYmFu

ZXNlLCBFLjwvYXV0aG9yPjxhdXRob3I+V2ltbywgQS48L2F1dGhvcj48YXV0aG9yPlJpYmVpcm8s

IFcuPC9hdXRob3I+PGF1dGhvcj5GZXJyaSwgQy4gUC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5JbnN0aXR1dGUgb2YgUHN5Y2hpYXRyeSwgS2luZyZhcG9z

O3MgQ29sbGVnZSBMb25kb24sIExvbmRvbiwgVUsuIE1hcnRpbi5QcmluY2VAa2NsLmFjLnVrPC9h

dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGhlIGdsb2JhbCBwcmV2YWxlbmNlIG9mIGRlbWVu

dGlhOiBhIHN5c3RlbWF0aWMgcmV2aWV3IGFuZCBtZXRhYW5hbHlzaXM8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+QWx6aGVpbWVycyBEZW1lbnQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFn

ZXM+NjMtNzUgZTI8L3BhZ2VzPjx2b2x1bWU+OTwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxr

ZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVy

PC9rZXl3b3JkPjxrZXl3b3JkPkRlbWVudGlhLyplcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkdsb2JhbCBIZWFsdGgvKnRyZW5kczwva2V5d29y

ZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TGlmZSBFeHBlY3RhbmN5L3RyZW5k

czwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9r

ZXl3b3JkPjxrZXl3b3JkPlByZXZhbGVuY2U8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxpc2JuPjE1NTItNTI3OSAoRWxlY3Ryb25pYykmI3hEOzE1NTItNTI2MCAoTGlua2luZyk8

L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjMzMDU4MjM8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0

ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzMzA1ODIz

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4x

MDE2L2ouamFsei4yMDEyLjExLjAwNzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+

PC9DaXRlPjxDaXRlPjxBdXRob3I+V2ltbzwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJlY051

bT4zMjE0PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zMjE0PC9yZWMtbnVtYmVyPjxmb3Jl

aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRz

enpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzUzODE3MTUiPjMyMTQ8L2tleT48L2ZvcmVpZ24ta2V5

cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1

dG9ycz48YXV0aG9ycz48YXV0aG9yPldpbW8sIEEuPC9hdXRob3I+PGF1dGhvcj5Kb25zc29uLCBM

LjwvYXV0aG9yPjxhdXRob3I+Qm9uZCwgSi48L2F1dGhvcj48YXV0aG9yPlByaW5jZSwgTS48L2F1

dGhvcj48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5BbHpoZWltZXIgRGlzZWFz

ZSwgSW50ZXJuYXRpb25hbDwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1h

ZGRyZXNzPktJLUFsemhlaW1lciBEaXNlYXNlIFJlc2VhcmNoIENlbnRyZSwgS2Fyb2xpbnNrYSBJ

bnN0aXR1dGV0LCBTdG9ja2hvbG0sIFN3ZWRlbi4gV2ltb0BraS5zZTwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPlRoZSB3b3JsZHdpZGUgZWNvbm9taWMgaW1wYWN0IG9mIGRlbWVudGlhIDIw

MTA8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWx6aGVpbWVycyBEZW1lbnQ8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+MS0xMSBlMzwvcGFnZXM+PHZvbHVtZT45PC92b2x1bWU+PG51

bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPipDb3N0IG9mIElsbG5lc3M8L2tleXdv

cmQ+PGtleXdvcmQ+RGVtZW50aWEvKmVjb25vbWljczwva2V5d29yZD48a2V5d29yZD5HbG9iYWwg

SGVhbHRoLyplY29ub21pY3M8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjwva2V5

d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KYW48L2RhdGU+

PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTUyLTUyNzkgKEVsZWN0cm9uaWMpJiN4RDsxNTUy

LTUyNjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIzMzA1ODIxPC9hY2Nlc3Npb24t

bnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292

L3B1Ym1lZC8yMzMwNTgyMTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+MTAuMTAxNi9qLmphbHouMjAxMi4xMS4wMDY8L2VsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 7,9,10. Thus, solving the AD puzzle should be hand in hand with increasing the lifespan of humans, in order to reach for healthy aging, one of the main goals for the World Health Organization (WHO) and for many governments around the globe PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DbGFyazwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

Y051bT4zMDExPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTEsMTI8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zMDExPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzUzNzk0NzQiPjMwMTE8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkNsYXJrLCBCLiBGLjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTW9sZWN1

bGFyIEJpb2xvZ3ksIEFhcmh1cyBVbml2ZXJzaXR5LCBHdXN0YXYgV2llZHMgVmVqIDEwLCA4MDAw

IEFhcmh1cywgRGVubWFyay4gYmZjY0BtYi5hdS5kazwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRp

dGxlPkhlYWx0aHkgaHVtYW4gYWdlaW5nPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk4gQmlvdGVj

aG5vbDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMy01PC9wYWdlcz48dm9sdW1l

PjI1PC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnaW5nLypw

aHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPipIZWFsdGg8L2tleXdvcmQ+PGtleXdvcmQ+SHVt

YW5zPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDg8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT5KdW48L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xODcxLTY3ODQgKFBy

aW50KSYjeEQ7MTg3MS02Nzg0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xODUwNDAw

NTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNi

aS5ubG0ubmloLmdvdi9wdWJtZWQvMTg1MDQwMDU8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uYnQuMjAwOC4wMS4wMDI8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkRhc2thbG9w

b3Vsb3U8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxSZWNOdW0+MjY0ODwvUmVjTnVtPjxyZWNv

cmQ+PHJlYy1udW1iZXI+MjY0ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1w

PSIxNTM1Mzc5NDI2Ij4yNjQ4PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5EYXNrYWxvcG91bG91LCBDLjwvYXV0aG9yPjxhdXRob3I+U3R1YmJzLCBCLjwvYXV0aG9yPjxh

dXRob3I+S3JhbGosIEMuPC9hdXRob3I+PGF1dGhvcj5Lb3Vrb3VuYXJpLCBBLjwvYXV0aG9yPjxh

dXRob3I+UHJpbmNlLCBNLjwvYXV0aG9yPjxhdXRob3I+UHJpbmEsIEEuIE0uPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+SGVhbHRoIFNlcnZpY2UgYW5kIFBv

cHVsYXRpb24gUmVzZWFyY2ggRGVwYXJ0bWVudCwgQ2VudHJlIGZvciBHbG9iYWwgTWVudGFsIEhl

YWx0aCwgSW5zdGl0dXRlIG9mIFBzeWNoaWF0cnksIFBzeWNob2xvZ3kgYW5kIE5ldXJvc2NpZW5j

ZSwgS2luZyZhcG9zO3MgQ29sbGVnZSBMb25kb24sIExvbmRvbiwgVUsuJiN4RDtIZWFsdGggU2Vy

dmljZSBhbmQgUG9wdWxhdGlvbiBSZXNlYXJjaCBEZXBhcnRtZW50LCBJbnN0aXR1dGUgb2YgUHN5

Y2hpYXRyeSwgUHN5Y2hvbG9neSBhbmQgTmV1cm9zY2llbmNlLCBLaW5nJmFwb3M7cyBDb2xsZWdl

IExvbmRvbiwgTG9uZG9uLCBVSy4mI3hEO1BoeXNpb3RoZXJhcHkgRGVwYXJ0bWVudCwgU291dGgg

TG9uZG9uIGFuZCBNYXVkc2xleSBOSFMgRm91bmRhdGlvbiBUcnVzdCwgTG9uZG9uLCBVSy4mI3hE

O0RlcGFydG1lbnQgb2YgQ2xpbmljYWwgU2NpZW5jZXMsIExpdmVycG9vbCBTY2hvb2wgb2YgVHJv

cGljYWwgTWVkaWNpbmUsIExpdmVycG9vbCwgVUsuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+QXNzb2NpYXRpb25zIG9mIHNtb2tpbmcgYW5kIGFsY29ob2wgY29uc3VtcHRpb24gd2l0aCBo

ZWFsdGh5IGFnZWluZzogYSBzeXN0ZW1hdGljIHJldmlldyBhbmQgbWV0YS1hbmFseXNpcyBvZiBs

b25naXR1ZGluYWwgc3R1ZGllczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5CTUogT3Blbjwvc2Vj

b25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkJNSiBPcGVuPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+ZTAxOTU0MDwvcGFnZXM+PHZvbHVtZT44PC92

b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPmFsY29ob2wgY29uc3Vt

cHRpb248L2tleXdvcmQ+PGtleXdvcmQ+ZHJpbmtpbmc8L2tleXdvcmQ+PGtleXdvcmQ+aGVhbHRo

eSBhZ2Vpbmc8L2tleXdvcmQ+PGtleXdvcmQ+bWV0YS1hbmFseXNpczwva2V5d29yZD48a2V5d29y

ZD5zbW9raW5nPC9rZXl3b3JkPjxrZXl3b3JkPmJ5IGEgZ3JhbnQgZnVuZGVkIGJ5IHRoZSBOYXRp

b25hbCBJbnN0aXR1dGUgZm9yIEhlYWx0aCBSZXNlYXJjaCAoTklIUikgQmlvbWVkaWNhbDwva2V5

d29yZD48a2V5d29yZD5SZXNlYXJjaCBDZW50cmUgYXQgU291dGggTG9uZG9uIGFuZCBNYXVkc2xl

eSBOYXRpb25hbCBIZWFsdGggU2VydmljZSAoTkhTKTwva2V5d29yZD48a2V5d29yZD5Gb3VuZGF0

aW9uIFRydXN0IGFuZCBLaW5ncyZhcG9zOyBDb2xsZWdlIExvbmRvbiB3aGVyZSBtb3N0IG9mIHRo

aXMgd29yayB3YXMgY29uZHVjdGVkLjwva2V5d29yZD48a2V5d29yZD5BSyBpcyBub3cgZm9ybWFs

bHkgYmFzZWQgYXQgdGhlIExpdmVycG9vbCBTY2hvb2wgb2YgVHJvcGljYWwgTWVkaWNpbmUuPC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5BcHIgMTc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4yMDQ0LTYwNTUgKEVsZWN0

cm9uaWMpJiN4RDsyMDQ0LTYwNTUgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5NjY2

MTI3PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yOTY2NjEyNzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48Y3VzdG9tMj5QTUM1OTA1NzUyPC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4x

MC4xMTM2L2Jtam9wZW4tMjAxNy0wMTk1NDA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVj

b3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DbGFyazwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

Y051bT4zMDExPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTEsMTI8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zMDExPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzUzNzk0NzQiPjMwMTE8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkNsYXJrLCBCLiBGLjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTW9sZWN1

bGFyIEJpb2xvZ3ksIEFhcmh1cyBVbml2ZXJzaXR5LCBHdXN0YXYgV2llZHMgVmVqIDEwLCA4MDAw

IEFhcmh1cywgRGVubWFyay4gYmZjY0BtYi5hdS5kazwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRp

dGxlPkhlYWx0aHkgaHVtYW4gYWdlaW5nPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk4gQmlvdGVj

aG5vbDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMy01PC9wYWdlcz48dm9sdW1l

PjI1PC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnaW5nLypw

aHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPipIZWFsdGg8L2tleXdvcmQ+PGtleXdvcmQ+SHVt

YW5zPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDg8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT5KdW48L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xODcxLTY3ODQgKFBy

aW50KSYjeEQ7MTg3MS02Nzg0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xODUwNDAw

NTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNi

aS5ubG0ubmloLmdvdi9wdWJtZWQvMTg1MDQwMDU8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uYnQuMjAwOC4wMS4wMDI8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkRhc2thbG9w

b3Vsb3U8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxSZWNOdW0+MjY0ODwvUmVjTnVtPjxyZWNv

cmQ+PHJlYy1udW1iZXI+MjY0ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1w

PSIxNTM1Mzc5NDI2Ij4yNjQ4PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5EYXNrYWxvcG91bG91LCBDLjwvYXV0aG9yPjxhdXRob3I+U3R1YmJzLCBCLjwvYXV0aG9yPjxh

dXRob3I+S3JhbGosIEMuPC9hdXRob3I+PGF1dGhvcj5Lb3Vrb3VuYXJpLCBBLjwvYXV0aG9yPjxh

dXRob3I+UHJpbmNlLCBNLjwvYXV0aG9yPjxhdXRob3I+UHJpbmEsIEEuIE0uPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+SGVhbHRoIFNlcnZpY2UgYW5kIFBv

cHVsYXRpb24gUmVzZWFyY2ggRGVwYXJ0bWVudCwgQ2VudHJlIGZvciBHbG9iYWwgTWVudGFsIEhl

YWx0aCwgSW5zdGl0dXRlIG9mIFBzeWNoaWF0cnksIFBzeWNob2xvZ3kgYW5kIE5ldXJvc2NpZW5j

ZSwgS2luZyZhcG9zO3MgQ29sbGVnZSBMb25kb24sIExvbmRvbiwgVUsuJiN4RDtIZWFsdGggU2Vy

dmljZSBhbmQgUG9wdWxhdGlvbiBSZXNlYXJjaCBEZXBhcnRtZW50LCBJbnN0aXR1dGUgb2YgUHN5

Y2hpYXRyeSwgUHN5Y2hvbG9neSBhbmQgTmV1cm9zY2llbmNlLCBLaW5nJmFwb3M7cyBDb2xsZWdl

IExvbmRvbiwgTG9uZG9uLCBVSy4mI3hEO1BoeXNpb3RoZXJhcHkgRGVwYXJ0bWVudCwgU291dGgg

TG9uZG9uIGFuZCBNYXVkc2xleSBOSFMgRm91bmRhdGlvbiBUcnVzdCwgTG9uZG9uLCBVSy4mI3hE

O0RlcGFydG1lbnQgb2YgQ2xpbmljYWwgU2NpZW5jZXMsIExpdmVycG9vbCBTY2hvb2wgb2YgVHJv

cGljYWwgTWVkaWNpbmUsIExpdmVycG9vbCwgVUsuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+QXNzb2NpYXRpb25zIG9mIHNtb2tpbmcgYW5kIGFsY29ob2wgY29uc3VtcHRpb24gd2l0aCBo

ZWFsdGh5IGFnZWluZzogYSBzeXN0ZW1hdGljIHJldmlldyBhbmQgbWV0YS1hbmFseXNpcyBvZiBs

b25naXR1ZGluYWwgc3R1ZGllczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5CTUogT3Blbjwvc2Vj

b25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkJNSiBPcGVuPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+ZTAxOTU0MDwvcGFnZXM+PHZvbHVtZT44PC92

b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPmFsY29ob2wgY29uc3Vt

cHRpb248L2tleXdvcmQ+PGtleXdvcmQ+ZHJpbmtpbmc8L2tleXdvcmQ+PGtleXdvcmQ+aGVhbHRo

eSBhZ2Vpbmc8L2tleXdvcmQ+PGtleXdvcmQ+bWV0YS1hbmFseXNpczwva2V5d29yZD48a2V5d29y

ZD5zbW9raW5nPC9rZXl3b3JkPjxrZXl3b3JkPmJ5IGEgZ3JhbnQgZnVuZGVkIGJ5IHRoZSBOYXRp

b25hbCBJbnN0aXR1dGUgZm9yIEhlYWx0aCBSZXNlYXJjaCAoTklIUikgQmlvbWVkaWNhbDwva2V5

d29yZD48a2V5d29yZD5SZXNlYXJjaCBDZW50cmUgYXQgU291dGggTG9uZG9uIGFuZCBNYXVkc2xl

eSBOYXRpb25hbCBIZWFsdGggU2VydmljZSAoTkhTKTwva2V5d29yZD48a2V5d29yZD5Gb3VuZGF0

aW9uIFRydXN0IGFuZCBLaW5ncyZhcG9zOyBDb2xsZWdlIExvbmRvbiB3aGVyZSBtb3N0IG9mIHRo

aXMgd29yayB3YXMgY29uZHVjdGVkLjwva2V5d29yZD48a2V5d29yZD5BSyBpcyBub3cgZm9ybWFs

bHkgYmFzZWQgYXQgdGhlIExpdmVycG9vbCBTY2hvb2wgb2YgVHJvcGljYWwgTWVkaWNpbmUuPC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5BcHIgMTc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4yMDQ0LTYwNTUgKEVsZWN0

cm9uaWMpJiN4RDsyMDQ0LTYwNTUgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5NjY2

MTI3PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yOTY2NjEyNzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48Y3VzdG9tMj5QTUM1OTA1NzUyPC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4x

MC4xMTM2L2Jtam9wZW4tMjAxNy0wMTk1NDA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVj

b3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 11,12. Currently, AD has no treatment available to modify its progression. Pioneering efforts from scientists and clinicians led to discovery and development of cholinesterase inhibitors for AD, capable of improving symptoms such as mood swings or dyskinesia, but these treatments do not halt AD progression nor improve memory performance in patients, revised by Mangialasche et al. 2010 and by Schneider et al. 2010 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2huZWlkZXI8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy

PjxSZWNOdW0+MzIxNjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjEzLDE0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzIxNjwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1MzgzMDMwIj4zMjE2PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TY2huZWlkZXIsIEwuIFMuPC9h

dXRob3I+PGF1dGhvcj5NYW5naWFsYXNjaGUsIEYuPC9hdXRob3I+PGF1dGhvcj5BbmRyZWFzZW4s

IE4uPC9hdXRob3I+PGF1dGhvcj5GZWxkbWFuLCBILjwvYXV0aG9yPjxhdXRob3I+R2lhY29iaW5p

LCBFLjwvYXV0aG9yPjxhdXRob3I+Sm9uZXMsIFIuPC9hdXRob3I+PGF1dGhvcj5NYW50dWEsIFYu

PC9hdXRob3I+PGF1dGhvcj5NZWNvY2NpLCBQLjwvYXV0aG9yPjxhdXRob3I+UGFuaSwgTC48L2F1

dGhvcj48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5LaXZpcGVsdG8sIE0uPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudHMg

b2YgUHN5Y2hpYXRyeSBhbmQgdGhlIEJlaGF2aW9yYWwgU2NpZW5jZXMsIGFuZCBOZXVyb2xvZ3ks

IEtlY2sgU2Nob29sIG9mIE1lZGljaW5lLCBMZW9uYXJkIERhdmlzIFNjaG9vbCBvZiBHZXJvbnRv

bG9neSBvZiB0aGUgVW5pdmVyc2l0eSBvZiBTb3V0aGVybiBDYWxpZm9ybmlhLCBMb3MgQW5nZWxl

cywgQ0EsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5DbGluaWNhbCB0cmlhbHMg

YW5kIGxhdGUtc3RhZ2UgZHJ1ZyBkZXZlbG9wbWVudCBmb3IgQWx6aGVpbWVyJmFwb3M7cyBkaXNl

YXNlOiBhbiBhcHByYWlzYWwgZnJvbSAxOTg0IHRvIDIwMTQ8L3RpdGxlPjxzZWNvbmRhcnktdGl0

bGU+SiBJbnRlcm4gTWVkPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1

bGwtdGl0bGU+SiBJbnRlcm4gTWVkPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjUx

LTgzPC9wYWdlcz48dm9sdW1lPjI3NTwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxrZXl3b3Jk

cz48a2V5d29yZD4qQWx6aGVpbWVyIERpc2Vhc2UvY29tcGxpY2F0aW9ucy9kcnVnIHRoZXJhcHkv

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5CaW9tYXJrZXJzLyphbmFseXNpczwva2V5d29y

ZD48a2V5d29yZD5DaG9saW5lc3RlcmFzZSBJbmhpYml0b3JzLyp0aGVyYXBldXRpYyB1c2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RG9wYW1pbmUgQWdlbnRzL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48

a2V5d29yZD5EcnVnIE1vbml0b3JpbmcvbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8

L2tleXdvcmQ+PGtleXdvcmQ+TWVkaWNhdGlvbiBUaGVyYXB5IE1hbmFnZW1lbnQ8L2tleXdvcmQ+

PGtleXdvcmQ+TWVtYW50aW5lLyp0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+TWVt

b3J5IERpc29yZGVycy8qZHJ1ZyB0aGVyYXB5L2V0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk5v

b3Ryb3BpYyBBZ2VudHMvKnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5QcmFjdGlj

ZSBHdWlkZWxpbmVzIGFzIFRvcGljPC9rZXl3b3JkPjxrZXl3b3JkPlJhbmRvbWl6ZWQgQ29udHJv

bGxlZCBUcmlhbHMgYXMgVG9waWM8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyPC9rZXl3b3Jk

PjxrZXl3b3JkPmNsaW5pY2FsIHRyaWFsPC9rZXl3b3JkPjxrZXl3b3JkPmRlbWVudGlhPC9rZXl3

b3JkPjxrZXl3b3JkPmRydWcgZGV2ZWxvcG1lbnQ8L2tleXdvcmQ+PGtleXdvcmQ+dHJlYXRtZW50

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5NYXI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMzY1LTI3OTYgKEVsZWN0

cm9uaWMpJiN4RDswOTU0LTY4MjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI0NjA1

ODA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNDYwNTgwODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48Y3VzdG9tMj5QTUMzOTU2NzUyPC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4x

MC4xMTExL2pvaW0uMTIxOTE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0

ZT48Q2l0ZT48QXV0aG9yPk1hbmdpYWxhc2NoZTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl

Y051bT4zMjE3PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zMjE3PC9yZWMtbnVtYmVyPjxm

b3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5

enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzUzODMwMzAiPjMyMTc8L2tleT48L2ZvcmVpZ24t

a2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRy

aWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1hbmdpYWxhc2NoZSwgRi48L2F1dGhvcj48YXV0aG9y

PlNvbG9tb24sIEEuPC9hdXRob3I+PGF1dGhvcj5XaW5ibGFkLCBCLjwvYXV0aG9yPjxhdXRob3I+

TWVjb2NjaSwgUC48L2F1dGhvcj48YXV0aG9yPktpdmlwZWx0bywgTS48L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5BZ2luZyBSZXNlYXJjaCBDZW50ZXIsIEth

cm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW4uPC9hdXRoLWFkZHJlc3M+PHRp

dGxlcz48dGl0bGU+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlOiBjbGluaWNhbCB0cmlhbHMgYW5k

IGRydWcgZGV2ZWxvcG1lbnQ8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TGFuY2V0IE5ldXJvbDwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz43MDItMTY8L3BhZ2VzPjx2b2x1bWU+OTwv

dm9sdW1lPjxudW1iZXI+NzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlz

ZWFzZS8qZHJ1ZyB0aGVyYXB5L2V0aW9sb2d5L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5B

bnRpcHN5Y2hvdGljIEFnZW50cy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNs

aW5pY2FsIFRyaWFscyBhcyBUb3BpYzwva2V5d29yZD48a2V5d29yZD4qRHJ1ZyBEZXNpZ248L2tl

eXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTA8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWw8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNDc0LTQ0NjUgKEVsZWN0cm9uaWMpJiN4RDsxNDc0LTQ0MjIgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIwNjEwMzQ2PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMDYxMDM0NjwvdXJs

PjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9T

MTQ3NC00NDIyKDEwKTcwMTE5LTg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2huZWlkZXI8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy

PjxSZWNOdW0+MzIxNjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjEzLDE0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzIxNjwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1MzgzMDMwIj4zMjE2PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TY2huZWlkZXIsIEwuIFMuPC9h

dXRob3I+PGF1dGhvcj5NYW5naWFsYXNjaGUsIEYuPC9hdXRob3I+PGF1dGhvcj5BbmRyZWFzZW4s

IE4uPC9hdXRob3I+PGF1dGhvcj5GZWxkbWFuLCBILjwvYXV0aG9yPjxhdXRob3I+R2lhY29iaW5p

LCBFLjwvYXV0aG9yPjxhdXRob3I+Sm9uZXMsIFIuPC9hdXRob3I+PGF1dGhvcj5NYW50dWEsIFYu

PC9hdXRob3I+PGF1dGhvcj5NZWNvY2NpLCBQLjwvYXV0aG9yPjxhdXRob3I+UGFuaSwgTC48L2F1

dGhvcj48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5LaXZpcGVsdG8sIE0uPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudHMg

b2YgUHN5Y2hpYXRyeSBhbmQgdGhlIEJlaGF2aW9yYWwgU2NpZW5jZXMsIGFuZCBOZXVyb2xvZ3ks

IEtlY2sgU2Nob29sIG9mIE1lZGljaW5lLCBMZW9uYXJkIERhdmlzIFNjaG9vbCBvZiBHZXJvbnRv

bG9neSBvZiB0aGUgVW5pdmVyc2l0eSBvZiBTb3V0aGVybiBDYWxpZm9ybmlhLCBMb3MgQW5nZWxl

cywgQ0EsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5DbGluaWNhbCB0cmlhbHMg

YW5kIGxhdGUtc3RhZ2UgZHJ1ZyBkZXZlbG9wbWVudCBmb3IgQWx6aGVpbWVyJmFwb3M7cyBkaXNl

YXNlOiBhbiBhcHByYWlzYWwgZnJvbSAxOTg0IHRvIDIwMTQ8L3RpdGxlPjxzZWNvbmRhcnktdGl0

bGU+SiBJbnRlcm4gTWVkPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1

bGwtdGl0bGU+SiBJbnRlcm4gTWVkPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjUx

LTgzPC9wYWdlcz48dm9sdW1lPjI3NTwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxrZXl3b3Jk

cz48a2V5d29yZD4qQWx6aGVpbWVyIERpc2Vhc2UvY29tcGxpY2F0aW9ucy9kcnVnIHRoZXJhcHkv

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5CaW9tYXJrZXJzLyphbmFseXNpczwva2V5d29y

ZD48a2V5d29yZD5DaG9saW5lc3RlcmFzZSBJbmhpYml0b3JzLyp0aGVyYXBldXRpYyB1c2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RG9wYW1pbmUgQWdlbnRzL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48

a2V5d29yZD5EcnVnIE1vbml0b3JpbmcvbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8

L2tleXdvcmQ+PGtleXdvcmQ+TWVkaWNhdGlvbiBUaGVyYXB5IE1hbmFnZW1lbnQ8L2tleXdvcmQ+

PGtleXdvcmQ+TWVtYW50aW5lLyp0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+TWVt

b3J5IERpc29yZGVycy8qZHJ1ZyB0aGVyYXB5L2V0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk5v

b3Ryb3BpYyBBZ2VudHMvKnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5QcmFjdGlj

ZSBHdWlkZWxpbmVzIGFzIFRvcGljPC9rZXl3b3JkPjxrZXl3b3JkPlJhbmRvbWl6ZWQgQ29udHJv

bGxlZCBUcmlhbHMgYXMgVG9waWM8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyPC9rZXl3b3Jk

PjxrZXl3b3JkPmNsaW5pY2FsIHRyaWFsPC9rZXl3b3JkPjxrZXl3b3JkPmRlbWVudGlhPC9rZXl3

b3JkPjxrZXl3b3JkPmRydWcgZGV2ZWxvcG1lbnQ8L2tleXdvcmQ+PGtleXdvcmQ+dHJlYXRtZW50

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5NYXI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMzY1LTI3OTYgKEVsZWN0

cm9uaWMpJiN4RDswOTU0LTY4MjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI0NjA1

ODA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNDYwNTgwODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48Y3VzdG9tMj5QTUMzOTU2NzUyPC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4x

MC4xMTExL2pvaW0uMTIxOTE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0

ZT48Q2l0ZT48QXV0aG9yPk1hbmdpYWxhc2NoZTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl

Y051bT4zMjE3PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zMjE3PC9yZWMtbnVtYmVyPjxm

b3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5

enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzUzODMwMzAiPjMyMTc8L2tleT48L2ZvcmVpZ24t

a2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRy

aWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1hbmdpYWxhc2NoZSwgRi48L2F1dGhvcj48YXV0aG9y

PlNvbG9tb24sIEEuPC9hdXRob3I+PGF1dGhvcj5XaW5ibGFkLCBCLjwvYXV0aG9yPjxhdXRob3I+

TWVjb2NjaSwgUC48L2F1dGhvcj48YXV0aG9yPktpdmlwZWx0bywgTS48L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5BZ2luZyBSZXNlYXJjaCBDZW50ZXIsIEth

cm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW4uPC9hdXRoLWFkZHJlc3M+PHRp

dGxlcz48dGl0bGU+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlOiBjbGluaWNhbCB0cmlhbHMgYW5k

IGRydWcgZGV2ZWxvcG1lbnQ8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TGFuY2V0IE5ldXJvbDwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz43MDItMTY8L3BhZ2VzPjx2b2x1bWU+OTwv

dm9sdW1lPjxudW1iZXI+NzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlz

ZWFzZS8qZHJ1ZyB0aGVyYXB5L2V0aW9sb2d5L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5B

bnRpcHN5Y2hvdGljIEFnZW50cy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNs

aW5pY2FsIFRyaWFscyBhcyBUb3BpYzwva2V5d29yZD48a2V5d29yZD4qRHJ1ZyBEZXNpZ248L2tl

eXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTA8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWw8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNDc0LTQ0NjUgKEVsZWN0cm9uaWMpJiN4RDsxNDc0LTQ0MjIgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIwNjEwMzQ2PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMDYxMDM0NjwvdXJs

PjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9T

MTQ3NC00NDIyKDEwKTcwMTE5LTg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 13,14. Antibody therapies have been developed from the main pathological hallmarks of AD, Amyloid beta (Aβ) and Tau proteins, to normalize their levels in the brain. These therapies are based on the amyloid cascade hypothesis, proposing that Aβ and Tau accumulation in the brain mediate synapse loss and neuronal death, leading to diminished memory function ADDIN EN.CITE <EndNote><Cite><Author>Hardy</Author><Year>1992</Year><RecNum>2064</RecNum><DisplayText><style face="superscript">15</style></DisplayText><record><rec-number>2064</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1534779853">2064</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hardy, J. A.</author><author>Higgins, G. A.</author></authors></contributors><auth-address>Department of Biochemistry, St. Mary&apos;s Hospital Medical School, London, U.K.</auth-address><titles><title>Alzheimer&apos;s disease: the amyloid cascade hypothesis</title><secondary-title>Science</secondary-title></titles><periodical><full-title>Science</full-title></periodical><pages>184-5</pages><volume>256</volume><number>5054</number><edition>1992/04/10</edition><keywords><keyword>Alzheimer Disease/*etiology/genetics/physiopathology</keyword><keyword>Amyloid/*genetics/metabolism/physiology</keyword><keyword>Amyloid beta-Protein Precursor/genetics</keyword><keyword>Brain/pathology/physiopathology</keyword><keyword>Cell Death</keyword><keyword>Humans</keyword><keyword>*Mutation</keyword><keyword>Neurofibrillary Tangles/physiology</keyword></keywords><dates><year>1992</year><pub-dates><date>Apr 10</date></pub-dates></dates><isbn>0036-8075 (Print)&#xD;0036-8075 (Linking)</isbn><accession-num>1566067</accession-num><urls><related-urls><url>. Nevertheless, many clinical trials aimed at reducing amyloid levels have not reached significant improvement in memory performance, or caused secondary, often-adverse effects and have dropped out PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYXJyYW48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

ZWNOdW0+MjEzMTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjE2PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjEzMTwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0ODYzNzk5Ij4yMTMxPC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LYXJyYW4sIEUuPC9hdXRob3I+PGF1dGhv

cj5EZSBTdHJvb3BlciwgQi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgt

YWRkcmVzcz5BbHpoZWltZXImYXBvcztzIFJlc2VhcmNoIFVLIFJlc2VhcmNoLCBDYW1icmlkZ2Us

IENhbWJyaWRnZXNoaXJlLCBVSy4gZXJpYy5rYXJyYW5AYWJidmllLmNvbS4mI3hEO1ZJQiBDZW50

ZXIgZm9yIHRoZSBCaW9sb2d5IG9mIERpc2Vhc2UsIFZJQi1MZXV2ZW4sIExldXZlbiwgQmVsZ2l1

bS4gZXJpYy5rYXJyYW5AYWJidmllLmNvbS4mI3hEO0luc3RpdHV0ZSBvZiBOZXVyb2xvZ3ksIFVu

aXZlcnNpdHkgQ29sbGVnZSBMb25kb24sIExvbmRvbiwgVUsuIGVyaWMua2FycmFuQGFiYnZpZS5j

b20uJiN4RDtWSUIgQ2VudGVyIGZvciB0aGUgQmlvbG9neSBvZiBEaXNlYXNlLCBWSUItTGV1dmVu

LCBMZXV2ZW4sIEJlbGdpdW0uJiN4RDtDZW50ZXIgZm9yIEh1bWFuIEdlbmV0aWNzLCBVbml2ZXJz

aXRhaXJlIHppZWtlbmh1aXplbiBhbmQgTElORCwgS1UgTGV1dmVuLCBMZXV2ZW4sIEJlbGdpdW0u

JiN4RDtJbnN0aXR1dGUgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IENvbGxlZ2UgTG9uZG9uLCBM

b25kb24sIFVLLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSBhbXlsb2lkIGNhc2Nh

ZGUgaHlwb3RoZXNpczogYXJlIHdlIHBvaXNlZCBmb3Igc3VjY2VzcyBvciBmYWlsdXJlPzwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5KIE5ldXJvY2hlbTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9jaGVtPC9mdWxsLXRpdGxlPjwvcGVyaW9k

aWNhbD48cGFnZXM+MjM3LTI1MjwvcGFnZXM+PHZvbHVtZT4xMzkgU3VwcGwgMjwvdm9sdW1lPjxl

ZGl0aW9uPjIwMTYvMTEvMDE8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBE

aXNlYXNlL2dlbmV0aWNzLyptZXRhYm9saXNtL3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QW1p

bm8gQWNpZCBTZXF1ZW5jZTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkL2dlbmV0aWNzL21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL2FudGFnb25pc3Rz

ICZhbXA7IGluaGliaXRvcnMvZ2VuZXRpY3MvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZG9nZW5pYyBQcm90ZWlucy9hbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzL2dlbmV0

aWNzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZG9zaXMvZ2VuZXRpY3MvKm1l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BbnRp

Ym9kaWVzLCBNb25vY2xvbmFsL3BoYXJtYWNvbG9neS90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+

PGtleXdvcmQ+QnJhaW4vZHJ1ZyBlZmZlY3RzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD5TaWduYWwgVHJhbnNkdWN0aW9uL2RydWcgZWZmZWN0

cy8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8

L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBjYXNjYWRlIGNsaW5pY2FsIGRldmVsb3BtZW50PC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5PY3Q8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDcxLTQxNTkgKEVsZWN0cm9u

aWMpJiN4RDswMDIyLTMwNDIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3MjU1OTU4

PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3B1Ym1lZC8yNzI1NTk1ODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTExMS9qbmMuMTM2MzI8L2VsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYXJyYW48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

ZWNOdW0+MjEzMTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjE2PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjEzMTwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0ODYzNzk5Ij4yMTMxPC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LYXJyYW4sIEUuPC9hdXRob3I+PGF1dGhv

cj5EZSBTdHJvb3BlciwgQi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgt

YWRkcmVzcz5BbHpoZWltZXImYXBvcztzIFJlc2VhcmNoIFVLIFJlc2VhcmNoLCBDYW1icmlkZ2Us

IENhbWJyaWRnZXNoaXJlLCBVSy4gZXJpYy5rYXJyYW5AYWJidmllLmNvbS4mI3hEO1ZJQiBDZW50

ZXIgZm9yIHRoZSBCaW9sb2d5IG9mIERpc2Vhc2UsIFZJQi1MZXV2ZW4sIExldXZlbiwgQmVsZ2l1

bS4gZXJpYy5rYXJyYW5AYWJidmllLmNvbS4mI3hEO0luc3RpdHV0ZSBvZiBOZXVyb2xvZ3ksIFVu

aXZlcnNpdHkgQ29sbGVnZSBMb25kb24sIExvbmRvbiwgVUsuIGVyaWMua2FycmFuQGFiYnZpZS5j

b20uJiN4RDtWSUIgQ2VudGVyIGZvciB0aGUgQmlvbG9neSBvZiBEaXNlYXNlLCBWSUItTGV1dmVu

LCBMZXV2ZW4sIEJlbGdpdW0uJiN4RDtDZW50ZXIgZm9yIEh1bWFuIEdlbmV0aWNzLCBVbml2ZXJz

aXRhaXJlIHppZWtlbmh1aXplbiBhbmQgTElORCwgS1UgTGV1dmVuLCBMZXV2ZW4sIEJlbGdpdW0u

JiN4RDtJbnN0aXR1dGUgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IENvbGxlZ2UgTG9uZG9uLCBM

b25kb24sIFVLLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSBhbXlsb2lkIGNhc2Nh

ZGUgaHlwb3RoZXNpczogYXJlIHdlIHBvaXNlZCBmb3Igc3VjY2VzcyBvciBmYWlsdXJlPzwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5KIE5ldXJvY2hlbTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9jaGVtPC9mdWxsLXRpdGxlPjwvcGVyaW9k

aWNhbD48cGFnZXM+MjM3LTI1MjwvcGFnZXM+PHZvbHVtZT4xMzkgU3VwcGwgMjwvdm9sdW1lPjxl

ZGl0aW9uPjIwMTYvMTEvMDE8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBE

aXNlYXNlL2dlbmV0aWNzLyptZXRhYm9saXNtL3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QW1p

bm8gQWNpZCBTZXF1ZW5jZTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkL2dlbmV0aWNzL21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL2FudGFnb25pc3Rz

ICZhbXA7IGluaGliaXRvcnMvZ2VuZXRpY3MvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZG9nZW5pYyBQcm90ZWlucy9hbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzL2dlbmV0

aWNzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZG9zaXMvZ2VuZXRpY3MvKm1l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BbnRp

Ym9kaWVzLCBNb25vY2xvbmFsL3BoYXJtYWNvbG9neS90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+

PGtleXdvcmQ+QnJhaW4vZHJ1ZyBlZmZlY3RzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD5TaWduYWwgVHJhbnNkdWN0aW9uL2RydWcgZWZmZWN0

cy8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8

L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBjYXNjYWRlIGNsaW5pY2FsIGRldmVsb3BtZW50PC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5PY3Q8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDcxLTQxNTkgKEVsZWN0cm9u

aWMpJiN4RDswMDIyLTMwNDIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3MjU1OTU4

PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3B1Ym1lZC8yNzI1NTk1ODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTExMS9qbmMuMTM2MzI8L2VsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 16. To date, the scientific community holds high hopes for some antibody therapies and a Tau vaccine. The results of the phase I clinical trial are most expected PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ob3ZhazwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

Y051bT4yMDgzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTc8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDgzPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NjE1NzUiPjIwODM8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk5vdmFrLCBQLjwvYXV0aG9yPjxhdXRob3I+

U2NobWlkdCwgUi48L2F1dGhvcj48YXV0aG9yPktvbnRzZWtvdmEsIEUuPC9hdXRob3I+PGF1dGhv

cj5aaWxrYSwgTi48L2F1dGhvcj48YXV0aG9yPktvdmFjZWNoLCBCLjwvYXV0aG9yPjxhdXRob3I+

U2tyYWJhbmEsIFIuPC9hdXRob3I+PGF1dGhvcj5WaW5jZS1LYXptZXJvdmEsIFouPC9hdXRob3I+

PGF1dGhvcj5LYXRpbmEsIFMuPC9hdXRob3I+PGF1dGhvcj5GaWFsb3ZhLCBMLjwvYXV0aG9yPjxh

dXRob3I+UHJjaW5hLCBNLjwvYXV0aG9yPjxhdXRob3I+UGFycmFrLCBWLjwvYXV0aG9yPjxhdXRo

b3I+RGFsLUJpYW5jbywgUC48L2F1dGhvcj48YXV0aG9yPkJydW5uZXIsIE0uPC9hdXRob3I+PGF1

dGhvcj5TdGFmZmVuLCBXLjwvYXV0aG9yPjxhdXRob3I+UmFpbmVyLCBNLjwvYXV0aG9yPjxhdXRo

b3I+T25kcnVzLCBNLjwvYXV0aG9yPjxhdXRob3I+Um9wZWxlLCBTLjwvYXV0aG9yPjxhdXRob3I+

U21pc2VrLCBNLjwvYXV0aG9yPjxhdXRob3I+U2l2YWssIFIuPC9hdXRob3I+PGF1dGhvcj5XaW5i

bGFkLCBCLjwvYXV0aG9yPjxhdXRob3I+Tm92YWssIE0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+QVhPTiBOZXVyb3NjaWVuY2UgU0UsIEJyYXRpc2xhdmEs

IFNsb3Zha2lhLiBFbGVjdHJvbmljIGFkZHJlc3M6IHBldHIubm92YWtAYXhvbi1uZXVyb3NjaWVu

Y2UuZXUuJiN4RDtDbGluaWNhbCBEaXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIERlcGFydG1l

bnQgb2YgTmV1cm9sb2d5LCBNZWRpY2FsIFVuaXZlcnNpdHkgR3JheiwgR3JheiwgQXVzdHJpYS4m

I3hEO0FYT04gTmV1cm9zY2llbmNlIFNFLCBCcmF0aXNsYXZhLCBTbG92YWtpYS4mI3hEO1VuaXZl

cnNpdHkgQ2xpbmljIG9mIE5ldXJvbG9neSwgTWVkaWNhbCBVbml2ZXJzaXR5IG9mIFZpZW5uYSwg

Vmllbm5hLCBBdXN0cmlhLiYjeEQ7VW5pdmVyc2l0eSBDbGluaWMgb2YgQ2xpbmljYWwgUGhhcm1h

Y29sb2d5LCBNZWRpY2FsIFVuaXZlcnNpdHkgb2YgVmllbm5hLCBWaWVubmEsIEF1c3RyaWEuJiN4

RDtVbml2ZXJzaXR5IENsaW5pYyBvZiBOZXVyb2xvZ3ksIENocmlzdGlhbi1Eb3BwbGVyLUNsaW5p

YywgU2FsemJ1cmcsIEF1c3RyaWEuJiN4RDtTb2NpYWwgYW5kIE1lZGljYWwgQ2VudHJlIEVhc3Qs

IERhbnViZSBIb3NwaXRhbCwgS2FybCBMYW5kc3RlaW5lciBJbnN0aXR1dGUgZm9yIE1lbW9yeSBh

bmQgQWx6aGVpbWVyIFJlc2VhcmNoLCBWaWVubmEsIEF1c3RyaWEuJiN4RDtEaXZpc2lvbiBvZiBH

ZW5lcmFsIE5ldXJvbG9neSwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIE1lZGljYWwgVW5pdmVy

c2l0eSBHcmF6LCBHcmF6LCBBdXN0cmlhLiYjeEQ7S2Fyb2xpbnNrYSBJbnN0aXR1dGUgQWx6aGVp

bWVyIERpc2Vhc2UgUmVzZWFyY2ggQ2VudHJlIGFuZCBDbGluaWNhbCBUcmlhbCBVbml0LCBHZXJp

YXRyaWMgQ2xpbmljLCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCBT

d2VkZW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+U2FmZXR5IGFuZCBpbW11bm9nZW5p

Y2l0eSBvZiB0aGUgdGF1IHZhY2NpbmUgQUFEdmFjMSBpbiBwYXRpZW50cyB3aXRoIEFsemhlaW1l

ciZhcG9zO3MgZGlzZWFzZTogYSByYW5kb21pc2VkLCBkb3VibGUtYmxpbmQsIHBsYWNlYm8tY29u

dHJvbGxlZCwgcGhhc2UgMSB0cmlhbDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5MYW5jZXQgTmV1

cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEyMy0xMzQ8L3BhZ2VzPjx2b2x1

bWU+MTY8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48ZWRpdGlvbj4yMDE2LzEyLzE0PC9lZGl0

aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFu

ZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLyp0aGVyYXB5PC9rZXl3

b3JkPjxrZXl3b3JkPkFsemhlaW1lciBWYWNjaW5lcy9hZHZlcnNlIGVmZmVjdHMvKnBoYXJtYWNv

bG9neTwva2V5d29yZD48a2V5d29yZD5Eb3VibGUtQmxpbmQgTWV0aG9kPC9rZXl3b3JkPjxrZXl3

b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1t

dW5vdGhlcmFweS9hZHZlcnNlIGVmZmVjdHMvKm1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFs

ZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD4qT3V0Y29t

ZSBBc3Nlc3NtZW50IChIZWFsdGggQ2FyZSk8L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5z

LyppbW11bm9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5GZWI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDc0

LTQ0NjUgKEVsZWN0cm9uaWMpJiN4RDsxNDc0LTQ0MjIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI3OTU1OTk1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNzk1NTk5NTwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMTQ3NC00NDIy

KDE2KTMwMzMxLTM8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0Vu

ZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ob3ZhazwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

Y051bT4yMDgzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTc8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDgzPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NjE1NzUiPjIwODM8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk5vdmFrLCBQLjwvYXV0aG9yPjxhdXRob3I+

U2NobWlkdCwgUi48L2F1dGhvcj48YXV0aG9yPktvbnRzZWtvdmEsIEUuPC9hdXRob3I+PGF1dGhv

cj5aaWxrYSwgTi48L2F1dGhvcj48YXV0aG9yPktvdmFjZWNoLCBCLjwvYXV0aG9yPjxhdXRob3I+

U2tyYWJhbmEsIFIuPC9hdXRob3I+PGF1dGhvcj5WaW5jZS1LYXptZXJvdmEsIFouPC9hdXRob3I+

PGF1dGhvcj5LYXRpbmEsIFMuPC9hdXRob3I+PGF1dGhvcj5GaWFsb3ZhLCBMLjwvYXV0aG9yPjxh

dXRob3I+UHJjaW5hLCBNLjwvYXV0aG9yPjxhdXRob3I+UGFycmFrLCBWLjwvYXV0aG9yPjxhdXRo

b3I+RGFsLUJpYW5jbywgUC48L2F1dGhvcj48YXV0aG9yPkJydW5uZXIsIE0uPC9hdXRob3I+PGF1

dGhvcj5TdGFmZmVuLCBXLjwvYXV0aG9yPjxhdXRob3I+UmFpbmVyLCBNLjwvYXV0aG9yPjxhdXRo

b3I+T25kcnVzLCBNLjwvYXV0aG9yPjxhdXRob3I+Um9wZWxlLCBTLjwvYXV0aG9yPjxhdXRob3I+

U21pc2VrLCBNLjwvYXV0aG9yPjxhdXRob3I+U2l2YWssIFIuPC9hdXRob3I+PGF1dGhvcj5XaW5i

bGFkLCBCLjwvYXV0aG9yPjxhdXRob3I+Tm92YWssIE0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+QVhPTiBOZXVyb3NjaWVuY2UgU0UsIEJyYXRpc2xhdmEs

IFNsb3Zha2lhLiBFbGVjdHJvbmljIGFkZHJlc3M6IHBldHIubm92YWtAYXhvbi1uZXVyb3NjaWVu

Y2UuZXUuJiN4RDtDbGluaWNhbCBEaXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIERlcGFydG1l

bnQgb2YgTmV1cm9sb2d5LCBNZWRpY2FsIFVuaXZlcnNpdHkgR3JheiwgR3JheiwgQXVzdHJpYS4m

I3hEO0FYT04gTmV1cm9zY2llbmNlIFNFLCBCcmF0aXNsYXZhLCBTbG92YWtpYS4mI3hEO1VuaXZl

cnNpdHkgQ2xpbmljIG9mIE5ldXJvbG9neSwgTWVkaWNhbCBVbml2ZXJzaXR5IG9mIFZpZW5uYSwg

Vmllbm5hLCBBdXN0cmlhLiYjeEQ7VW5pdmVyc2l0eSBDbGluaWMgb2YgQ2xpbmljYWwgUGhhcm1h

Y29sb2d5LCBNZWRpY2FsIFVuaXZlcnNpdHkgb2YgVmllbm5hLCBWaWVubmEsIEF1c3RyaWEuJiN4

RDtVbml2ZXJzaXR5IENsaW5pYyBvZiBOZXVyb2xvZ3ksIENocmlzdGlhbi1Eb3BwbGVyLUNsaW5p

YywgU2FsemJ1cmcsIEF1c3RyaWEuJiN4RDtTb2NpYWwgYW5kIE1lZGljYWwgQ2VudHJlIEVhc3Qs

IERhbnViZSBIb3NwaXRhbCwgS2FybCBMYW5kc3RlaW5lciBJbnN0aXR1dGUgZm9yIE1lbW9yeSBh

bmQgQWx6aGVpbWVyIFJlc2VhcmNoLCBWaWVubmEsIEF1c3RyaWEuJiN4RDtEaXZpc2lvbiBvZiBH

ZW5lcmFsIE5ldXJvbG9neSwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIE1lZGljYWwgVW5pdmVy

c2l0eSBHcmF6LCBHcmF6LCBBdXN0cmlhLiYjeEQ7S2Fyb2xpbnNrYSBJbnN0aXR1dGUgQWx6aGVp

bWVyIERpc2Vhc2UgUmVzZWFyY2ggQ2VudHJlIGFuZCBDbGluaWNhbCBUcmlhbCBVbml0LCBHZXJp

YXRyaWMgQ2xpbmljLCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCBT

d2VkZW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+U2FmZXR5IGFuZCBpbW11bm9nZW5p

Y2l0eSBvZiB0aGUgdGF1IHZhY2NpbmUgQUFEdmFjMSBpbiBwYXRpZW50cyB3aXRoIEFsemhlaW1l

ciZhcG9zO3MgZGlzZWFzZTogYSByYW5kb21pc2VkLCBkb3VibGUtYmxpbmQsIHBsYWNlYm8tY29u

dHJvbGxlZCwgcGhhc2UgMSB0cmlhbDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5MYW5jZXQgTmV1

cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEyMy0xMzQ8L3BhZ2VzPjx2b2x1

bWU+MTY8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48ZWRpdGlvbj4yMDE2LzEyLzE0PC9lZGl0

aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFu

ZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLyp0aGVyYXB5PC9rZXl3

b3JkPjxrZXl3b3JkPkFsemhlaW1lciBWYWNjaW5lcy9hZHZlcnNlIGVmZmVjdHMvKnBoYXJtYWNv

bG9neTwva2V5d29yZD48a2V5d29yZD5Eb3VibGUtQmxpbmQgTWV0aG9kPC9rZXl3b3JkPjxrZXl3

b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1t

dW5vdGhlcmFweS9hZHZlcnNlIGVmZmVjdHMvKm1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFs

ZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD4qT3V0Y29t

ZSBBc3Nlc3NtZW50IChIZWFsdGggQ2FyZSk8L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5z

LyppbW11bm9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5GZWI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDc0

LTQ0NjUgKEVsZWN0cm9uaWMpJiN4RDsxNDc0LTQ0MjIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI3OTU1OTk1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNzk1NTk5NTwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMTQ3NC00NDIy

KDE2KTMwMzMxLTM8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0Vu

ZE5vdGU+

ADDIN EN.CITE.DATA 17. Unfortunately, a few large pharmaceutical companies have decided to stop their research on AD and redirect their efforts to other disorders ADDIN EN.CITE <EndNote><Cite><Author>Jobke</Author><Year>2018</Year><RecNum>3218</RecNum><DisplayText><style face="superscript">18</style></DisplayText><record><rec-number>3218</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535384060">3218</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jobke, B.</author><author>McBride, T.</author><author>Nevin, L.</author><author>Peiperl, L.</author><author>Ross, A.</author><author>Stone, C.</author><author>Turner, R.</author><author>as the, Plos Medicine Editors</author></authors></contributors><auth-address>Public Library of Science, San Francisco, California, United States of America, and Cambridge, United Kingdom.</auth-address><titles><title>Setbacks in Alzheimer research demand new strategies, not surrender</title><secondary-title>PLoS Med</secondary-title></titles><pages>e1002518</pages><volume>15</volume><number>2</number><dates><year>2018</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1549-1676 (Electronic)&#xD;1549-1277 (Linking)</isbn><accession-num>29486005</accession-num><urls><related-urls><url>. Moreover, some failed clinical trials also led to the scientific community to explore additional hypotheses for AD pathogenesis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJkeTwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

Y051bT4yMTI1PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTktMjM8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMTI1PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NjM3MTEiPjIxMjU8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhhcmR5LCBKLjwvYXV0aG9yPjxhdXRo

b3I+RGUgU3Ryb29wZXIsIEIuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRs

ZXM+PHRpdGxlPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogd2hlcmUgbmV4dCBmb3IgYW50aS1h

bXlsb2lkIHRoZXJhcGllcz88L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QnJhaW48L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5CcmFpbjwvZnVsbC10aXRs

ZT48L3BlcmlvZGljYWw+PHBhZ2VzPjg1My04NTU8L3BhZ2VzPjx2b2x1bWU+MTQwPC92b2x1bWU+

PG51bWJlcj40PC9udW1iZXI+PGVkaXRpb24+MjAxNy8wNC8wNTwvZWRpdGlvbj48ZGF0ZXM+PHll

YXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkFwciAxPC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PGlzYm4+MTQ2MC0yMTU2IChFbGVjdHJvbmljKSYjeEQ7MDAwNi04OTUwIChMaW5raW5n

KTwvaXNibj48YWNjZXNzaW9uLW51bT4yODM3NTQ2MTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVs

YXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjgzNzU0

NjE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEw

LjEwOTMvYnJhaW4vYXd4MDU5PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5QdWdhemhlbnRoaTwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

Y051bT4xMjQ8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEyNDwvcmVjLW51bWJlcj48Zm9y

ZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InN3d3I1NXNzNDJydjJ6ZTl3MnM1MHQ5c3gy

OXR0YTAycDV0ZSIgdGltZXN0YW1wPSIxNTM2MjI3MzQzIj4xMjQ8L2tleT48L2ZvcmVpZ24ta2V5

cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1

dG9ycz48YXV0aG9ycz48YXV0aG9yPlB1Z2F6aGVudGhpLCBTLjwvYXV0aG9yPjwvYXV0aG9ycz48

L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlVuaXZlcnNpdHkgb2YgQ29sb3JhZG8sIEF1cm9y

YSwgQ08sIFVuaXRlZCBTdGF0ZXM7IEVhc3Rlcm4gQ29sb3JhZG8gSGVhbHRoIENhcmUgU3lzdGVt

LCBEZW52ZXIsIENPLCBVbml0ZWQgU3RhdGVzLiBFbGVjdHJvbmljIGFkZHJlc3M6IHN1YmJpYWgu

cHVnYXpoZW50aGlAdWNkZW52ZXIuZWR1LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPk1l

dGFib2xpYyBTeW5kcm9tZSBhbmQgdGhlIENlbGx1bGFyIFBoYXNlIG9mIEFsemhlaW1lciZhcG9z

O3MgRGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Qcm9nIE1vbCBCaW9sIFRyYW5zbCBT

Y2k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Qcm9n

IE1vbCBCaW9sIFRyYW5zbCBTY2k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yNDMt

MjU4PC9wYWdlcz48dm9sdW1lPjE0Njwvdm9sdW1lPjxlZGl0aW9uPjIwMTcvMDMvMDQ8L2VkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypjb21wbGljYXRpb25zLypw

YXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkluZmxh

bW1hdGlvbi9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWV0YWJvbGljIFN5bmRyb21lLypj

b21wbGljYXRpb25zLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWljcm9nbGlhL3BhdGhv

bG9neTwva2V5d29yZD48a2V5d29yZD5Nb2RlbHMsIEJpb2xvZ2ljYWw8L2tleXdvcmQ+PGtleXdv

cmQ+U2lydHVpbiAzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+KkFsemhlaW1lciZhcG9z

O3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD4qQmxvb2QtYnJhaW4gYmFycmllcjwva2V5d29y

ZD48a2V5d29yZD4qTWV0YWJvbGljIHN5bmRyb21lPC9rZXl3b3JkPjxrZXl3b3JkPipNaWNyb2ds

aWE8L2tleXdvcmQ+PGtleXdvcmQ+Kk1pdG9jaG9uZHJpYTwva2V5d29yZD48a2V5d29yZD4qTmV1

cm9pbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+Kk5ldXJvdmFzY3VsYXIgdW5pdCBhbmQg

Y2VyZWJyYWwgaXNjaGVtaWE8L2tleXdvcmQ+PGtleXdvcmQ+KlNpcnR1aW4gcGF0aHdheTwva2V5

d29yZD48a2V5d29yZD4qVmFzY3VsYXIgZGVtZW50aWE8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0

ZXM+PHllYXI+MjAxNzwveWVhcj48L2RhdGVzPjxpc2JuPjE4NzgtMDgxNCAoRWxlY3Ryb25pYykm

I3hEOzE4NzctMTE3MyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjgyNTM5ODc8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxt

Lm5paC5nb3YvcHVibWVkLzI4MjUzOTg3PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVj

dHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2JzLnBtYnRzLjIwMTYuMTIuMDE2PC9lbGVjdHJv

bmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5EZSBTdHJvb3Bl

cjwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051bT4yMTc0PC9SZWNOdW0+PHJlY29yZD48

cmVjLW51bWJlcj4yMTc0PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk

Yi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1

MzQ4NjQxMjEiPjIxNzQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h

bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkRl

IFN0cm9vcGVyLCBCLjwvYXV0aG9yPjxhdXRob3I+S2FycmFuLCBFLjwvYXV0aG9yPjwvYXV0aG9y

cz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlZJQiBDZW50ZXIgZm9yIHRoZSBCaW9sb2d5

IG9mIERpc2Vhc2UsIFZJQi1MZXV2ZW4sIDMwMDAgTGV1dmVuLCBCZWxnaXVtOyBDZW50ZXIgZm9y

IEh1bWFuIEdlbmV0aWNzLCBVbml2ZXJzaXRhaXJlIFppZWtlbmh1aXplbiBhbmQgTElORCwgS1Ug

TGV1dmVuLCAzMDAwIExldXZlbiwgQmVsZ2l1bTsgSW5zdGl0dXRlIG9mIE5ldXJvbG9neSwgVW5p

dmVyc2l0eSBDb2xsZWdlIExvbmRvbiwgUXVlZW4gU3F1YXJlLCBXQzFOIDNCRyBMb25kb24sIFVL

LiBFbGVjdHJvbmljIGFkZHJlc3M6IGJhcnQuZGVzdHJvb3BlckBjbWUudmliLWt1bGV1dmVuLmJl

LiYjeEQ7Q2VudGVyIGZvciBIdW1hbiBHZW5ldGljcywgVW5pdmVyc2l0YWlyZSBaaWVrZW5odWl6

ZW4gYW5kIExJTkQsIEtVIExldXZlbiwgMzAwMCBMZXV2ZW4sIEJlbGdpdW07IEluc3RpdHV0ZSBv

ZiBOZXVyb2xvZ3ksIFVuaXZlcnNpdHkgQ29sbGVnZSBMb25kb24sIFF1ZWVuIFNxdWFyZSwgV0Mx

TiAzQkcgTG9uZG9uLCBVSzsgQWx6aGVpbWVyIFJlc2VhcmNoIFVLLCBDYW1icmlkZ2UsIENCMjEg

NkFELCBVSy48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5UaGUgQ2VsbHVsYXIgUGhhc2Ug

b2YgQWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNlbGw8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5DZWxsPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NjAzLTE1PC9wYWdlcz48dm9sdW1lPjE2NDwv

dm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxlZGl0aW9uPjIwMTYvMDIvMTM8L2VkaXRpb24+PGtl

eXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL21ldGFib2xpc20vKnBhdGhvbG9neS9w

aHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL21l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5Bc3Ry

b2N5dGVzL21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL3BhdGhv

bG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5

d29yZD48a2V5d29yZD5NaWNyb2dsaWEvbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+TmV1cmFsIFBhdGh3YXlzPC9rZXl3b3JkPjxrZXl3b3JkPk9saWdvZGVuZHJvZ2xpYS9w

YXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+U2luZ2xlLUNlbGwgQW5hbHlzaXM8L2tleXdvcmQ+

PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkZlYiAx

MTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjEwOTctNDE3MiAoRWxlY3Ryb25pYykm

I3hEOzAwOTItODY3NCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjY4NzE2Mjc8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxt

Lm5paC5nb3YvcHVibWVkLzI2ODcxNjI3PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVj

dHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ouY2VsbC4yMDE1LjEyLjA1NjwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TWNHZWVyPC9BdXRo

b3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVtPjIxNDA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVt

YmVyPjIxNDA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJm

d2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDg2Mzc5

OSI+MjE0MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj

bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWNHZWVyLCBQ

LiBMLjwvYXV0aG9yPjxhdXRob3I+TWNHZWVyLCBFLiBHLjwvYXV0aG9yPjwvYXV0aG9ycz48L2Nv

bnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPktpbnNtZW4gTGFib3JhdG9yeSBvZiBOZXVyb2xvZ2lj

YWwgUmVzZWFyY2gsIFVuaXZlcnNpdHkgb2YgQnJpdGlzaCBDb2x1bWJpYSwgMjI1NSBXZXNicm9v

ayBNYWxsLCBWYW5jb3V2ZXIsIEJDLCBWNlQxWjMsIENhbmFkYSwgbWNnZWVycGxAbWFpbC51YmMu

Y2EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGhlIGFteWxvaWQgY2FzY2FkZS1pbmZs

YW1tYXRvcnkgaHlwb3RoZXNpcyBvZiBBbHpoZWltZXIgZGlzZWFzZTogaW1wbGljYXRpb25zIGZv

ciB0aGVyYXB5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFjdGEgTmV1cm9wYXRob2w8L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BY3RhIE5ldXJvcGF0

aG9sPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NDc5LTk3PC9wYWdlcz48dm9sdW1l

PjEyNjwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxlZGl0aW9uPjIwMTMvMDkvMjE8L2VkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypnZW5ldGljcy9tZXRhYm9s

aXNtL3BhdGhvbG9neS8qdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgVmFjY2lu

ZXMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQvKmdlbmV0aWNzPC9r

ZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9nZW5ldGljczwva2V5d29yZD48

a2V5d29yZD5BbXlsb2lkIGJldGEtUHJvdGVpbiBQcmVjdXJzb3IvZ2VuZXRpY3M8L2tleXdvcmQ+

PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BbmltYWxzLCBHZW5ldGljYWxseSBN

b2RpZmllZDwva2V5d29yZD48a2V5d29yZD5BbnRpLUluZmxhbW1hdG9yeSBBZ2VudHMvdGhlcmFw

ZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFudGktSW5mbGFtbWF0b3J5IEFnZW50cywgTm9u

LVN0ZXJvaWRhbC90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aW94aWRhbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5CaW9tYXJrZXJzPC9rZXl3b3JkPjxr

ZXl3b3JkPkRpZXQ8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPklt

bXVuaXphdGlvbjwva2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb24vKmdlbmV0aWNzL21ldGFi

b2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk11dGF0aW9uL2dlbmV0aWNzPC9rZXl3

b3JkPjxrZXl3b3JkPlBlcHRpZGUgRnJhZ21lbnRzL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3Jk

PlRyYW5zbGF0aW9uYWwgTWVkaWNhbCBSZXNlYXJjaDwva2V5d29yZD48L2tleXdvcmRzPjxkYXRl

cz48eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+T2N0PC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PGlzYm4+MTQzMi0wNTMzIChFbGVjdHJvbmljKSYjeEQ7MDAwMS02MzIyIChMaW5r

aW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNDA1MjEwODwvYWNjZXNzaW9uLW51bT48dXJscz48

cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjQw

NTIxMDg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjEwLjEwMDcvczAwNDAxLTAxMy0xMTc3LTc8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVj

b3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlNhcmF6aW48L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFy

PjxSZWNOdW0+MjI0MjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MjI0MjwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhw

Znd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0OTI3Nzk4Ij4yMjQyPC9rZXk+PC9mb3Jl

aWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxj

b250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TYXJhemluLCBNLjwvYXV0aG9yPjxhdXRob3I+

RG9yb3RoZWUsIEcuPC9hdXRob3I+PGF1dGhvcj5kZSBTb3V6YSwgTC4gQy48L2F1dGhvcj48YXV0

aG9yPkF1Y291dHVyaWVyLCBQLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0

aC1hZGRyZXNzPlVuaXZlcnNpdGUgUGFyaXMgRGVzY2FydGVzLCBTb3Jib25uZSBQYXJpcyBDaXRl

LCBGcmFuY2UuIG1hcmllLnNhcmF6aW5AcHNsLmFwaHAuZnI8L2F1dGgtYWRkcmVzcz48dGl0bGVz

Pjx0aXRsZT5JbW11bm90aGVyYXB5IGluIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogZG8gd2Ug

aGF2ZSBhbGwgdGhlIHBpZWNlcyBvZiB0aGUgcHV6emxlPzwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5CaW9sIFBzeWNoaWF0cnk8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5CaW9sIFBzeWNoaWF0cnk8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdl

cz4zMjktMzI8L3BhZ2VzPjx2b2x1bWU+NzQ8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48ZWRp

dGlvbj4yMDEzLzA1LzIxPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlz

ZWFzZS8qdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvaW1t

dW5vbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+KkltbXVu

b3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3

b3JkPjxrZXl3b3JkPmFteWxvaWQgYmV0YTwva2V5d29yZD48a2V5d29yZD5hbnRpYm9kaWVzPC9r

ZXl3b3JkPjxrZXl3b3JkPmNlbGx1bGFyIGltbXVuaXR5PC9rZXl3b3JkPjxrZXl3b3JkPmNlcmVi

cmFsIGFteWxvaWQgYW5naW9wYXRoeTwva2V5d29yZD48a2V5d29yZD5pbW11bm90aGVyYXB5PC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5TZXAgMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE4NzMtMjQwMiAoRWxlY3Ry

b25pYykmI3hEOzAwMDYtMzIyMyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjM2ODM2

NTY8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5j

YmkubmxtLm5paC5nb3YvcHVibWVkLzIzNjgzNjU2PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxz

PjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ouYmlvcHN5Y2guMjAxMy4wNC4wMTE8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJkeTwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

Y051bT4yMTI1PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTktMjM8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMTI1PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NjM3MTEiPjIxMjU8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhhcmR5LCBKLjwvYXV0aG9yPjxhdXRo

b3I+RGUgU3Ryb29wZXIsIEIuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRs

ZXM+PHRpdGxlPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogd2hlcmUgbmV4dCBmb3IgYW50aS1h

bXlsb2lkIHRoZXJhcGllcz88L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QnJhaW48L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5CcmFpbjwvZnVsbC10aXRs

ZT48L3BlcmlvZGljYWw+PHBhZ2VzPjg1My04NTU8L3BhZ2VzPjx2b2x1bWU+MTQwPC92b2x1bWU+

PG51bWJlcj40PC9udW1iZXI+PGVkaXRpb24+MjAxNy8wNC8wNTwvZWRpdGlvbj48ZGF0ZXM+PHll

YXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkFwciAxPC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PGlzYm4+MTQ2MC0yMTU2IChFbGVjdHJvbmljKSYjeEQ7MDAwNi04OTUwIChMaW5raW5n

KTwvaXNibj48YWNjZXNzaW9uLW51bT4yODM3NTQ2MTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVs

YXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjgzNzU0

NjE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEw

LjEwOTMvYnJhaW4vYXd4MDU5PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5QdWdhemhlbnRoaTwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

Y051bT4xMjQ8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEyNDwvcmVjLW51bWJlcj48Zm9y

ZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InN3d3I1NXNzNDJydjJ6ZTl3MnM1MHQ5c3gy

OXR0YTAycDV0ZSIgdGltZXN0YW1wPSIxNTM2MjI3MzQzIj4xMjQ8L2tleT48L2ZvcmVpZ24ta2V5

cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1

dG9ycz48YXV0aG9ycz48YXV0aG9yPlB1Z2F6aGVudGhpLCBTLjwvYXV0aG9yPjwvYXV0aG9ycz48

L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlVuaXZlcnNpdHkgb2YgQ29sb3JhZG8sIEF1cm9y

YSwgQ08sIFVuaXRlZCBTdGF0ZXM7IEVhc3Rlcm4gQ29sb3JhZG8gSGVhbHRoIENhcmUgU3lzdGVt

LCBEZW52ZXIsIENPLCBVbml0ZWQgU3RhdGVzLiBFbGVjdHJvbmljIGFkZHJlc3M6IHN1YmJpYWgu

cHVnYXpoZW50aGlAdWNkZW52ZXIuZWR1LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPk1l

dGFib2xpYyBTeW5kcm9tZSBhbmQgdGhlIENlbGx1bGFyIFBoYXNlIG9mIEFsemhlaW1lciZhcG9z

O3MgRGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Qcm9nIE1vbCBCaW9sIFRyYW5zbCBT

Y2k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Qcm9n

IE1vbCBCaW9sIFRyYW5zbCBTY2k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yNDMt

MjU4PC9wYWdlcz48dm9sdW1lPjE0Njwvdm9sdW1lPjxlZGl0aW9uPjIwMTcvMDMvMDQ8L2VkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypjb21wbGljYXRpb25zLypw

YXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkluZmxh

bW1hdGlvbi9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWV0YWJvbGljIFN5bmRyb21lLypj

b21wbGljYXRpb25zLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWljcm9nbGlhL3BhdGhv

bG9neTwva2V5d29yZD48a2V5d29yZD5Nb2RlbHMsIEJpb2xvZ2ljYWw8L2tleXdvcmQ+PGtleXdv

cmQ+U2lydHVpbiAzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+KkFsemhlaW1lciZhcG9z

O3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD4qQmxvb2QtYnJhaW4gYmFycmllcjwva2V5d29y

ZD48a2V5d29yZD4qTWV0YWJvbGljIHN5bmRyb21lPC9rZXl3b3JkPjxrZXl3b3JkPipNaWNyb2ds

aWE8L2tleXdvcmQ+PGtleXdvcmQ+Kk1pdG9jaG9uZHJpYTwva2V5d29yZD48a2V5d29yZD4qTmV1

cm9pbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+Kk5ldXJvdmFzY3VsYXIgdW5pdCBhbmQg

Y2VyZWJyYWwgaXNjaGVtaWE8L2tleXdvcmQ+PGtleXdvcmQ+KlNpcnR1aW4gcGF0aHdheTwva2V5

d29yZD48a2V5d29yZD4qVmFzY3VsYXIgZGVtZW50aWE8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0

ZXM+PHllYXI+MjAxNzwveWVhcj48L2RhdGVzPjxpc2JuPjE4NzgtMDgxNCAoRWxlY3Ryb25pYykm

I3hEOzE4NzctMTE3MyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjgyNTM5ODc8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxt

Lm5paC5nb3YvcHVibWVkLzI4MjUzOTg3PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVj

dHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2JzLnBtYnRzLjIwMTYuMTIuMDE2PC9lbGVjdHJv

bmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5EZSBTdHJvb3Bl

cjwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051bT4yMTc0PC9SZWNOdW0+PHJlY29yZD48

cmVjLW51bWJlcj4yMTc0PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk

Yi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1

MzQ4NjQxMjEiPjIxNzQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h

bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkRl

IFN0cm9vcGVyLCBCLjwvYXV0aG9yPjxhdXRob3I+S2FycmFuLCBFLjwvYXV0aG9yPjwvYXV0aG9y

cz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlZJQiBDZW50ZXIgZm9yIHRoZSBCaW9sb2d5

IG9mIERpc2Vhc2UsIFZJQi1MZXV2ZW4sIDMwMDAgTGV1dmVuLCBCZWxnaXVtOyBDZW50ZXIgZm9y

IEh1bWFuIEdlbmV0aWNzLCBVbml2ZXJzaXRhaXJlIFppZWtlbmh1aXplbiBhbmQgTElORCwgS1Ug

TGV1dmVuLCAzMDAwIExldXZlbiwgQmVsZ2l1bTsgSW5zdGl0dXRlIG9mIE5ldXJvbG9neSwgVW5p

dmVyc2l0eSBDb2xsZWdlIExvbmRvbiwgUXVlZW4gU3F1YXJlLCBXQzFOIDNCRyBMb25kb24sIFVL

LiBFbGVjdHJvbmljIGFkZHJlc3M6IGJhcnQuZGVzdHJvb3BlckBjbWUudmliLWt1bGV1dmVuLmJl

LiYjeEQ7Q2VudGVyIGZvciBIdW1hbiBHZW5ldGljcywgVW5pdmVyc2l0YWlyZSBaaWVrZW5odWl6

ZW4gYW5kIExJTkQsIEtVIExldXZlbiwgMzAwMCBMZXV2ZW4sIEJlbGdpdW07IEluc3RpdHV0ZSBv

ZiBOZXVyb2xvZ3ksIFVuaXZlcnNpdHkgQ29sbGVnZSBMb25kb24sIFF1ZWVuIFNxdWFyZSwgV0Mx

TiAzQkcgTG9uZG9uLCBVSzsgQWx6aGVpbWVyIFJlc2VhcmNoIFVLLCBDYW1icmlkZ2UsIENCMjEg

NkFELCBVSy48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5UaGUgQ2VsbHVsYXIgUGhhc2Ug

b2YgQWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNlbGw8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5DZWxsPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NjAzLTE1PC9wYWdlcz48dm9sdW1lPjE2NDwv

dm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxlZGl0aW9uPjIwMTYvMDIvMTM8L2VkaXRpb24+PGtl

eXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL21ldGFib2xpc20vKnBhdGhvbG9neS9w

aHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL21l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5Bc3Ry

b2N5dGVzL21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL3BhdGhv

bG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5

d29yZD48a2V5d29yZD5NaWNyb2dsaWEvbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+TmV1cmFsIFBhdGh3YXlzPC9rZXl3b3JkPjxrZXl3b3JkPk9saWdvZGVuZHJvZ2xpYS9w

YXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+U2luZ2xlLUNlbGwgQW5hbHlzaXM8L2tleXdvcmQ+

PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkZlYiAx

MTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjEwOTctNDE3MiAoRWxlY3Ryb25pYykm

I3hEOzAwOTItODY3NCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjY4NzE2Mjc8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxt

Lm5paC5nb3YvcHVibWVkLzI2ODcxNjI3PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVj

dHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ouY2VsbC4yMDE1LjEyLjA1NjwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TWNHZWVyPC9BdXRo

b3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVtPjIxNDA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVt

YmVyPjIxNDA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJm

d2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDg2Mzc5

OSI+MjE0MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj

bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWNHZWVyLCBQ

LiBMLjwvYXV0aG9yPjxhdXRob3I+TWNHZWVyLCBFLiBHLjwvYXV0aG9yPjwvYXV0aG9ycz48L2Nv

bnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPktpbnNtZW4gTGFib3JhdG9yeSBvZiBOZXVyb2xvZ2lj

YWwgUmVzZWFyY2gsIFVuaXZlcnNpdHkgb2YgQnJpdGlzaCBDb2x1bWJpYSwgMjI1NSBXZXNicm9v

ayBNYWxsLCBWYW5jb3V2ZXIsIEJDLCBWNlQxWjMsIENhbmFkYSwgbWNnZWVycGxAbWFpbC51YmMu

Y2EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGhlIGFteWxvaWQgY2FzY2FkZS1pbmZs

YW1tYXRvcnkgaHlwb3RoZXNpcyBvZiBBbHpoZWltZXIgZGlzZWFzZTogaW1wbGljYXRpb25zIGZv

ciB0aGVyYXB5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFjdGEgTmV1cm9wYXRob2w8L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BY3RhIE5ldXJvcGF0

aG9sPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NDc5LTk3PC9wYWdlcz48dm9sdW1l

PjEyNjwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxlZGl0aW9uPjIwMTMvMDkvMjE8L2VkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypnZW5ldGljcy9tZXRhYm9s

aXNtL3BhdGhvbG9neS8qdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgVmFjY2lu

ZXMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQvKmdlbmV0aWNzPC9r

ZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9nZW5ldGljczwva2V5d29yZD48

a2V5d29yZD5BbXlsb2lkIGJldGEtUHJvdGVpbiBQcmVjdXJzb3IvZ2VuZXRpY3M8L2tleXdvcmQ+

PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BbmltYWxzLCBHZW5ldGljYWxseSBN

b2RpZmllZDwva2V5d29yZD48a2V5d29yZD5BbnRpLUluZmxhbW1hdG9yeSBBZ2VudHMvdGhlcmFw

ZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFudGktSW5mbGFtbWF0b3J5IEFnZW50cywgTm9u

LVN0ZXJvaWRhbC90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aW94aWRhbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5CaW9tYXJrZXJzPC9rZXl3b3JkPjxr

ZXl3b3JkPkRpZXQ8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPklt

bXVuaXphdGlvbjwva2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb24vKmdlbmV0aWNzL21ldGFi

b2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk11dGF0aW9uL2dlbmV0aWNzPC9rZXl3

b3JkPjxrZXl3b3JkPlBlcHRpZGUgRnJhZ21lbnRzL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3Jk

PlRyYW5zbGF0aW9uYWwgTWVkaWNhbCBSZXNlYXJjaDwva2V5d29yZD48L2tleXdvcmRzPjxkYXRl

cz48eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+T2N0PC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PGlzYm4+MTQzMi0wNTMzIChFbGVjdHJvbmljKSYjeEQ7MDAwMS02MzIyIChMaW5r

aW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNDA1MjEwODwvYWNjZXNzaW9uLW51bT48dXJscz48

cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjQw

NTIxMDg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjEwLjEwMDcvczAwNDAxLTAxMy0xMTc3LTc8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVj

b3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlNhcmF6aW48L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFy

PjxSZWNOdW0+MjI0MjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MjI0MjwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhw

Znd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0OTI3Nzk4Ij4yMjQyPC9rZXk+PC9mb3Jl

aWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxj

b250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TYXJhemluLCBNLjwvYXV0aG9yPjxhdXRob3I+

RG9yb3RoZWUsIEcuPC9hdXRob3I+PGF1dGhvcj5kZSBTb3V6YSwgTC4gQy48L2F1dGhvcj48YXV0

aG9yPkF1Y291dHVyaWVyLCBQLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0

aC1hZGRyZXNzPlVuaXZlcnNpdGUgUGFyaXMgRGVzY2FydGVzLCBTb3Jib25uZSBQYXJpcyBDaXRl

LCBGcmFuY2UuIG1hcmllLnNhcmF6aW5AcHNsLmFwaHAuZnI8L2F1dGgtYWRkcmVzcz48dGl0bGVz

Pjx0aXRsZT5JbW11bm90aGVyYXB5IGluIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogZG8gd2Ug

aGF2ZSBhbGwgdGhlIHBpZWNlcyBvZiB0aGUgcHV6emxlPzwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5CaW9sIFBzeWNoaWF0cnk8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5CaW9sIFBzeWNoaWF0cnk8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdl

cz4zMjktMzI8L3BhZ2VzPjx2b2x1bWU+NzQ8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48ZWRp

dGlvbj4yMDEzLzA1LzIxPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlz

ZWFzZS8qdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvaW1t

dW5vbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+KkltbXVu

b3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3

b3JkPjxrZXl3b3JkPmFteWxvaWQgYmV0YTwva2V5d29yZD48a2V5d29yZD5hbnRpYm9kaWVzPC9r

ZXl3b3JkPjxrZXl3b3JkPmNlbGx1bGFyIGltbXVuaXR5PC9rZXl3b3JkPjxrZXl3b3JkPmNlcmVi

cmFsIGFteWxvaWQgYW5naW9wYXRoeTwva2V5d29yZD48a2V5d29yZD5pbW11bm90aGVyYXB5PC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5TZXAgMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE4NzMtMjQwMiAoRWxlY3Ry

b25pYykmI3hEOzAwMDYtMzIyMyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjM2ODM2

NTY8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5j

YmkubmxtLm5paC5nb3YvcHVibWVkLzIzNjgzNjU2PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxz

PjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ouYmlvcHN5Y2guMjAxMy4wNC4wMTE8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 19-23. Therefore, it has become more important to come up with novel strategies and targets that will effectively alter in any form the progression and the underlying causes of memory loss in AD. Novel evidence behind alternative mechanisms of the disease and improvements in technology from imaging to gene editing have opened new lines of research that could help to explain the origin and progression of AD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb2VyYS1WYWxlbmNpYTwvQXV0aG9yPjxZZWFyPjIwMTg8

L1llYXI+PFJlY051bT4zNjg8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVy

c2NyaXB0Ij4yNC0yNzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM2

ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUy

cHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTQ5MDEyIj4zNjg8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkxvZXJhLVZhbGVuY2lhLCBS

LjwvYXV0aG9yPjxhdXRob3I+UGlyYXMsIEEuPC9hdXRob3I+PGF1dGhvcj5Jc21haWwsIE0uIEEu

IE0uPC9hdXRob3I+PGF1dGhvcj5NYW5jaGFuZGEsIFMuPC9hdXRob3I+PGF1dGhvcj5FeWpvbGZz

ZG90dGlyLCBILjwvYXV0aG9yPjxhdXRob3I+U2FpZG8sIFQuIEMuPC9hdXRob3I+PGF1dGhvcj5K

b2hhbnNzb24sIEouPC9hdXRob3I+PGF1dGhvcj5Fcmlrc2RvdHRlciwgTS48L2F1dGhvcj48YXV0

aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5OaWxzc29uLCBQLjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0

cmljcywgRGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2ll

dHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBLYXJvbGluc2thIEluc3RpdHV0ZXQs

IFNvbG5hLCBTd2VkZW4uJiN4RDtUaGVtZSBOZXVybywgRGlzZWFzZXMgb2YgdGhlIE5lcnZvdXMg

U3lzdGVtIFBhdGllbnQgRmxvdywgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIdWRk

aW5nZSwgU3dlZGVuLiYjeEQ7RGl2aXNpb24gb2YgQ2xpbmljYWwgR2VyaWF0cmljcywgRGVwYXJ0

bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIEthcm9saW5z

a2EgSW5zdGl0dXRldCwgSHVkZGluZ2UsIFN3ZWRlbi4mI3hEO1RoZW1lIEFnaW5nLCBLYXJvbGlu

c2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtSSUtFTiBCcmFp

biBTY2llbmNlIEluc3RpdHV0ZSwgV2FrbywgU2FpdGFtYSwgSmFwYW4uPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+VGFyZ2V0aW5nIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZSB3aXRoIGdl

bmUgYW5kIGNlbGwgdGhlcmFwaWVzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogSW50ZXJuIE1l

ZDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogSW50

ZXJuIE1lZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjItMzY8L3BhZ2VzPjx2b2x1

bWU+Mjg0PC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhl

aW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5jZWxsIHRoZXJhcHk8L2tleXdv

cmQ+PGtleXdvcmQ+Z2VuZSB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPmluZHVjZWQgbmV1cm9n

ZW5lc2lzPC9rZXl3b3JkPjxrZXl3b3JkPm5lcHJpbHlzaW48L2tleXdvcmQ+PGtleXdvcmQ+dGF1

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5KdWw8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMzY1LTI3OTYgKEVsZWN0

cm9uaWMpJiN4RDswOTU0LTY4MjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5NTgy

NDk1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5j

YmkubmxtLm5paC5nb3YvcHVibWVkLzI5NTgyNDk1PC91cmw+PHVybD5odHRwczovL29ubGluZWxp

YnJhcnkud2lsZXkuY29tL2RvaS9wZGYvMTAuMTExMS9qb2ltLjEyNzU5PC91cmw+PC9yZWxhdGVk

LXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTExL2pvaW0uMTI3NTk8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPktl

bXBwYWluZW48L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxSZWNOdW0+MzU4PC9SZWNOdW0+PHJl

Y29yZD48cmVjLW51bWJlcj4zNTg8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFt

cD0iMTUzMjU0ODYzNCI+MzU4PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5LZW1wcGFpbmVuLCBOLjwvYXV0aG9yPjxhdXRob3I+Sm9oYW5zc29uLCBKLjwvYXV0aG9yPjxh

dXRob3I+VGV1aG8sIEouPC9hdXRob3I+PGF1dGhvcj5QYXJra29sYSwgUi48L2F1dGhvcj48YXV0

aG9yPkpvdXRzYSwgSi48L2F1dGhvcj48YXV0aG9yPk5nYW5kdSwgVC48L2F1dGhvcj48YXV0aG9y

PlNvbG9tb24sIEEuPC9hdXRob3I+PGF1dGhvcj5TdGVwaGVuLCBSLjwvYXV0aG9yPjxhdXRob3I+

TGl1LCBZLjwvYXV0aG9yPjxhdXRob3I+SGFubmluZW4sIFQuPC9hdXRob3I+PGF1dGhvcj5QYWFq

YW5lbiwgVC48L2F1dGhvcj48YXV0aG9yPkxhYXRpa2FpbmVuLCBULjwvYXV0aG9yPjxhdXRob3I+

U29pbmluZW4sIEguPC9hdXRob3I+PGF1dGhvcj5KdWxhLCBBLjwvYXV0aG9yPjxhdXRob3I+Um9r

a2EsIEouPC9hdXRob3I+PGF1dGhvcj5SaXNzYW5lbiwgRS48L2F1dGhvcj48YXV0aG9yPlZhaGxi

ZXJnLCBULjwvYXV0aG9yPjxhdXRob3I+UGVsdG9uaWVtaSwgSi48L2F1dGhvcj48YXV0aG9yPktp

dmlwZWx0bywgTS48L2F1dGhvcj48YXV0aG9yPlJpbm5lLCBKLiBPLjwvYXV0aG9yPjwvYXV0aG9y

cz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkZyb20gdGhlIFR1cmt1IFBFVCBDZW50cmUg

KE4uSy4sIEouIEpvaGFuc3NvbiwgSi5ULiwgSi4gSm91dHNhLCBKLlIuLCBFLlIuLCBKLlAuLCBK

Lk8uUi4pLCBVbml2ZXJzaXR5IG9mIFR1cmt1OyBEaXZpc2lvbiBvZiBDbGluaWNhbCBOZXVyb3Nj

aWVuY2VzIChOLksuLCBKLiBKb3V0c2EsIEUuUi4sIEouTy5SLiksIFR1cmt1IFVuaXZlcnNpdHkg

SG9zcGl0YWw7IERlcGFydG1lbnQgb2YgUmFkaW9sb2d5IChSLlAuKSwgVHVya3UgVW5pdmVyc2l0

eSBIb3NwaXRhbCBhbmQgVW5pdmVyc2l0eSBvZiBUdXJrdSwgRmlubGFuZDsgQXRoaW5vdWxhIEEu

IE1hcnRpbm9zIENlbnRlciBmb3IgQmlvbWVkaWNhbCBJbWFnaW5nIChKLiBKb3V0c2EpLCBNYXNz

YWNodXNldHRzIEdlbmVyYWwgSG9zcGl0YWwgYW5kIEhhcnZhcmQgTWVkaWNhbCBTY2hvb2wsIENo

YXJsZXN0b3duOyBCZXJlbnNvbi1BbGxlbiBDZW50ZXIgZm9yIE5vbmludmFzaXZlIEJyYWluIFN0

aW11bGF0aW9uIChKLiBKb3V0c2EpLCBCZXRoIElzcmFlbCBEZWFjb25lc3MgTWVkaWNhbCBDZW50

ZXIgYW5kIEhhcnZhcmQgTWVkaWNhbCBTY2hvb2wsIEJvc3RvbiwgTUE7IERlcGFydG1lbnQgb2Yg

UHVibGljIEhlYWx0aCBTb2x1dGlvbnMgKFQuTi4sIFQuTC4sIE0uSy4pLCBDaHJvbmljIERpc2Vh

c2UgUHJldmVudGlvbiBVbml0LCBOYXRpb25hbCBJbnN0aXR1dGUgZm9yIEhlYWx0aCBhbmQgV2Vs

ZmFyZSwgSGVsc2lua2ksIEZpbmxhbmQ7IERpdmlzaW9uIG9mIENsaW5pY2FsIEdlcmlhdHJpY3Mg

KFQuTi4sIEEuUy4sIE0uSy4pLCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgTlZTLCBh

bmQgQWdpbmcgUmVzZWFyY2ggQ2VudGVyIChBLlMuLCBNLksuKSwgS2Fyb2xpbnNrYSBJbnN0aXR1

dGV0LCBTdG9ja2hvbG0sIFN3ZWRlbjsgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3kgKEEuUy4sIFIu

Uy4sIFkuTC4sIEguUy4sIE0uSy4pLCBJbnN0aXR1dGUgb2YgQ2xpbmljYWwgTWVkaWNpbmUsIGFu

ZCBJbnN0aXR1dGUgb2YgUHVibGljIEhlYWx0aCBhbmQgQ2xpbmljYWwgTnV0cml0aW9uIChULkwu

KSwgVW5pdmVyc2l0eSBvZiBFYXN0ZXJuIEZpbmxhbmQsIEt1b3BpbzsgRGVwYXJ0bWVudCBvZiBO

ZXVyb2xvZ3kgKFQuSC4sIEguUy4pLCBLdW9waW8gVW5pdmVyc2l0eSBIb3NwaXRhbDsgUmVzZWFy

Y2ggYW5kIFNlcnZpY2UgQ2VudHJlIGZvciBPY2N1cGF0aW9uYWwgSGVhbHRoIChULlAuKSwgRmlu

bmlzaCBJbnN0aXR1dGUgb2YgT2NjdXBhdGlvbmFsIEhlYWx0aCwgSGVsc2lua2k7IEpvaW50IE11

bmljaXBhbCBBdXRob3JpdHkgZm9yIE5vcnRoIEthcmVsaWEgU29jaWFsIGFuZCBIZWFsdGggU2Vy

dmljZXMgKFQuTC4pLCBKb2Vuc3V1OyBOYXRpb25hbCBJbnN0aXR1dGUgZm9yIEhlYWx0aCBhbmQg

V2VsZmFyZSAoQS5KLik7IGFuZCBEZXBhcnRtZW50IG9mIEJpb3N0YXRpc3RpY3MgKFQuVi4pLCBV

bml2ZXJzaXR5IG9mIFR1cmt1IGFuZCBUdXJrdSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBUdXJrdSwg

RmlubGFuZC4gbmluYS5rZW1wcGFpbmVuQHR5a3MuZmkuJiN4RDtGcm9tIHRoZSBUdXJrdSBQRVQg

Q2VudHJlIChOLksuLCBKLiBKb2hhbnNzb24sIEouVC4sIEouIEpvdXRzYSwgSi5SLiwgRS5SLiwg

Si5QLiwgSi5PLlIuKSwgVW5pdmVyc2l0eSBvZiBUdXJrdTsgRGl2aXNpb24gb2YgQ2xpbmljYWwg

TmV1cm9zY2llbmNlcyAoTi5LLiwgSi4gSm91dHNhLCBFLlIuLCBKLk8uUi4pLCBUdXJrdSBVbml2

ZXJzaXR5IEhvc3BpdGFsOyBEZXBhcnRtZW50IG9mIFJhZGlvbG9neSAoUi5QLiksIFR1cmt1IFVu

aXZlcnNpdHkgSG9zcGl0YWwgYW5kIFVuaXZlcnNpdHkgb2YgVHVya3UsIEZpbmxhbmQ7IEF0aGlu

b3VsYSBBLiBNYXJ0aW5vcyBDZW50ZXIgZm9yIEJpb21lZGljYWwgSW1hZ2luZyAoSi4gSm91dHNh

KSwgTWFzc2FjaHVzZXR0cyBHZW5lcmFsIEhvc3BpdGFsIGFuZCBIYXJ2YXJkIE1lZGljYWwgU2No

b29sLCBDaGFybGVzdG93bjsgQmVyZW5zb24tQWxsZW4gQ2VudGVyIGZvciBOb25pbnZhc2l2ZSBC

cmFpbiBTdGltdWxhdGlvbiAoSi4gSm91dHNhKSwgQmV0aCBJc3JhZWwgRGVhY29uZXNzIE1lZGlj

YWwgQ2VudGVyIGFuZCBIYXJ2YXJkIE1lZGljYWwgU2Nob29sLCBCb3N0b24sIE1BOyBEZXBhcnRt

ZW50IG9mIFB1YmxpYyBIZWFsdGggU29sdXRpb25zIChULk4uLCBULkwuLCBNLksuKSwgQ2hyb25p

YyBEaXNlYXNlIFByZXZlbnRpb24gVW5pdCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGgg

YW5kIFdlbGZhcmUsIEhlbHNpbmtpLCBGaW5sYW5kOyBEaXZpc2lvbiBvZiBDbGluaWNhbCBHZXJp

YXRyaWNzIChULk4uLCBBLlMuLCBNLksuKSwgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gs

IE5WUywgYW5kIEFnaW5nIFJlc2VhcmNoIENlbnRlciAoQS5TLiwgTS5LLiksIEthcm9saW5za2Eg

SW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW47IERlcGFydG1lbnQgb2YgTmV1cm9sb2d5IChB

LlMuLCBSLlMuLCBZLkwuLCBILlMuLCBNLksuKSwgSW5zdGl0dXRlIG9mIENsaW5pY2FsIE1lZGlj

aW5lLCBhbmQgSW5zdGl0dXRlIG9mIFB1YmxpYyBIZWFsdGggYW5kIENsaW5pY2FsIE51dHJpdGlv

biAoVC5MLiksIFVuaXZlcnNpdHkgb2YgRWFzdGVybiBGaW5sYW5kLCBLdW9waW87IERlcGFydG1l

bnQgb2YgTmV1cm9sb2d5IChULkguLCBILlMuKSwgS3VvcGlvIFVuaXZlcnNpdHkgSG9zcGl0YWw7

IFJlc2VhcmNoIGFuZCBTZXJ2aWNlIENlbnRyZSBmb3IgT2NjdXBhdGlvbmFsIEhlYWx0aCAoVC5Q

LiksIEZpbm5pc2ggSW5zdGl0dXRlIG9mIE9jY3VwYXRpb25hbCBIZWFsdGgsIEhlbHNpbmtpOyBK

b2ludCBNdW5pY2lwYWwgQXV0aG9yaXR5IGZvciBOb3J0aCBLYXJlbGlhIFNvY2lhbCBhbmQgSGVh

bHRoIFNlcnZpY2VzIChULkwuKSwgSm9lbnN1dTsgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFs

dGggYW5kIFdlbGZhcmUgKEEuSi4pOyBhbmQgRGVwYXJ0bWVudCBvZiBCaW9zdGF0aXN0aWNzIChU

LlYuKSwgVW5pdmVyc2l0eSBvZiBUdXJrdSBhbmQgVHVya3UgVW5pdmVyc2l0eSBIb3NwaXRhbCwg

VHVya3UsIEZpbmxhbmQuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QnJhaW4gYW15bG9p

ZCBsb2FkIGFuZCBpdHMgYXNzb2NpYXRpb25zIHdpdGggY29nbml0aW9uIGFuZCB2YXNjdWxhciBy

aXNrIGZhY3RvcnMgaW4gRklOR0VSIFN0dWR5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5ldXJv

bG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5l

dXJvbG9neTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPmUyMDYtZTIxMzwvcGFnZXM+

PHZvbHVtZT45MDwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDE4PC95

ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SmFuIDE2PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlz

Ym4+MTUyNi02MzJYIChFbGVjdHJvbmljKSYjeEQ7MDAyOC0zODc4IChMaW5raW5nKTwvaXNibj48

YWNjZXNzaW9uLW51bT4yOTI2MzIyMDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxz

Pjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yOTI2MzIyMDwvdXJsPjwv

cmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTIxMi9XTkwu

MDAwMDAwMDAwMDAwNDgyNzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRl

PjxDaXRlPjxBdXRob3I+V29ya2VyPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVjTnVtPjI2

NjI8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjI2NjI8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBy

cHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTM3OTQyOCI+MjY2Mjwva2V5PjwvZm9yZWlnbi1rZXlzPjxy

ZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3Jz

PjxhdXRob3JzPjxhdXRob3I+V29ya2VyLCBBLjwvYXV0aG9yPjxhdXRob3I+RGltYSwgRC48L2F1

dGhvcj48YXV0aG9yPkNvbWJlcywgQS48L2F1dGhvcj48YXV0aG9yPkNydW0sIFcuIFIuPC9hdXRo

b3I+PGF1dGhvcj5TdHJlZmZlciwgSi48L2F1dGhvcj48YXV0aG9yPkVpbnN0ZWluLCBTLjwvYXV0

aG9yPjxhdXRob3I+TWVodGEsIE0uIEEuPC9hdXRob3I+PGF1dGhvcj5CYXJrZXIsIEcuIEouPC9h

dXRob3I+PGF1dGhvcj5DLiBSLiBXaWxsaWFtcyBTPC9hdXRob3I+PGF1dGhvcj5PJmFwb3M7RGFs

eSwgTy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5JbnN0

aXR1dGUgb2YgUHN5Y2hpYXRyeSwgUHN5Y2hvbG9neSBhbmQgTmV1cm9zY2llbmNlLCBLaW5nJmFw

b3M7cyBDb2xsZWdlIExvbmRvbiwgSW5zdGl0dXRlIG9mIFBzeWNoaWF0cnksIExvbmRvbiwgVW5p

dGVkIEtpbmdkb20uJiN4RDtKYW5zc2VuLVBoYXJtYWNldXRpY2FsIENvbXBhbmllcyBvZiBKb2hu

c29uICZhbXA7IEpvaG5zb24sIEphbnNzZW4gUmVzZWFyY2ggYW5kIERldmVsb3BtZW50LCBCZWVy

c2UsIEJlbGdpdW0uJiN4RDtKYW5zc2VuLVBoYXJtYWNldXRpY2FsIENvbXBhbmllcyBvZiBKb2hu

c29uICZhbXA7IEpvaG5zb24sIEphbnNzZW4gUmVzZWFyY2ggYW5kIERldmVsb3BtZW50LCBUaXR1

c3ZpbGxlLCBOZXcgSmVyc2V5LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRlc3QtcmV0

ZXN0IHJlbGlhYmlsaXR5IGFuZCBsb25naXR1ZGluYWwgYW5hbHlzaXMgb2YgYXV0b21hdGVkIGhp

cHBvY2FtcGFsIHN1YnJlZ2lvbiB2b2x1bWVzIGluIGhlYWx0aHkgYWdlaW5nIGFuZCBBbHpoZWlt

ZXImYXBvcztzIGRpc2Vhc2UgcG9wdWxhdGlvbnM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SHVt

IEJyYWluIE1hcHA8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10

aXRsZT5IdW0gQnJhaW4gTWFwcDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjE3NDMt

MTc1NDwvcGFnZXM+PHZvbHVtZT4zOTwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxrZXl3b3Jk

cz48a2V5d29yZD5GcmVlU3VyZmVyPC9rZXl3b3JkPjxrZXl3b3JkPk1hZ25ldGljIFJlc29uYW5j

ZSBJbWFnaW5nPC9rZXl3b3JkPjxrZXl3b3JkPmJyYWluIHN0cnVjdHVyZTwva2V5d29yZD48a2V5

d29yZD5oaXBwb2NhbXBhbCBzdWJmaWVsZHM8L2tleXdvcmQ+PGtleXdvcmQ+aGlwcG9jYW1wdXM8

L2tleXdvcmQ+PGtleXdvcmQ+aW50cmFjbGFzcyBjb3JyZWxhdGlvbiBjb2VmZmljaWVudDwva2V5

d29yZD48a2V5d29yZD5saW5lYXIgbWl4ZWQgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD50ZXN0

LXJldGVzdCByZWxpYWJpbGl0eTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE4

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXByPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlz

Ym4+MTA5Ny0wMTkzIChFbGVjdHJvbmljKSYjeEQ7MTA2NS05NDcxIChMaW5raW5nKTwvaXNibj48

YWNjZXNzaW9uLW51bT4yOTM0MTMyMzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxz

Pjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjkzNDEzMjM8L3VybD48

L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDIvaGJt

LjIzOTQ4PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1

dGhvcj5GcmFzZXI8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNOdW0+MjgwMTwvUmVjTnVt

PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjgwMTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg

YXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGlt

ZXN0YW1wPSIxNTM1Mzc5NDQ4Ij4yODAxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5GcmFzZXIsIE0uIEEuPC9hdXRob3I+PGF1dGhvcj5TaGF3LCBNLiBFLjwvYXV0aG9y

PjxhdXRob3I+Q2hlcmJ1aW4sIE4uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxh

dXRoLWFkZHJlc3M+Q2VudHJlIGZvciBSZXNlYXJjaCBvbiBBZ2VpbmcsIEhlYWx0aCBhbmQgV2Vs

bGJlaW5nLCBGbG9yZXksIEJ1aWxkaW5nIDU0LCBNaWxscyBSb2FkLCBBdXN0cmFsaWFuIE5hdGlv

bmFsIFVuaXZlcnNpdHksIENhbmJlcnJhLCBBQ1QgMjYwMSwgQXVzdHJhbGlhLiBFbGVjdHJvbmlj

IGFkZHJlc3M6IG1hcmsuZnJhc2VyQGFudS5lZHUuYXUuJiN4RDtDZW50cmUgZm9yIFJlc2VhcmNo

IG9uIEFnZWluZywgSGVhbHRoIGFuZCBXZWxsYmVpbmcsIEZsb3JleSwgQnVpbGRpbmcgNTQsIE1p

bGxzIFJvYWQsIEF1c3RyYWxpYW4gTmF0aW9uYWwgVW5pdmVyc2l0eSwgQ2FuYmVycmEsIEFDVCAy

NjAxLCBBdXN0cmFsaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QSBzeXN0ZW1hdGlj

IHJldmlldyBhbmQgbWV0YS1hbmFseXNpcyBvZiBsb25naXR1ZGluYWwgaGlwcG9jYW1wYWwgYXRy

b3BoeSBpbiBoZWFsdGh5IGh1bWFuIGFnZWluZzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVy

b2ltYWdlPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+

TmV1cm9pbWFnZTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjM2NC0zNzQ8L3BhZ2Vz

Pjx2b2x1bWU+MTEyPC92b2x1bWU+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxr

ZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+

PGtleXdvcmQ+QWdpbmcvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5BdHJvcGh5PC9rZXl3

b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5GdW5jdGlvbmFsIExhdGVyYWxp

dHkvcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5IaXBwb2NhbXB1cy8qcGF0aG9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxr

ZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlNleCBDaGFyYWN0ZXJpc3RpY3M8

L2tleXdvcmQ+PGtleXdvcmQ+WW91bmcgQWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlaW5nPC9r

ZXl3b3JkPjxrZXl3b3JkPkNvbnRyb2xzPC9rZXl3b3JkPjxrZXl3b3JkPkVwaWRlbWlvbG9neTwv

a2V5d29yZD48a2V5d29yZD5IaXBwb2NhbXB1czwva2V5d29yZD48a2V5d29yZD5Mb25naXR1ZGlu

YWw8L2tleXdvcmQ+PGtleXdvcmQ+TXJpPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFy

PjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXkgMTU8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4xMDk1LTk1NzIgKEVsZWN0cm9uaWMpJiN4RDsxMDUzLTgxMTkgKExpbmtpbmcp

PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1ODAwMjA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh

dGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNTgwMDIw

ODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu

MTAxNi9qLm5ldXJvaW1hZ2UuMjAxNS4wMy4wMzU8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwv

cmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb2VyYS1WYWxlbmNpYTwvQXV0aG9yPjxZZWFyPjIwMTg8

L1llYXI+PFJlY051bT4zNjg8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVy

c2NyaXB0Ij4yNC0yNzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM2

ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUy

cHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTQ5MDEyIj4zNjg8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkxvZXJhLVZhbGVuY2lhLCBS

LjwvYXV0aG9yPjxhdXRob3I+UGlyYXMsIEEuPC9hdXRob3I+PGF1dGhvcj5Jc21haWwsIE0uIEEu

IE0uPC9hdXRob3I+PGF1dGhvcj5NYW5jaGFuZGEsIFMuPC9hdXRob3I+PGF1dGhvcj5FeWpvbGZz

ZG90dGlyLCBILjwvYXV0aG9yPjxhdXRob3I+U2FpZG8sIFQuIEMuPC9hdXRob3I+PGF1dGhvcj5K

b2hhbnNzb24sIEouPC9hdXRob3I+PGF1dGhvcj5Fcmlrc2RvdHRlciwgTS48L2F1dGhvcj48YXV0

aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5OaWxzc29uLCBQLjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0

cmljcywgRGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2ll

dHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBLYXJvbGluc2thIEluc3RpdHV0ZXQs

IFNvbG5hLCBTd2VkZW4uJiN4RDtUaGVtZSBOZXVybywgRGlzZWFzZXMgb2YgdGhlIE5lcnZvdXMg

U3lzdGVtIFBhdGllbnQgRmxvdywgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIdWRk

aW5nZSwgU3dlZGVuLiYjeEQ7RGl2aXNpb24gb2YgQ2xpbmljYWwgR2VyaWF0cmljcywgRGVwYXJ0

bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIEthcm9saW5z

a2EgSW5zdGl0dXRldCwgSHVkZGluZ2UsIFN3ZWRlbi4mI3hEO1RoZW1lIEFnaW5nLCBLYXJvbGlu

c2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtSSUtFTiBCcmFp

biBTY2llbmNlIEluc3RpdHV0ZSwgV2FrbywgU2FpdGFtYSwgSmFwYW4uPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+VGFyZ2V0aW5nIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZSB3aXRoIGdl

bmUgYW5kIGNlbGwgdGhlcmFwaWVzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogSW50ZXJuIE1l

ZDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogSW50

ZXJuIE1lZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjItMzY8L3BhZ2VzPjx2b2x1

bWU+Mjg0PC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhl

aW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5jZWxsIHRoZXJhcHk8L2tleXdv

cmQ+PGtleXdvcmQ+Z2VuZSB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPmluZHVjZWQgbmV1cm9n

ZW5lc2lzPC9rZXl3b3JkPjxrZXl3b3JkPm5lcHJpbHlzaW48L2tleXdvcmQ+PGtleXdvcmQ+dGF1

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5KdWw8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMzY1LTI3OTYgKEVsZWN0

cm9uaWMpJiN4RDswOTU0LTY4MjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5NTgy

NDk1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5j

YmkubmxtLm5paC5nb3YvcHVibWVkLzI5NTgyNDk1PC91cmw+PHVybD5odHRwczovL29ubGluZWxp

YnJhcnkud2lsZXkuY29tL2RvaS9wZGYvMTAuMTExMS9qb2ltLjEyNzU5PC91cmw+PC9yZWxhdGVk

LXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTExL2pvaW0uMTI3NTk8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPktl

bXBwYWluZW48L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxSZWNOdW0+MzU4PC9SZWNOdW0+PHJl

Y29yZD48cmVjLW51bWJlcj4zNTg8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFt

cD0iMTUzMjU0ODYzNCI+MzU4PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5LZW1wcGFpbmVuLCBOLjwvYXV0aG9yPjxhdXRob3I+Sm9oYW5zc29uLCBKLjwvYXV0aG9yPjxh

dXRob3I+VGV1aG8sIEouPC9hdXRob3I+PGF1dGhvcj5QYXJra29sYSwgUi48L2F1dGhvcj48YXV0

aG9yPkpvdXRzYSwgSi48L2F1dGhvcj48YXV0aG9yPk5nYW5kdSwgVC48L2F1dGhvcj48YXV0aG9y

PlNvbG9tb24sIEEuPC9hdXRob3I+PGF1dGhvcj5TdGVwaGVuLCBSLjwvYXV0aG9yPjxhdXRob3I+

TGl1LCBZLjwvYXV0aG9yPjxhdXRob3I+SGFubmluZW4sIFQuPC9hdXRob3I+PGF1dGhvcj5QYWFq

YW5lbiwgVC48L2F1dGhvcj48YXV0aG9yPkxhYXRpa2FpbmVuLCBULjwvYXV0aG9yPjxhdXRob3I+

U29pbmluZW4sIEguPC9hdXRob3I+PGF1dGhvcj5KdWxhLCBBLjwvYXV0aG9yPjxhdXRob3I+Um9r

a2EsIEouPC9hdXRob3I+PGF1dGhvcj5SaXNzYW5lbiwgRS48L2F1dGhvcj48YXV0aG9yPlZhaGxi

ZXJnLCBULjwvYXV0aG9yPjxhdXRob3I+UGVsdG9uaWVtaSwgSi48L2F1dGhvcj48YXV0aG9yPktp

dmlwZWx0bywgTS48L2F1dGhvcj48YXV0aG9yPlJpbm5lLCBKLiBPLjwvYXV0aG9yPjwvYXV0aG9y

cz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkZyb20gdGhlIFR1cmt1IFBFVCBDZW50cmUg

KE4uSy4sIEouIEpvaGFuc3NvbiwgSi5ULiwgSi4gSm91dHNhLCBKLlIuLCBFLlIuLCBKLlAuLCBK

Lk8uUi4pLCBVbml2ZXJzaXR5IG9mIFR1cmt1OyBEaXZpc2lvbiBvZiBDbGluaWNhbCBOZXVyb3Nj

aWVuY2VzIChOLksuLCBKLiBKb3V0c2EsIEUuUi4sIEouTy5SLiksIFR1cmt1IFVuaXZlcnNpdHkg

SG9zcGl0YWw7IERlcGFydG1lbnQgb2YgUmFkaW9sb2d5IChSLlAuKSwgVHVya3UgVW5pdmVyc2l0

eSBIb3NwaXRhbCBhbmQgVW5pdmVyc2l0eSBvZiBUdXJrdSwgRmlubGFuZDsgQXRoaW5vdWxhIEEu

IE1hcnRpbm9zIENlbnRlciBmb3IgQmlvbWVkaWNhbCBJbWFnaW5nIChKLiBKb3V0c2EpLCBNYXNz

YWNodXNldHRzIEdlbmVyYWwgSG9zcGl0YWwgYW5kIEhhcnZhcmQgTWVkaWNhbCBTY2hvb2wsIENo

YXJsZXN0b3duOyBCZXJlbnNvbi1BbGxlbiBDZW50ZXIgZm9yIE5vbmludmFzaXZlIEJyYWluIFN0

aW11bGF0aW9uIChKLiBKb3V0c2EpLCBCZXRoIElzcmFlbCBEZWFjb25lc3MgTWVkaWNhbCBDZW50

ZXIgYW5kIEhhcnZhcmQgTWVkaWNhbCBTY2hvb2wsIEJvc3RvbiwgTUE7IERlcGFydG1lbnQgb2Yg

UHVibGljIEhlYWx0aCBTb2x1dGlvbnMgKFQuTi4sIFQuTC4sIE0uSy4pLCBDaHJvbmljIERpc2Vh

c2UgUHJldmVudGlvbiBVbml0LCBOYXRpb25hbCBJbnN0aXR1dGUgZm9yIEhlYWx0aCBhbmQgV2Vs

ZmFyZSwgSGVsc2lua2ksIEZpbmxhbmQ7IERpdmlzaW9uIG9mIENsaW5pY2FsIEdlcmlhdHJpY3Mg

KFQuTi4sIEEuUy4sIE0uSy4pLCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgTlZTLCBh

bmQgQWdpbmcgUmVzZWFyY2ggQ2VudGVyIChBLlMuLCBNLksuKSwgS2Fyb2xpbnNrYSBJbnN0aXR1

dGV0LCBTdG9ja2hvbG0sIFN3ZWRlbjsgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3kgKEEuUy4sIFIu

Uy4sIFkuTC4sIEguUy4sIE0uSy4pLCBJbnN0aXR1dGUgb2YgQ2xpbmljYWwgTWVkaWNpbmUsIGFu

ZCBJbnN0aXR1dGUgb2YgUHVibGljIEhlYWx0aCBhbmQgQ2xpbmljYWwgTnV0cml0aW9uIChULkwu

KSwgVW5pdmVyc2l0eSBvZiBFYXN0ZXJuIEZpbmxhbmQsIEt1b3BpbzsgRGVwYXJ0bWVudCBvZiBO

ZXVyb2xvZ3kgKFQuSC4sIEguUy4pLCBLdW9waW8gVW5pdmVyc2l0eSBIb3NwaXRhbDsgUmVzZWFy

Y2ggYW5kIFNlcnZpY2UgQ2VudHJlIGZvciBPY2N1cGF0aW9uYWwgSGVhbHRoIChULlAuKSwgRmlu

bmlzaCBJbnN0aXR1dGUgb2YgT2NjdXBhdGlvbmFsIEhlYWx0aCwgSGVsc2lua2k7IEpvaW50IE11

bmljaXBhbCBBdXRob3JpdHkgZm9yIE5vcnRoIEthcmVsaWEgU29jaWFsIGFuZCBIZWFsdGggU2Vy

dmljZXMgKFQuTC4pLCBKb2Vuc3V1OyBOYXRpb25hbCBJbnN0aXR1dGUgZm9yIEhlYWx0aCBhbmQg

V2VsZmFyZSAoQS5KLik7IGFuZCBEZXBhcnRtZW50IG9mIEJpb3N0YXRpc3RpY3MgKFQuVi4pLCBV

bml2ZXJzaXR5IG9mIFR1cmt1IGFuZCBUdXJrdSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBUdXJrdSwg

RmlubGFuZC4gbmluYS5rZW1wcGFpbmVuQHR5a3MuZmkuJiN4RDtGcm9tIHRoZSBUdXJrdSBQRVQg

Q2VudHJlIChOLksuLCBKLiBKb2hhbnNzb24sIEouVC4sIEouIEpvdXRzYSwgSi5SLiwgRS5SLiwg

Si5QLiwgSi5PLlIuKSwgVW5pdmVyc2l0eSBvZiBUdXJrdTsgRGl2aXNpb24gb2YgQ2xpbmljYWwg

TmV1cm9zY2llbmNlcyAoTi5LLiwgSi4gSm91dHNhLCBFLlIuLCBKLk8uUi4pLCBUdXJrdSBVbml2

ZXJzaXR5IEhvc3BpdGFsOyBEZXBhcnRtZW50IG9mIFJhZGlvbG9neSAoUi5QLiksIFR1cmt1IFVu

aXZlcnNpdHkgSG9zcGl0YWwgYW5kIFVuaXZlcnNpdHkgb2YgVHVya3UsIEZpbmxhbmQ7IEF0aGlu

b3VsYSBBLiBNYXJ0aW5vcyBDZW50ZXIgZm9yIEJpb21lZGljYWwgSW1hZ2luZyAoSi4gSm91dHNh

KSwgTWFzc2FjaHVzZXR0cyBHZW5lcmFsIEhvc3BpdGFsIGFuZCBIYXJ2YXJkIE1lZGljYWwgU2No

b29sLCBDaGFybGVzdG93bjsgQmVyZW5zb24tQWxsZW4gQ2VudGVyIGZvciBOb25pbnZhc2l2ZSBC

cmFpbiBTdGltdWxhdGlvbiAoSi4gSm91dHNhKSwgQmV0aCBJc3JhZWwgRGVhY29uZXNzIE1lZGlj

YWwgQ2VudGVyIGFuZCBIYXJ2YXJkIE1lZGljYWwgU2Nob29sLCBCb3N0b24sIE1BOyBEZXBhcnRt

ZW50IG9mIFB1YmxpYyBIZWFsdGggU29sdXRpb25zIChULk4uLCBULkwuLCBNLksuKSwgQ2hyb25p

YyBEaXNlYXNlIFByZXZlbnRpb24gVW5pdCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGgg

YW5kIFdlbGZhcmUsIEhlbHNpbmtpLCBGaW5sYW5kOyBEaXZpc2lvbiBvZiBDbGluaWNhbCBHZXJp

YXRyaWNzIChULk4uLCBBLlMuLCBNLksuKSwgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gs

IE5WUywgYW5kIEFnaW5nIFJlc2VhcmNoIENlbnRlciAoQS5TLiwgTS5LLiksIEthcm9saW5za2Eg

SW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW47IERlcGFydG1lbnQgb2YgTmV1cm9sb2d5IChB

LlMuLCBSLlMuLCBZLkwuLCBILlMuLCBNLksuKSwgSW5zdGl0dXRlIG9mIENsaW5pY2FsIE1lZGlj

aW5lLCBhbmQgSW5zdGl0dXRlIG9mIFB1YmxpYyBIZWFsdGggYW5kIENsaW5pY2FsIE51dHJpdGlv

biAoVC5MLiksIFVuaXZlcnNpdHkgb2YgRWFzdGVybiBGaW5sYW5kLCBLdW9waW87IERlcGFydG1l

bnQgb2YgTmV1cm9sb2d5IChULkguLCBILlMuKSwgS3VvcGlvIFVuaXZlcnNpdHkgSG9zcGl0YWw7

IFJlc2VhcmNoIGFuZCBTZXJ2aWNlIENlbnRyZSBmb3IgT2NjdXBhdGlvbmFsIEhlYWx0aCAoVC5Q

LiksIEZpbm5pc2ggSW5zdGl0dXRlIG9mIE9jY3VwYXRpb25hbCBIZWFsdGgsIEhlbHNpbmtpOyBK

b2ludCBNdW5pY2lwYWwgQXV0aG9yaXR5IGZvciBOb3J0aCBLYXJlbGlhIFNvY2lhbCBhbmQgSGVh

bHRoIFNlcnZpY2VzIChULkwuKSwgSm9lbnN1dTsgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFs

dGggYW5kIFdlbGZhcmUgKEEuSi4pOyBhbmQgRGVwYXJ0bWVudCBvZiBCaW9zdGF0aXN0aWNzIChU

LlYuKSwgVW5pdmVyc2l0eSBvZiBUdXJrdSBhbmQgVHVya3UgVW5pdmVyc2l0eSBIb3NwaXRhbCwg

VHVya3UsIEZpbmxhbmQuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QnJhaW4gYW15bG9p

ZCBsb2FkIGFuZCBpdHMgYXNzb2NpYXRpb25zIHdpdGggY29nbml0aW9uIGFuZCB2YXNjdWxhciBy

aXNrIGZhY3RvcnMgaW4gRklOR0VSIFN0dWR5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5ldXJv

bG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5l

dXJvbG9neTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPmUyMDYtZTIxMzwvcGFnZXM+

PHZvbHVtZT45MDwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDE4PC95

ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SmFuIDE2PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlz

Ym4+MTUyNi02MzJYIChFbGVjdHJvbmljKSYjeEQ7MDAyOC0zODc4IChMaW5raW5nKTwvaXNibj48

YWNjZXNzaW9uLW51bT4yOTI2MzIyMDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxz

Pjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yOTI2MzIyMDwvdXJsPjwv

cmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTIxMi9XTkwu

MDAwMDAwMDAwMDAwNDgyNzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRl

PjxDaXRlPjxBdXRob3I+V29ya2VyPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVjTnVtPjI2

NjI8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjI2NjI8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBy

cHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTM3OTQyOCI+MjY2Mjwva2V5PjwvZm9yZWlnbi1rZXlzPjxy

ZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3Jz

PjxhdXRob3JzPjxhdXRob3I+V29ya2VyLCBBLjwvYXV0aG9yPjxhdXRob3I+RGltYSwgRC48L2F1

dGhvcj48YXV0aG9yPkNvbWJlcywgQS48L2F1dGhvcj48YXV0aG9yPkNydW0sIFcuIFIuPC9hdXRo

b3I+PGF1dGhvcj5TdHJlZmZlciwgSi48L2F1dGhvcj48YXV0aG9yPkVpbnN0ZWluLCBTLjwvYXV0

aG9yPjxhdXRob3I+TWVodGEsIE0uIEEuPC9hdXRob3I+PGF1dGhvcj5CYXJrZXIsIEcuIEouPC9h

dXRob3I+PGF1dGhvcj5DLiBSLiBXaWxsaWFtcyBTPC9hdXRob3I+PGF1dGhvcj5PJmFwb3M7RGFs

eSwgTy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5JbnN0

aXR1dGUgb2YgUHN5Y2hpYXRyeSwgUHN5Y2hvbG9neSBhbmQgTmV1cm9zY2llbmNlLCBLaW5nJmFw

b3M7cyBDb2xsZWdlIExvbmRvbiwgSW5zdGl0dXRlIG9mIFBzeWNoaWF0cnksIExvbmRvbiwgVW5p

dGVkIEtpbmdkb20uJiN4RDtKYW5zc2VuLVBoYXJtYWNldXRpY2FsIENvbXBhbmllcyBvZiBKb2hu

c29uICZhbXA7IEpvaG5zb24sIEphbnNzZW4gUmVzZWFyY2ggYW5kIERldmVsb3BtZW50LCBCZWVy

c2UsIEJlbGdpdW0uJiN4RDtKYW5zc2VuLVBoYXJtYWNldXRpY2FsIENvbXBhbmllcyBvZiBKb2hu

c29uICZhbXA7IEpvaG5zb24sIEphbnNzZW4gUmVzZWFyY2ggYW5kIERldmVsb3BtZW50LCBUaXR1

c3ZpbGxlLCBOZXcgSmVyc2V5LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRlc3QtcmV0

ZXN0IHJlbGlhYmlsaXR5IGFuZCBsb25naXR1ZGluYWwgYW5hbHlzaXMgb2YgYXV0b21hdGVkIGhp

cHBvY2FtcGFsIHN1YnJlZ2lvbiB2b2x1bWVzIGluIGhlYWx0aHkgYWdlaW5nIGFuZCBBbHpoZWlt

ZXImYXBvcztzIGRpc2Vhc2UgcG9wdWxhdGlvbnM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SHVt

IEJyYWluIE1hcHA8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10

aXRsZT5IdW0gQnJhaW4gTWFwcDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjE3NDMt

MTc1NDwvcGFnZXM+PHZvbHVtZT4zOTwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxrZXl3b3Jk

cz48a2V5d29yZD5GcmVlU3VyZmVyPC9rZXl3b3JkPjxrZXl3b3JkPk1hZ25ldGljIFJlc29uYW5j

ZSBJbWFnaW5nPC9rZXl3b3JkPjxrZXl3b3JkPmJyYWluIHN0cnVjdHVyZTwva2V5d29yZD48a2V5

d29yZD5oaXBwb2NhbXBhbCBzdWJmaWVsZHM8L2tleXdvcmQ+PGtleXdvcmQ+aGlwcG9jYW1wdXM8

L2tleXdvcmQ+PGtleXdvcmQ+aW50cmFjbGFzcyBjb3JyZWxhdGlvbiBjb2VmZmljaWVudDwva2V5

d29yZD48a2V5d29yZD5saW5lYXIgbWl4ZWQgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD50ZXN0

LXJldGVzdCByZWxpYWJpbGl0eTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE4

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXByPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlz

Ym4+MTA5Ny0wMTkzIChFbGVjdHJvbmljKSYjeEQ7MTA2NS05NDcxIChMaW5raW5nKTwvaXNibj48

YWNjZXNzaW9uLW51bT4yOTM0MTMyMzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxz

Pjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjkzNDEzMjM8L3VybD48

L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDIvaGJt

LjIzOTQ4PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1

dGhvcj5GcmFzZXI8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNOdW0+MjgwMTwvUmVjTnVt

PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjgwMTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg

YXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGlt

ZXN0YW1wPSIxNTM1Mzc5NDQ4Ij4yODAxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5GcmFzZXIsIE0uIEEuPC9hdXRob3I+PGF1dGhvcj5TaGF3LCBNLiBFLjwvYXV0aG9y

PjxhdXRob3I+Q2hlcmJ1aW4sIE4uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxh

dXRoLWFkZHJlc3M+Q2VudHJlIGZvciBSZXNlYXJjaCBvbiBBZ2VpbmcsIEhlYWx0aCBhbmQgV2Vs

bGJlaW5nLCBGbG9yZXksIEJ1aWxkaW5nIDU0LCBNaWxscyBSb2FkLCBBdXN0cmFsaWFuIE5hdGlv

bmFsIFVuaXZlcnNpdHksIENhbmJlcnJhLCBBQ1QgMjYwMSwgQXVzdHJhbGlhLiBFbGVjdHJvbmlj

IGFkZHJlc3M6IG1hcmsuZnJhc2VyQGFudS5lZHUuYXUuJiN4RDtDZW50cmUgZm9yIFJlc2VhcmNo

IG9uIEFnZWluZywgSGVhbHRoIGFuZCBXZWxsYmVpbmcsIEZsb3JleSwgQnVpbGRpbmcgNTQsIE1p

bGxzIFJvYWQsIEF1c3RyYWxpYW4gTmF0aW9uYWwgVW5pdmVyc2l0eSwgQ2FuYmVycmEsIEFDVCAy

NjAxLCBBdXN0cmFsaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QSBzeXN0ZW1hdGlj

IHJldmlldyBhbmQgbWV0YS1hbmFseXNpcyBvZiBsb25naXR1ZGluYWwgaGlwcG9jYW1wYWwgYXRy

b3BoeSBpbiBoZWFsdGh5IGh1bWFuIGFnZWluZzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVy

b2ltYWdlPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+

TmV1cm9pbWFnZTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjM2NC0zNzQ8L3BhZ2Vz

Pjx2b2x1bWU+MTEyPC92b2x1bWU+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxr

ZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+

PGtleXdvcmQ+QWdpbmcvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5BdHJvcGh5PC9rZXl3

b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5GdW5jdGlvbmFsIExhdGVyYWxp

dHkvcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5IaXBwb2NhbXB1cy8qcGF0aG9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxr

ZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlNleCBDaGFyYWN0ZXJpc3RpY3M8

L2tleXdvcmQ+PGtleXdvcmQ+WW91bmcgQWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlaW5nPC9r

ZXl3b3JkPjxrZXl3b3JkPkNvbnRyb2xzPC9rZXl3b3JkPjxrZXl3b3JkPkVwaWRlbWlvbG9neTwv

a2V5d29yZD48a2V5d29yZD5IaXBwb2NhbXB1czwva2V5d29yZD48a2V5d29yZD5Mb25naXR1ZGlu

YWw8L2tleXdvcmQ+PGtleXdvcmQ+TXJpPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFy

PjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXkgMTU8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4xMDk1LTk1NzIgKEVsZWN0cm9uaWMpJiN4RDsxMDUzLTgxMTkgKExpbmtpbmcp

PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1ODAwMjA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh

dGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNTgwMDIw

ODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu

MTAxNi9qLm5ldXJvaW1hZ2UuMjAxNS4wMy4wMzU8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwv

cmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 24-27. In addition, the field is moving increasingly towards earlier and more accurate diagnostic of the pathology, where technology can help us to better classify and even redefine AD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Wb3M8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO

dW0+MTIzNjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjI4

PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTIzNjwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhw

Znd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0NDI1NzkzIj4xMjM2PC9rZXk+PC9mb3Jl

aWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxj

b250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Wb3MsIFMuIEouIEIuPC9hdXRob3I+PGF1dGhv

cj5Hb3Jkb24sIEIuIEEuPC9hdXRob3I+PGF1dGhvcj5TdSwgWS48L2F1dGhvcj48YXV0aG9yPlZp

c3NlciwgUC4gSi48L2F1dGhvcj48YXV0aG9yPkhvbHR6bWFuLCBELiBNLjwvYXV0aG9yPjxhdXRo

b3I+TW9ycmlzLCBKLiBDLjwvYXV0aG9yPjxhdXRob3I+RmFnYW4sIEEuIE0uPC9hdXRob3I+PGF1

dGhvcj5CZW56aW5nZXIsIFQuIEwuIFMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

PjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQc3ljaGlhdHJ5IGFuZCBOZXVyb3BzeWNob2xv

Z3ksIEFsemhlaW1lciBDZW50ZXIgTGltYnVyZywgU2Nob29sIGZvciBNZW50YWwgSGVhbHRoIGFu

ZCBOZXVyb3NjaWVuY2UsIE1hYXN0cmljaHQgVW5pdmVyc2l0eSwgTWFhc3RyaWNodCwgdGhlIE5l

dGhlcmxhbmRzLiBFbGVjdHJvbmljIGFkZHJlc3M6IHMudm9zQG1hYXN0cmljaHR1bml2ZXJzaXR5

Lm5sLiYjeEQ7RGVwYXJ0bWVudCBvZiBSYWRpb2xvZ3ksIFdhc2hpbmd0b24gVW5pdmVyc2l0eSBT

Y2hvb2wgb2YgTWVkaWNpbmUsIFNhaW50IExvdWlzLCBNTywgVVNBOyBLbmlnaHQgQWx6aGVpbWVy

JmFwb3M7cyBEaXNlYXNlIFJlc2VhcmNoIENlbnRlciwgV2FzaGluZ3RvbiBVbml2ZXJzaXR5IFNj

aG9vbCBvZiBNZWRpY2luZSwgU2FpbnQgTG91aXMsIE1PLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9m

IFBzeWNoaWF0cnkgYW5kIE5ldXJvcHN5Y2hvbG9neSwgQWx6aGVpbWVyIENlbnRlciBMaW1idXJn

LCBTY2hvb2wgZm9yIE1lbnRhbCBIZWFsdGggYW5kIE5ldXJvc2NpZW5jZSwgTWFhc3RyaWNodCBV

bml2ZXJzaXR5LCBNYWFzdHJpY2h0LCB0aGUgTmV0aGVybGFuZHM7IERlcGFydG1lbnQgb2YgTmV1

cm9sb2d5LCBBbHpoZWltZXIgQ2VudGVyLCBWVSBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBO

ZXVyb3NjaWVuY2UgQ2FtcHVzIEFtc3RlcmRhbSwgQW1zdGVyZGFtLCB0aGUgTmV0aGVybGFuZHMu

JiN4RDtLbmlnaHQgQWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlIFJlc2VhcmNoIENlbnRlciwgV2Fz

aGluZ3RvbiBVbml2ZXJzaXR5IFNjaG9vbCBvZiBNZWRpY2luZSwgU2FpbnQgTG91aXMsIE1PLCBV

U0E7IERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBXYXNoaW5ndG9uIFVuaXZlcnNpdHkgU2Nob29s

IG9mIE1lZGljaW5lLCBTYWludCBMb3VpcywgTU8sIFVTQTsgSG9wZSBDZW50ZXIgZm9yIE5ldXJv

bG9naWNhbCBEaXNvcmRlcnMsIFdhc2hpbmd0b24gVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNp

bmUsIFNhaW50IExvdWlzLCBNTywgVVNBLiYjeEQ7S25pZ2h0IEFsemhlaW1lciZhcG9zO3MgRGlz

ZWFzZSBSZXNlYXJjaCBDZW50ZXIsIFdhc2hpbmd0b24gVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVk

aWNpbmUsIFNhaW50IExvdWlzLCBNTywgVVNBOyBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgV2Fz

aGluZ3RvbiBVbml2ZXJzaXR5IFNjaG9vbCBvZiBNZWRpY2luZSwgU2FpbnQgTG91aXMsIE1PLCBV

U0E7IEhvcGUgQ2VudGVyIGZvciBOZXVyb2xvZ2ljYWwgRGlzb3JkZXJzLCBXYXNoaW5ndG9uIFVu

aXZlcnNpdHkgU2Nob29sIG9mIE1lZGljaW5lLCBTYWludCBMb3VpcywgTU8sIFVTQTsgRGVwYXJ0

bWVudCBvZiBQYXRob2xvZ3kgYW5kIEltbXVub2xvZ3ksIFdhc2hpbmd0b24gVW5pdmVyc2l0eSBT

Y2hvb2wgb2YgTWVkaWNpbmUsIFNhaW50IExvdWlzLCBNTywgVVNBLiYjeEQ7RGVwYXJ0bWVudCBv

ZiBSYWRpb2xvZ3ksIFdhc2hpbmd0b24gVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUsIFNh

aW50IExvdWlzLCBNTywgVVNBOyBLbmlnaHQgQWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlIFJlc2Vh

cmNoIENlbnRlciwgV2FzaGluZ3RvbiBVbml2ZXJzaXR5IFNjaG9vbCBvZiBNZWRpY2luZSwgU2Fp

bnQgTG91aXMsIE1PLCBVU0E7IEhvcGUgQ2VudGVyIGZvciBOZXVyb2xvZ2ljYWwgRGlzb3JkZXJz

LCBXYXNoaW5ndG9uIFVuaXZlcnNpdHkgU2Nob29sIG9mIE1lZGljaW5lLCBTYWludCBMb3Vpcywg

TU8sIFVTQTsgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ2ljYWwgU3VyZ2VyeSwgV2FzaGluZ3RvbiBV

bml2ZXJzaXR5IFNjaG9vbCBvZiBNZWRpY2luZSwgU2FpbnQgTG91aXMsIE1PLCBVU0EuIEVsZWN0

cm9uaWMgYWRkcmVzczogYmVuemluZ2VydEB3dXN0bC5lZHUuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TklBLUFBIHN0YWdpbmcgb2YgcHJlY2xpbmljYWwgQWx6aGVpbWVyIGRpc2Vhc2U6

IGRpc2NvcmRhbmNlIGFuZCBjb25jb3JkYW5jZSBvZiBDU0YgYW5kIGltYWdpbmcgYmlvbWFya2Vy

czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb2Jpb2wgQWdpbmc8L3NlY29uZGFyeS10aXRs

ZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb2Jpb2wgQWdpbmc8L2Z1bGwt

dGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xLTg8L3BhZ2VzPjx2b2x1bWU+NDQ8L3ZvbHVtZT48

a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zl

cjwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qZGlhZ25vc2lzLypkaWFnbm9z

dGljIGltYWdpbmcvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0

aWRlcy8qY2VyZWJyb3NwaW5hbCBmbHVpZDwva2V5d29yZD48a2V5d29yZD5CaW9tYXJrZXJzL2Nl

cmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3

b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NYWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZzwv

a2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3

b3JkPjxrZXl3b3JkPipOZXVyb2ltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+UGVwdGlkZSBGcmFn

bWVudHMvKmNlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+UG9zaXRyb24tRW1p

c3Npb24gVG9tb2dyYXBoeTwva2V5d29yZD48a2V5d29yZD5TZXZlcml0eSBvZiBJbGxuZXNzIElu

ZGV4PC9rZXl3b3JkPjxrZXl3b3JkPipBZ2luZzwva2V5d29yZD48a2V5d29yZD4qQWx6aGVpbWVy

JmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPipBbXlsb2lkPC9rZXl3b3JkPjxrZXl3

b3JkPipCaW9tYXJrZXJzPC9rZXl3b3JkPjxrZXl3b3JkPipDZXJlYnJvc3BpbmFsIGZsdWlkPC9r

ZXl3b3JkPjxrZXl3b3JkPipDb21vcmJpZGl0aWVzPC9rZXl3b3JkPjxrZXl3b3JkPipEaWFnbm9z

aXM8L2tleXdvcmQ+PGtleXdvcmQ+Kk1yaTwva2V5d29yZD48a2V5d29yZD4qTmV1cm9uYWwgaW5q

dXJ5PC9rZXl3b3JkPjxrZXl3b3JkPipQZXQ8L2tleXdvcmQ+PGtleXdvcmQ+KlByb2dub3Npczwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+QXVnPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU1OC0xNDk3IChFbGVjdHJv

bmljKSYjeEQ7MDE5Ny00NTgwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNzMxODEy

OTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNi

aS5ubG0ubmloLmdvdi9wdWJtZWQvMjczMTgxMjk8L3VybD48dXJsPmh0dHBzOi8vYWMuZWxzLWNk

bi5jb20vUzAxOTc0NTgwMTYzMDAxNjEvMS1zMi4wLVMwMTk3NDU4MDE2MzAwMTYxLW1haW4ucGRm

P190aWQ9ZjA2YzZjY2MtZjhmNC00MGEwLWJjMzQtOGI3NGIyMzE1NzViJmFtcDthY2RuYXQ9MTUz

NDQ5NDkxM19kNTRkYjk1OGQyNzZlZGJkMTFiYzI5ZTE0MjgwYTI4MTwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0OTEzMDM5PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC4xMDE2L2oubmV1cm9iaW9sYWdpbmcuMjAxNi4wMy4wMjU8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Wb3M8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO

dW0+MTIzNjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjI4

PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTIzNjwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhw

Znd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0NDI1NzkzIj4xMjM2PC9rZXk+PC9mb3Jl

aWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxj

b250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Wb3MsIFMuIEouIEIuPC9hdXRob3I+PGF1dGhv

cj5Hb3Jkb24sIEIuIEEuPC9hdXRob3I+PGF1dGhvcj5TdSwgWS48L2F1dGhvcj48YXV0aG9yPlZp

c3NlciwgUC4gSi48L2F1dGhvcj48YXV0aG9yPkhvbHR6bWFuLCBELiBNLjwvYXV0aG9yPjxhdXRo

b3I+TW9ycmlzLCBKLiBDLjwvYXV0aG9yPjxhdXRob3I+RmFnYW4sIEEuIE0uPC9hdXRob3I+PGF1

dGhvcj5CZW56aW5nZXIsIFQuIEwuIFMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

PjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQc3ljaGlhdHJ5IGFuZCBOZXVyb3BzeWNob2xv

Z3ksIEFsemhlaW1lciBDZW50ZXIgTGltYnVyZywgU2Nob29sIGZvciBNZW50YWwgSGVhbHRoIGFu

ZCBOZXVyb3NjaWVuY2UsIE1hYXN0cmljaHQgVW5pdmVyc2l0eSwgTWFhc3RyaWNodCwgdGhlIE5l

dGhlcmxhbmRzLiBFbGVjdHJvbmljIGFkZHJlc3M6IHMudm9zQG1hYXN0cmljaHR1bml2ZXJzaXR5

Lm5sLiYjeEQ7RGVwYXJ0bWVudCBvZiBSYWRpb2xvZ3ksIFdhc2hpbmd0b24gVW5pdmVyc2l0eSBT

Y2hvb2wgb2YgTWVkaWNpbmUsIFNhaW50IExvdWlzLCBNTywgVVNBOyBLbmlnaHQgQWx6aGVpbWVy

JmFwb3M7cyBEaXNlYXNlIFJlc2VhcmNoIENlbnRlciwgV2FzaGluZ3RvbiBVbml2ZXJzaXR5IFNj

aG9vbCBvZiBNZWRpY2luZSwgU2FpbnQgTG91aXMsIE1PLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9m

IFBzeWNoaWF0cnkgYW5kIE5ldXJvcHN5Y2hvbG9neSwgQWx6aGVpbWVyIENlbnRlciBMaW1idXJn

LCBTY2hvb2wgZm9yIE1lbnRhbCBIZWFsdGggYW5kIE5ldXJvc2NpZW5jZSwgTWFhc3RyaWNodCBV

bml2ZXJzaXR5LCBNYWFzdHJpY2h0LCB0aGUgTmV0aGVybGFuZHM7IERlcGFydG1lbnQgb2YgTmV1

cm9sb2d5LCBBbHpoZWltZXIgQ2VudGVyLCBWVSBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBO

ZXVyb3NjaWVuY2UgQ2FtcHVzIEFtc3RlcmRhbSwgQW1zdGVyZGFtLCB0aGUgTmV0aGVybGFuZHMu

JiN4RDtLbmlnaHQgQWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlIFJlc2VhcmNoIENlbnRlciwgV2Fz

aGluZ3RvbiBVbml2ZXJzaXR5IFNjaG9vbCBvZiBNZWRpY2luZSwgU2FpbnQgTG91aXMsIE1PLCBV

U0E7IERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBXYXNoaW5ndG9uIFVuaXZlcnNpdHkgU2Nob29s

IG9mIE1lZGljaW5lLCBTYWludCBMb3VpcywgTU8sIFVTQTsgSG9wZSBDZW50ZXIgZm9yIE5ldXJv

bG9naWNhbCBEaXNvcmRlcnMsIFdhc2hpbmd0b24gVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNp

bmUsIFNhaW50IExvdWlzLCBNTywgVVNBLiYjeEQ7S25pZ2h0IEFsemhlaW1lciZhcG9zO3MgRGlz

ZWFzZSBSZXNlYXJjaCBDZW50ZXIsIFdhc2hpbmd0b24gVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVk

aWNpbmUsIFNhaW50IExvdWlzLCBNTywgVVNBOyBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgV2Fz

aGluZ3RvbiBVbml2ZXJzaXR5IFNjaG9vbCBvZiBNZWRpY2luZSwgU2FpbnQgTG91aXMsIE1PLCBV

U0E7IEhvcGUgQ2VudGVyIGZvciBOZXVyb2xvZ2ljYWwgRGlzb3JkZXJzLCBXYXNoaW5ndG9uIFVu

aXZlcnNpdHkgU2Nob29sIG9mIE1lZGljaW5lLCBTYWludCBMb3VpcywgTU8sIFVTQTsgRGVwYXJ0

bWVudCBvZiBQYXRob2xvZ3kgYW5kIEltbXVub2xvZ3ksIFdhc2hpbmd0b24gVW5pdmVyc2l0eSBT

Y2hvb2wgb2YgTWVkaWNpbmUsIFNhaW50IExvdWlzLCBNTywgVVNBLiYjeEQ7RGVwYXJ0bWVudCBv

ZiBSYWRpb2xvZ3ksIFdhc2hpbmd0b24gVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUsIFNh

aW50IExvdWlzLCBNTywgVVNBOyBLbmlnaHQgQWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlIFJlc2Vh

cmNoIENlbnRlciwgV2FzaGluZ3RvbiBVbml2ZXJzaXR5IFNjaG9vbCBvZiBNZWRpY2luZSwgU2Fp

bnQgTG91aXMsIE1PLCBVU0E7IEhvcGUgQ2VudGVyIGZvciBOZXVyb2xvZ2ljYWwgRGlzb3JkZXJz

LCBXYXNoaW5ndG9uIFVuaXZlcnNpdHkgU2Nob29sIG9mIE1lZGljaW5lLCBTYWludCBMb3Vpcywg

TU8sIFVTQTsgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ2ljYWwgU3VyZ2VyeSwgV2FzaGluZ3RvbiBV

bml2ZXJzaXR5IFNjaG9vbCBvZiBNZWRpY2luZSwgU2FpbnQgTG91aXMsIE1PLCBVU0EuIEVsZWN0

cm9uaWMgYWRkcmVzczogYmVuemluZ2VydEB3dXN0bC5lZHUuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TklBLUFBIHN0YWdpbmcgb2YgcHJlY2xpbmljYWwgQWx6aGVpbWVyIGRpc2Vhc2U6

IGRpc2NvcmRhbmNlIGFuZCBjb25jb3JkYW5jZSBvZiBDU0YgYW5kIGltYWdpbmcgYmlvbWFya2Vy

czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb2Jpb2wgQWdpbmc8L3NlY29uZGFyeS10aXRs

ZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb2Jpb2wgQWdpbmc8L2Z1bGwt

dGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xLTg8L3BhZ2VzPjx2b2x1bWU+NDQ8L3ZvbHVtZT48

a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zl

cjwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qZGlhZ25vc2lzLypkaWFnbm9z

dGljIGltYWdpbmcvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0

aWRlcy8qY2VyZWJyb3NwaW5hbCBmbHVpZDwva2V5d29yZD48a2V5d29yZD5CaW9tYXJrZXJzL2Nl

cmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3

b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NYWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZzwv

a2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3

b3JkPjxrZXl3b3JkPipOZXVyb2ltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+UGVwdGlkZSBGcmFn

bWVudHMvKmNlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+UG9zaXRyb24tRW1p

c3Npb24gVG9tb2dyYXBoeTwva2V5d29yZD48a2V5d29yZD5TZXZlcml0eSBvZiBJbGxuZXNzIElu

ZGV4PC9rZXl3b3JkPjxrZXl3b3JkPipBZ2luZzwva2V5d29yZD48a2V5d29yZD4qQWx6aGVpbWVy

JmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPipBbXlsb2lkPC9rZXl3b3JkPjxrZXl3

b3JkPipCaW9tYXJrZXJzPC9rZXl3b3JkPjxrZXl3b3JkPipDZXJlYnJvc3BpbmFsIGZsdWlkPC9r

ZXl3b3JkPjxrZXl3b3JkPipDb21vcmJpZGl0aWVzPC9rZXl3b3JkPjxrZXl3b3JkPipEaWFnbm9z

aXM8L2tleXdvcmQ+PGtleXdvcmQ+Kk1yaTwva2V5d29yZD48a2V5d29yZD4qTmV1cm9uYWwgaW5q

dXJ5PC9rZXl3b3JkPjxrZXl3b3JkPipQZXQ8L2tleXdvcmQ+PGtleXdvcmQ+KlByb2dub3Npczwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+QXVnPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU1OC0xNDk3IChFbGVjdHJv

bmljKSYjeEQ7MDE5Ny00NTgwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNzMxODEy

OTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNi

aS5ubG0ubmloLmdvdi9wdWJtZWQvMjczMTgxMjk8L3VybD48dXJsPmh0dHBzOi8vYWMuZWxzLWNk

bi5jb20vUzAxOTc0NTgwMTYzMDAxNjEvMS1zMi4wLVMwMTk3NDU4MDE2MzAwMTYxLW1haW4ucGRm

P190aWQ9ZjA2YzZjY2MtZjhmNC00MGEwLWJjMzQtOGI3NGIyMzE1NzViJmFtcDthY2RuYXQ9MTUz

NDQ5NDkxM19kNTRkYjk1OGQyNzZlZGJkMTFiYzI5ZTE0MjgwYTI4MTwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0OTEzMDM5PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC4xMDE2L2oubmV1cm9iaW9sYWdpbmcuMjAxNi4wMy4wMjU8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 28. This review summarizes pioneering efforts in mechanisms of disease and novel drug targets for Alzheimer?s disease research. We would like to emphasize the importance of multidisciplinary research in finding new treatment avenues in what it is a complex disease with many challenges.Different treatment approaches based on pathogenesis:Amyloid beta in Alzheimer’s disease: an overviewAβ load in the brain correlates well with the degree of dementia, where it becomes more neurotoxic after polymerization PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYUZlcmxhPC9BdXRob3I+PFllYXI+MTk5NzwvWWVhcj48

UmVjTnVtPjEyNTE8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4yOSwzMDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEyNTE8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDQ5NjEyMSI+MTI1MTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TGFGZXJsYSwgRi4gTS48L2F1dGhv

cj48YXV0aG9yPlRyb25jb3NvLCBKLiBDLjwvYXV0aG9yPjxhdXRob3I+U3RyaWNrbGFuZCwgRC4g

Sy48L2F1dGhvcj48YXV0aG9yPkthd2FzLCBDLiBILjwvYXV0aG9yPjxhdXRob3I+SmF5LCBHLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQg

b2YgVmlyb2xvZ3ksIEplcm9tZSBILiBIb2xsYW5kIExhYm9yYXRvcnksIFJvY2t2aWxsZSwgTWFy

eWxhbmQgMjA4NTUsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5OZXVyb25hbCBj

ZWxsIGRlYXRoIGluIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZSBjb3JyZWxhdGVzIHdpdGggYXBv

RSB1cHRha2UgYW5kIGludHJhY2VsbHVsYXIgQWJldGEgc3RhYmlsaXphdGlvbjwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5KIENsaW4gSW52ZXN0PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBh

Z2VzPjMxMC0yMDwvcGFnZXM+PHZvbHVtZT4xMDA8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48

ZWRpdGlvbj4xOTk3LzA3LzE1PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIg

RGlzZWFzZS8qbWV0YWJvbGlzbS8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQg

YmV0YS1QZXB0aWRlcy9pbW11bm9sb2d5LyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFw

b2xpcG9wcm90ZWlucyBFLyptZXRhYm9saXNtL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29y

ZD5CcmFpbi8qbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBEZWF0

aDwva2V5d29yZD48a2V5d29yZD5ETkEvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5ETkEg

RnJhZ21lbnRhdGlvbjwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+

R2VuZSBFeHByZXNzaW9uIFJlZ3VsYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+SGV5bWFubiBOZXBo

cml0aXMgQW50aWdlbmljIENvbXBsZXg8L2tleXdvcmQ+PGtleXdvcmQ+SGlzdG9jeXRvY2hlbWlz

dHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5Mb3cgRGVuc2l0

eSBMaXBvcHJvdGVpbiBSZWNlcHRvci1SZWxhdGVkIFByb3RlaW4tMTwva2V5d29yZD48a2V5d29y

ZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbWJyYW5lIEdseWNvcHJvdGVpbnMvaW1tdW5vbG9n

eS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbnMvKnBhdGhvbG9neTwva2V5d29y

ZD48a2V5d29yZD5SZWNlcHRvcnMsIExpcG9wcm90ZWluL21ldGFib2xpc208L2tleXdvcmQ+PC9r

ZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MTk5NzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bCAxNTwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMjEtOTczOCAoUHJpbnQpJiN4RDswMDIx

LTk3MzggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjkyMTg1MDc8L2FjY2Vzc2lvbi1u

dW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3Yv

cHVibWVkLzkyMTg1MDc8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNTA4

MTkzPC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTcyL0pDSTExOTUzNjwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Q3Vt

bWluZ3M8L0F1dGhvcj48WWVhcj4xOTk1PC9ZZWFyPjxSZWNOdW0+MTI1MDwvUmVjTnVtPjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTI1MDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1w

PSIxNTM0NDk2MDgzIj4xMjUwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5DdW1taW5ncywgQi4gSi48L2F1dGhvcj48YXV0aG9yPkNvdG1hbiwgQy4gVy48L2F1dGhvcj48

L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5JbnN0aXR1dGUgZm9yIEJyYWlu

IEFnaW5nIGFuZCBEZW1lbnRpYSwgVW5pdmVyc2l0eSBvZiBDYWxpZm9ybmlhLCBJcnZpbmUgOTI3

MTctNDU1MCwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkltYWdlIGFuYWx5c2lz

IG9mIGJldGEtYW15bG9pZCBsb2FkIGluIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZSBhbmQgcmVs

YXRpb24gdG8gZGVtZW50aWEgc2V2ZXJpdHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TGFuY2V0

PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjE1MjQtODwvcGFnZXM+PHZvbHVtZT4z

NDY8L3ZvbHVtZT48bnVtYmVyPjg5ODk8L251bWJlcj48ZWRpdGlvbj4xOTk1LzEyLzA5PC9lZGl0

aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFu

ZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2V0aW9sb2d5LyptZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9hbmFseXNpcy8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5CcmFpbiBDaGVtaXN0cnkvcGh5c2lvbG9neTwv

a2V5d29yZD48a2V5d29yZD5Db2duaXRpb24vcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5F

bnRvcmhpbmFsIENvcnRleC9jaGVtaXN0cnkvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5G

ZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2hp

c3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWVu

dGFsIFN0YXR1cyBTY2hlZHVsZS9zdGF0aXN0aWNzICZhbXA7IG51bWVyaWNhbCBkYXRhPC9rZXl3

b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5E

ZWMgOTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAxNDAtNjczNiAoUHJpbnQpJiN4

RDswMTQwLTY3MzYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjc0OTEwNDg8L2FjY2Vz

c2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5p

aC5nb3YvcHVibWVkLzc0OTEwNDg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+

PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYUZlcmxhPC9BdXRob3I+PFllYXI+MTk5NzwvWWVhcj48

UmVjTnVtPjEyNTE8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4yOSwzMDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEyNTE8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDQ5NjEyMSI+MTI1MTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TGFGZXJsYSwgRi4gTS48L2F1dGhv

cj48YXV0aG9yPlRyb25jb3NvLCBKLiBDLjwvYXV0aG9yPjxhdXRob3I+U3RyaWNrbGFuZCwgRC4g

Sy48L2F1dGhvcj48YXV0aG9yPkthd2FzLCBDLiBILjwvYXV0aG9yPjxhdXRob3I+SmF5LCBHLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQg

b2YgVmlyb2xvZ3ksIEplcm9tZSBILiBIb2xsYW5kIExhYm9yYXRvcnksIFJvY2t2aWxsZSwgTWFy

eWxhbmQgMjA4NTUsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5OZXVyb25hbCBj

ZWxsIGRlYXRoIGluIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZSBjb3JyZWxhdGVzIHdpdGggYXBv

RSB1cHRha2UgYW5kIGludHJhY2VsbHVsYXIgQWJldGEgc3RhYmlsaXphdGlvbjwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5KIENsaW4gSW52ZXN0PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBh

Z2VzPjMxMC0yMDwvcGFnZXM+PHZvbHVtZT4xMDA8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48

ZWRpdGlvbj4xOTk3LzA3LzE1PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIg

RGlzZWFzZS8qbWV0YWJvbGlzbS8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQg

YmV0YS1QZXB0aWRlcy9pbW11bm9sb2d5LyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFw

b2xpcG9wcm90ZWlucyBFLyptZXRhYm9saXNtL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29y

ZD5CcmFpbi8qbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBEZWF0

aDwva2V5d29yZD48a2V5d29yZD5ETkEvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5ETkEg

RnJhZ21lbnRhdGlvbjwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+

R2VuZSBFeHByZXNzaW9uIFJlZ3VsYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+SGV5bWFubiBOZXBo

cml0aXMgQW50aWdlbmljIENvbXBsZXg8L2tleXdvcmQ+PGtleXdvcmQ+SGlzdG9jeXRvY2hlbWlz

dHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5Mb3cgRGVuc2l0

eSBMaXBvcHJvdGVpbiBSZWNlcHRvci1SZWxhdGVkIFByb3RlaW4tMTwva2V5d29yZD48a2V5d29y

ZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbWJyYW5lIEdseWNvcHJvdGVpbnMvaW1tdW5vbG9n

eS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbnMvKnBhdGhvbG9neTwva2V5d29y

ZD48a2V5d29yZD5SZWNlcHRvcnMsIExpcG9wcm90ZWluL21ldGFib2xpc208L2tleXdvcmQ+PC9r

ZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MTk5NzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bCAxNTwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMjEtOTczOCAoUHJpbnQpJiN4RDswMDIx

LTk3MzggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjkyMTg1MDc8L2FjY2Vzc2lvbi1u

dW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3Yv

cHVibWVkLzkyMTg1MDc8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNTA4

MTkzPC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTcyL0pDSTExOTUzNjwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Q3Vt

bWluZ3M8L0F1dGhvcj48WWVhcj4xOTk1PC9ZZWFyPjxSZWNOdW0+MTI1MDwvUmVjTnVtPjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTI1MDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1w

PSIxNTM0NDk2MDgzIj4xMjUwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5DdW1taW5ncywgQi4gSi48L2F1dGhvcj48YXV0aG9yPkNvdG1hbiwgQy4gVy48L2F1dGhvcj48

L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5JbnN0aXR1dGUgZm9yIEJyYWlu

IEFnaW5nIGFuZCBEZW1lbnRpYSwgVW5pdmVyc2l0eSBvZiBDYWxpZm9ybmlhLCBJcnZpbmUgOTI3

MTctNDU1MCwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkltYWdlIGFuYWx5c2lz

IG9mIGJldGEtYW15bG9pZCBsb2FkIGluIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZSBhbmQgcmVs

YXRpb24gdG8gZGVtZW50aWEgc2V2ZXJpdHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TGFuY2V0

PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjE1MjQtODwvcGFnZXM+PHZvbHVtZT4z

NDY8L3ZvbHVtZT48bnVtYmVyPjg5ODk8L251bWJlcj48ZWRpdGlvbj4xOTk1LzEyLzA5PC9lZGl0

aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFu

ZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2V0aW9sb2d5LyptZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9hbmFseXNpcy8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5CcmFpbiBDaGVtaXN0cnkvcGh5c2lvbG9neTwv

a2V5d29yZD48a2V5d29yZD5Db2duaXRpb24vcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5F

bnRvcmhpbmFsIENvcnRleC9jaGVtaXN0cnkvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5G

ZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2hp

c3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWVu

dGFsIFN0YXR1cyBTY2hlZHVsZS9zdGF0aXN0aWNzICZhbXA7IG51bWVyaWNhbCBkYXRhPC9rZXl3

b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5E

ZWMgOTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAxNDAtNjczNiAoUHJpbnQpJiN4

RDswMTQwLTY3MzYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjc0OTEwNDg8L2FjY2Vz

c2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5p

aC5nb3YvcHVibWVkLzc0OTEwNDg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+

PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 29,30. Most familial cases show increased Aβ isoforms with 42 to 43 amino acids in the CSF PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYWxhcmlhPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48

UmVjTnVtPjEyNTI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMS0zNDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEyNTI8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDQ5NjI1NSI+MTI1Mjwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+S2FsYXJpYSwgUi4gTi48L2F1dGhv

cj48YXV0aG9yPkNvaGVuLCBELiBMLjwvYXV0aG9yPjxhdXRob3I+R3JlZW5iZXJnLCBCLiBELjwv

YXV0aG9yPjxhdXRob3I+U2F2YWdlLCBNLiBKLjwvYXV0aG9yPjxhdXRob3I+Qm9nZGFub3ZpYywg

Ti4gRS48L2F1dGhvcj48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5MYW5uZmVs

dCwgTC48L2F1dGhvcj48YXV0aG9yPkFkZW0sIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp

YnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIENhc2UgV2VzdGVy

biBSZXNlcnZlIFVuaXZlcnNpdHksIENsZXZlbGFuZCwgT0ggNDQxMDYsIFVTQS48L2F1dGgtYWRk

cmVzcz48dGl0bGVzPjx0aXRsZT5BYnVuZGFuY2Ugb2YgdGhlIGxvbmdlciBBIGJldGEgNDIgaW4g

bmVvY29ydGljYWwgYW5kIGNlcmVicm92YXNjdWxhciBhbXlsb2lkIGJldGEgZGVwb3NpdHMgaW4g

U3dlZGlzaCBmYW1pbGlhbCBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgYW5kIERvd24mYXBvcztz

IHN5bmRyb21lPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5ldXJvcmVwb3J0PC9zZWNvbmRhcnkt

dGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmV1cm9yZXBvcnQ8L2Z1bGwt

dGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMzc3LTgxPC9wYWdlcz48dm9sdW1lPjc8L3ZvbHVt

ZT48bnVtYmVyPjg8L251bWJlcj48ZWRpdGlvbj4xOTk2LzA1LzMxPC9lZGl0aW9uPjxrZXl3b3Jk

cz48a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3Jk

PkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2dl

bmV0aWNzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRl

cy8qYW5hbHlzaXMvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3Rl

aW4gUHJlY3Vyc29yL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIENvcnRleC8q

Y2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicm92YXNjdWxhciBDaXJjdWxhdGlvbi8q

cGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5Eb3duIFN5bmRyb21lL2dlbmV0aWNzLyptZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9o

aXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5

d29yZD5NdXRhdGlvbjwva2V5d29yZD48a2V5d29yZD5OZXJ2ZSBUaXNzdWUgUHJvdGVpbnMvKmFu

YWx5c2lzL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPlBlcmlvZGljaXR5PC9rZXl3b3JkPjxr

ZXl3b3JkPlN3ZWRlbjwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk2PC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+TWF5IDMxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+

MDk1OS00OTY1IChQcmludCkmI3hEOzA5NTktNDk2NSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lv

bi1udW0+ODg1NjY3OTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvODg1NjY3OTwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5NYXR0c3NvbjwvQXV0aG9y

PjxZZWFyPjIwMDk8L1llYXI+PFJlY051bT4xMjUzPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJl

cj4xMjUzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndh

MHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ0OTYzMzci

PjEyNTM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xl

Ij4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1hdHRzc29uLCBO

LjwvYXV0aG9yPjxhdXRob3I+WmV0dGVyYmVyZywgSC48L2F1dGhvcj48YXV0aG9yPkhhbnNzb24s

IE8uPC9hdXRob3I+PGF1dGhvcj5BbmRyZWFzZW4sIE4uPC9hdXRob3I+PGF1dGhvcj5QYXJuZXR0

aSwgTC48L2F1dGhvcj48YXV0aG9yPkpvbnNzb24sIE0uPC9hdXRob3I+PGF1dGhvcj5IZXJ1a2th

LCBTLiBLLjwvYXV0aG9yPjxhdXRob3I+dmFuIGRlciBGbGllciwgVy4gTS48L2F1dGhvcj48YXV0

aG9yPkJsYW5rZW5zdGVpbiwgTS4gQS48L2F1dGhvcj48YXV0aG9yPkV3ZXJzLCBNLjwvYXV0aG9y

PjxhdXRob3I+UmljaCwgSy48L2F1dGhvcj48YXV0aG9yPkthaXNlciwgRS48L2F1dGhvcj48YXV0

aG9yPlZlcmJlZWssIE0uPC9hdXRob3I+PGF1dGhvcj5Uc29sYWtpLCBNLjwvYXV0aG9yPjxhdXRo

b3I+TXVsdWdldGEsIEUuPC9hdXRob3I+PGF1dGhvcj5Sb3NlbiwgRS48L2F1dGhvcj48YXV0aG9y

PkFhcnNsYW5kLCBELjwvYXV0aG9yPjxhdXRob3I+Vmlzc2VyLCBQLiBKLjwvYXV0aG9yPjxhdXRo

b3I+U2Nocm9kZXIsIEouPC9hdXRob3I+PGF1dGhvcj5NYXJjdXNzb24sIEouPC9hdXRob3I+PGF1

dGhvcj5kZSBMZW9uLCBNLjwvYXV0aG9yPjxhdXRob3I+SGFtcGVsLCBILjwvYXV0aG9yPjxhdXRo

b3I+U2NoZWx0ZW5zLCBQLjwvYXV0aG9yPjxhdXRob3I+UGlydHRpbGEsIFQuPC9hdXRob3I+PGF1

dGhvcj5XYWxsaW4sIEEuPC9hdXRob3I+PGF1dGhvcj5Kb25oYWdlbiwgTS4gRS48L2F1dGhvcj48

YXV0aG9yPk1pbnRob24sIEwuPC9hdXRob3I+PGF1dGhvcj5XaW5ibGFkLCBCLjwvYXV0aG9yPjxh

dXRob3I+Qmxlbm5vdywgSy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgt

YWRkcmVzcz5JbnN0aXR1dGUgb2YgTmV1cm9zY2llbmNlIGFuZCBQaHlzaW9sb2d5LCBEZXBhcnRt

ZW50IG9mIE5ldXJvY2hlbWlzdHJ5IGFuZCBQc3ljaGlhdHJ5LCBUaGUgU2FobGdyZW5za2EgQWNh

ZGVteSBhdCBVbml2ZXJzaXR5IG9mIEdvdGhlbmJ1cmcsIE1vbG5kYWwsIFN3ZWRlbi4gbmlrbGFz

Lm1hdHRzc29uQG5ldXJvLmd1LnNlPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Q1NGIGJp

b21hcmtlcnMgYW5kIGluY2lwaWVudCBBbHpoZWltZXIgZGlzZWFzZSBpbiBwYXRpZW50cyB3aXRo

IG1pbGQgY29nbml0aXZlIGltcGFpcm1lbnQ8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SkFNQTwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4zODUtOTM8L3BhZ2VzPjx2b2x1bWU+MzAy

PC92b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PGVkaXRpb24+MjAwOS8wNy8yMzwvZWRpdGlvbj48

a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48

a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlz

ZWFzZS8qY2VyZWJyb3NwaW5hbCBmbHVpZC8qZGlhZ25vc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkFt

eWxvaWQgYmV0YS1QZXB0aWRlcy8qY2VyZWJyb3NwaW5hbCBmbHVpZDwva2V5d29yZD48a2V5d29y

ZD5CaW9tYXJrZXJzL2NlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+Q29nbml0

aW9uIERpc29yZGVycy8qY2VyZWJyb3NwaW5hbCBmbHVpZDwva2V5d29yZD48a2V5d29yZD5Db2hv

cnQgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5Dcm9zcy1TZWN0aW9uYWwgU3R1ZGllczwva2V5

d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxr

ZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdv

cmQ+UGVwdGlkZSBGcmFnbWVudHMvKmNlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdv

cmQ+UGhvc3Bob3RocmVvbmluZTwva2V5d29yZD48a2V5d29yZD5TZW5zaXRpdml0eSBhbmQgU3Bl

Y2lmaWNpdHk8L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5zLypjZXJlYnJvc3BpbmFsIGZs

dWlkL2NoZW1pc3RyeTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA5PC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+SnVsIDIyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+

MTUzOC0zNTk4IChFbGVjdHJvbmljKSYjeEQ7MDA5OC03NDg0IChMaW5raW5nKTwvaXNibj48YWNj

ZXNzaW9uLW51bT4xOTYyMjgxNzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1

cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTk2MjI4MTc8L3VybD48L3Jl

bGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDEvamFtYS4y

MDA5LjEwNjQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48

QXV0aG9yPkVja21hbjwvQXV0aG9yPjxZZWFyPjE5OTc8L1llYXI+PFJlY051bT4xMjY3PC9SZWNO

dW0+PHJlY29yZD48cmVjLW51bWJlcj4xMjY3PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0

aW1lc3RhbXA9IjE1MzQ0OTY5MzEiPjEyNjc8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUg

bmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9y

cz48YXV0aG9yPkVja21hbiwgQy4gQi48L2F1dGhvcj48YXV0aG9yPk1laHRhLCBOLiBELjwvYXV0

aG9yPjxhdXRob3I+Q3Jvb2ssIFIuPC9hdXRob3I+PGF1dGhvcj5QZXJlei10dXIsIEouPC9hdXRo

b3I+PGF1dGhvcj5QcmloYXIsIEcuPC9hdXRob3I+PGF1dGhvcj5QZmVpZmZlciwgRS48L2F1dGhv

cj48YXV0aG9yPkdyYWZmLVJhZGZvcmQsIE4uPC9hdXRob3I+PGF1dGhvcj5IaW5kZXIsIFAuPC9h

dXRob3I+PGF1dGhvcj5ZYWdlciwgRC48L2F1dGhvcj48YXV0aG9yPlplbmssIEIuPC9hdXRob3I+

PGF1dGhvcj5SZWZvbG8sIEwuIE0uPC9hdXRob3I+PGF1dGhvcj5QcmFkYSwgQy4gTS48L2F1dGhv

cj48YXV0aG9yPllvdW5raW4sIFMuIEcuPC9hdXRob3I+PGF1dGhvcj5IdXR0b24sIE0uPC9hdXRo

b3I+PGF1dGhvcj5IYXJkeSwgSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1

dGgtYWRkcmVzcz5NYXlvIENsaW5pYyBKYWNrc29udmlsbGUsIDQ1MDAgU2FuIFBhYmxvIFJvYWQs

IEphY2tzb252aWxsZSwgRkwgMzIyMjQsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRs

ZT5BIG5ldyBwYXRob2dlbmljIG11dGF0aW9uIGluIHRoZSBBUFAgZ2VuZSAoSTcxNlYpIGluY3Jl

YXNlcyB0aGUgcmVsYXRpdmUgcHJvcG9ydGlvbiBvZiBBIGJldGEgNDIoNDMpPC90aXRsZT48c2Vj

b25kYXJ5LXRpdGxlPkh1bSBNb2wgR2VuZXQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5IdW0gTW9sIEdlbmV0PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNh

bD48cGFnZXM+MjA4Ny05PC9wYWdlcz48dm9sdW1lPjY8L3ZvbHVtZT48bnVtYmVyPjEyPC9udW1i

ZXI+PGVkaXRpb24+MTk5Ny8xMS8wNTwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWdlIG9m

IE9uc2V0PC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2V0aW9sb2d5LypnZW5l

dGljczwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvKmdlbmV0aWNzPC9r

ZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1Qcm90ZWluIFByZWN1cnNvci8qZ2VuZXRpY3M8

L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29y

ZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5QZXB0aWRlIEZyYWdtZW50

cy8qZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+KlBvaW50IE11dGF0aW9uPC9rZXl3b3JkPjwv

a2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5Ob3Y8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wOTY0LTY5MDYgKFByaW50KSYjeEQ7MDk2NC02

OTA2IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT45MzI4NDcyPC9hY2Nlc3Npb24tbnVt

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC85MzI4NDcyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48

Q2l0ZT48QXV0aG9yPlNhbmRlYnJpbmc8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNOdW0+

MTI2OTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTI2OTwvcmVjLW51bWJlcj48Zm9yZWln

bi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6

cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0NDk4MzkzIj4xMjY5PC9rZXk+PC9mb3JlaWduLWtleXM+

PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRv

cnM+PGF1dGhvcnM+PGF1dGhvcj5TYW5kZWJyaW5nLCBBLjwvYXV0aG9yPjxhdXRob3I+V2VsYW5k

ZXIsIEguPC9hdXRob3I+PGF1dGhvcj5XaW5ibGFkLCBCLjwvYXV0aG9yPjxhdXRob3I+R3JhZmYs

IEMuPC9hdXRob3I+PGF1dGhvcj5UamVybmJlcmcsIEwuIE8uPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENh

cmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0dXRldCwgS0ktQWx6aGVp

bWVyJmFwb3M7cyBEaXNlYXNlIFJlc2VhcmNoIGNlbnRlciAoS0ktQURSQyksIEh1ZGRpbmdlLCBT

d2VkZW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGhlIHBhdGhvZ2VuaWMgYWJldGE0

MyBpcyBlbnJpY2hlZCBpbiBmYW1pbGlhbCBhbmQgc3BvcmFkaWMgQWx6aGVpbWVyIGRpc2Vhc2U8

L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UExvUyBPbmU8L3NlY29uZGFyeS10aXRsZT48L3RpdGxl

cz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5QTG9TIE9uZTwvZnVsbC10aXRsZT48L3BlcmlvZGlj

YWw+PHBhZ2VzPmU1NTg0NzwvcGFnZXM+PHZvbHVtZT44PC92b2x1bWU+PG51bWJlcj4yPC9udW1i

ZXI+PGVkaXRpb24+MjAxMy8wMi8xNTwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8

L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zl

cjwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qbWV0YWJvbGlzbS9wYXRob2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzLyptZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPkJyYWluL21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPkVuenltZS1MaW5rZWQgSW1tdW5vc29yYmVudCBBc3NheTwva2V5d29yZD48a2V5d29yZD5G

ZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tl

eXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVpbiBJc29m

b3Jtczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEzPC95ZWFyPjwvZGF0ZXM+

PGlzYm4+MTkzMi02MjAzIChFbGVjdHJvbmljKSYjeEQ7MTkzMi02MjAzIChMaW5raW5nKTwvaXNi

bj48YWNjZXNzaW9uLW51bT4yMzQwOTA2MzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11

cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjM0MDkwNjM8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMzU2OTQ2NzwvY3VzdG9tMj48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTM3MS9qb3VybmFsLnBvbmUuMDA1NTg0NzwvZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYWxhcmlhPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48

UmVjTnVtPjEyNTI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMS0zNDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEyNTI8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDQ5NjI1NSI+MTI1Mjwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+S2FsYXJpYSwgUi4gTi48L2F1dGhv

cj48YXV0aG9yPkNvaGVuLCBELiBMLjwvYXV0aG9yPjxhdXRob3I+R3JlZW5iZXJnLCBCLiBELjwv

YXV0aG9yPjxhdXRob3I+U2F2YWdlLCBNLiBKLjwvYXV0aG9yPjxhdXRob3I+Qm9nZGFub3ZpYywg

Ti4gRS48L2F1dGhvcj48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5MYW5uZmVs

dCwgTC48L2F1dGhvcj48YXV0aG9yPkFkZW0sIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp

YnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIENhc2UgV2VzdGVy

biBSZXNlcnZlIFVuaXZlcnNpdHksIENsZXZlbGFuZCwgT0ggNDQxMDYsIFVTQS48L2F1dGgtYWRk

cmVzcz48dGl0bGVzPjx0aXRsZT5BYnVuZGFuY2Ugb2YgdGhlIGxvbmdlciBBIGJldGEgNDIgaW4g

bmVvY29ydGljYWwgYW5kIGNlcmVicm92YXNjdWxhciBhbXlsb2lkIGJldGEgZGVwb3NpdHMgaW4g

U3dlZGlzaCBmYW1pbGlhbCBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgYW5kIERvd24mYXBvcztz

IHN5bmRyb21lPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5ldXJvcmVwb3J0PC9zZWNvbmRhcnkt

dGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmV1cm9yZXBvcnQ8L2Z1bGwt

dGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMzc3LTgxPC9wYWdlcz48dm9sdW1lPjc8L3ZvbHVt

ZT48bnVtYmVyPjg8L251bWJlcj48ZWRpdGlvbj4xOTk2LzA1LzMxPC9lZGl0aW9uPjxrZXl3b3Jk

cz48a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3Jk

PkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2dl

bmV0aWNzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRl

cy8qYW5hbHlzaXMvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3Rl

aW4gUHJlY3Vyc29yL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIENvcnRleC8q

Y2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicm92YXNjdWxhciBDaXJjdWxhdGlvbi8q

cGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5Eb3duIFN5bmRyb21lL2dlbmV0aWNzLyptZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9o

aXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5

d29yZD5NdXRhdGlvbjwva2V5d29yZD48a2V5d29yZD5OZXJ2ZSBUaXNzdWUgUHJvdGVpbnMvKmFu

YWx5c2lzL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPlBlcmlvZGljaXR5PC9rZXl3b3JkPjxr

ZXl3b3JkPlN3ZWRlbjwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk2PC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+TWF5IDMxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+

MDk1OS00OTY1IChQcmludCkmI3hEOzA5NTktNDk2NSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lv

bi1udW0+ODg1NjY3OTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvODg1NjY3OTwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5NYXR0c3NvbjwvQXV0aG9y

PjxZZWFyPjIwMDk8L1llYXI+PFJlY051bT4xMjUzPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJl

cj4xMjUzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndh

MHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ0OTYzMzci

PjEyNTM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xl

Ij4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1hdHRzc29uLCBO

LjwvYXV0aG9yPjxhdXRob3I+WmV0dGVyYmVyZywgSC48L2F1dGhvcj48YXV0aG9yPkhhbnNzb24s

IE8uPC9hdXRob3I+PGF1dGhvcj5BbmRyZWFzZW4sIE4uPC9hdXRob3I+PGF1dGhvcj5QYXJuZXR0

aSwgTC48L2F1dGhvcj48YXV0aG9yPkpvbnNzb24sIE0uPC9hdXRob3I+PGF1dGhvcj5IZXJ1a2th

LCBTLiBLLjwvYXV0aG9yPjxhdXRob3I+dmFuIGRlciBGbGllciwgVy4gTS48L2F1dGhvcj48YXV0

aG9yPkJsYW5rZW5zdGVpbiwgTS4gQS48L2F1dGhvcj48YXV0aG9yPkV3ZXJzLCBNLjwvYXV0aG9y

PjxhdXRob3I+UmljaCwgSy48L2F1dGhvcj48YXV0aG9yPkthaXNlciwgRS48L2F1dGhvcj48YXV0

aG9yPlZlcmJlZWssIE0uPC9hdXRob3I+PGF1dGhvcj5Uc29sYWtpLCBNLjwvYXV0aG9yPjxhdXRo

b3I+TXVsdWdldGEsIEUuPC9hdXRob3I+PGF1dGhvcj5Sb3NlbiwgRS48L2F1dGhvcj48YXV0aG9y

PkFhcnNsYW5kLCBELjwvYXV0aG9yPjxhdXRob3I+Vmlzc2VyLCBQLiBKLjwvYXV0aG9yPjxhdXRo

b3I+U2Nocm9kZXIsIEouPC9hdXRob3I+PGF1dGhvcj5NYXJjdXNzb24sIEouPC9hdXRob3I+PGF1

dGhvcj5kZSBMZW9uLCBNLjwvYXV0aG9yPjxhdXRob3I+SGFtcGVsLCBILjwvYXV0aG9yPjxhdXRo

b3I+U2NoZWx0ZW5zLCBQLjwvYXV0aG9yPjxhdXRob3I+UGlydHRpbGEsIFQuPC9hdXRob3I+PGF1

dGhvcj5XYWxsaW4sIEEuPC9hdXRob3I+PGF1dGhvcj5Kb25oYWdlbiwgTS4gRS48L2F1dGhvcj48

YXV0aG9yPk1pbnRob24sIEwuPC9hdXRob3I+PGF1dGhvcj5XaW5ibGFkLCBCLjwvYXV0aG9yPjxh

dXRob3I+Qmxlbm5vdywgSy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgt

YWRkcmVzcz5JbnN0aXR1dGUgb2YgTmV1cm9zY2llbmNlIGFuZCBQaHlzaW9sb2d5LCBEZXBhcnRt

ZW50IG9mIE5ldXJvY2hlbWlzdHJ5IGFuZCBQc3ljaGlhdHJ5LCBUaGUgU2FobGdyZW5za2EgQWNh

ZGVteSBhdCBVbml2ZXJzaXR5IG9mIEdvdGhlbmJ1cmcsIE1vbG5kYWwsIFN3ZWRlbi4gbmlrbGFz

Lm1hdHRzc29uQG5ldXJvLmd1LnNlPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Q1NGIGJp

b21hcmtlcnMgYW5kIGluY2lwaWVudCBBbHpoZWltZXIgZGlzZWFzZSBpbiBwYXRpZW50cyB3aXRo

IG1pbGQgY29nbml0aXZlIGltcGFpcm1lbnQ8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SkFNQTwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4zODUtOTM8L3BhZ2VzPjx2b2x1bWU+MzAy

PC92b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PGVkaXRpb24+MjAwOS8wNy8yMzwvZWRpdGlvbj48

a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48

a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlz

ZWFzZS8qY2VyZWJyb3NwaW5hbCBmbHVpZC8qZGlhZ25vc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkFt

eWxvaWQgYmV0YS1QZXB0aWRlcy8qY2VyZWJyb3NwaW5hbCBmbHVpZDwva2V5d29yZD48a2V5d29y

ZD5CaW9tYXJrZXJzL2NlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+Q29nbml0

aW9uIERpc29yZGVycy8qY2VyZWJyb3NwaW5hbCBmbHVpZDwva2V5d29yZD48a2V5d29yZD5Db2hv

cnQgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5Dcm9zcy1TZWN0aW9uYWwgU3R1ZGllczwva2V5

d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxr

ZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdv

cmQ+UGVwdGlkZSBGcmFnbWVudHMvKmNlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdv

cmQ+UGhvc3Bob3RocmVvbmluZTwva2V5d29yZD48a2V5d29yZD5TZW5zaXRpdml0eSBhbmQgU3Bl

Y2lmaWNpdHk8L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5zLypjZXJlYnJvc3BpbmFsIGZs

dWlkL2NoZW1pc3RyeTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA5PC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+SnVsIDIyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+

MTUzOC0zNTk4IChFbGVjdHJvbmljKSYjeEQ7MDA5OC03NDg0IChMaW5raW5nKTwvaXNibj48YWNj

ZXNzaW9uLW51bT4xOTYyMjgxNzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1

cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTk2MjI4MTc8L3VybD48L3Jl

bGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDEvamFtYS4y

MDA5LjEwNjQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48

QXV0aG9yPkVja21hbjwvQXV0aG9yPjxZZWFyPjE5OTc8L1llYXI+PFJlY051bT4xMjY3PC9SZWNO

dW0+PHJlY29yZD48cmVjLW51bWJlcj4xMjY3PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0

aW1lc3RhbXA9IjE1MzQ0OTY5MzEiPjEyNjc8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUg

bmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9y

cz48YXV0aG9yPkVja21hbiwgQy4gQi48L2F1dGhvcj48YXV0aG9yPk1laHRhLCBOLiBELjwvYXV0

aG9yPjxhdXRob3I+Q3Jvb2ssIFIuPC9hdXRob3I+PGF1dGhvcj5QZXJlei10dXIsIEouPC9hdXRo

b3I+PGF1dGhvcj5QcmloYXIsIEcuPC9hdXRob3I+PGF1dGhvcj5QZmVpZmZlciwgRS48L2F1dGhv

cj48YXV0aG9yPkdyYWZmLVJhZGZvcmQsIE4uPC9hdXRob3I+PGF1dGhvcj5IaW5kZXIsIFAuPC9h

dXRob3I+PGF1dGhvcj5ZYWdlciwgRC48L2F1dGhvcj48YXV0aG9yPlplbmssIEIuPC9hdXRob3I+

PGF1dGhvcj5SZWZvbG8sIEwuIE0uPC9hdXRob3I+PGF1dGhvcj5QcmFkYSwgQy4gTS48L2F1dGhv

cj48YXV0aG9yPllvdW5raW4sIFMuIEcuPC9hdXRob3I+PGF1dGhvcj5IdXR0b24sIE0uPC9hdXRo

b3I+PGF1dGhvcj5IYXJkeSwgSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1

dGgtYWRkcmVzcz5NYXlvIENsaW5pYyBKYWNrc29udmlsbGUsIDQ1MDAgU2FuIFBhYmxvIFJvYWQs

IEphY2tzb252aWxsZSwgRkwgMzIyMjQsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRs

ZT5BIG5ldyBwYXRob2dlbmljIG11dGF0aW9uIGluIHRoZSBBUFAgZ2VuZSAoSTcxNlYpIGluY3Jl

YXNlcyB0aGUgcmVsYXRpdmUgcHJvcG9ydGlvbiBvZiBBIGJldGEgNDIoNDMpPC90aXRsZT48c2Vj

b25kYXJ5LXRpdGxlPkh1bSBNb2wgR2VuZXQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5IdW0gTW9sIEdlbmV0PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNh

bD48cGFnZXM+MjA4Ny05PC9wYWdlcz48dm9sdW1lPjY8L3ZvbHVtZT48bnVtYmVyPjEyPC9udW1i

ZXI+PGVkaXRpb24+MTk5Ny8xMS8wNTwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWdlIG9m

IE9uc2V0PC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2V0aW9sb2d5LypnZW5l

dGljczwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvKmdlbmV0aWNzPC9r

ZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1Qcm90ZWluIFByZWN1cnNvci8qZ2VuZXRpY3M8

L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29y

ZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5QZXB0aWRlIEZyYWdtZW50

cy8qZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+KlBvaW50IE11dGF0aW9uPC9rZXl3b3JkPjwv

a2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5Ob3Y8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wOTY0LTY5MDYgKFByaW50KSYjeEQ7MDk2NC02

OTA2IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT45MzI4NDcyPC9hY2Nlc3Npb24tbnVt

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC85MzI4NDcyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48

Q2l0ZT48QXV0aG9yPlNhbmRlYnJpbmc8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNOdW0+

MTI2OTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTI2OTwvcmVjLW51bWJlcj48Zm9yZWln

bi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6

cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0NDk4MzkzIj4xMjY5PC9rZXk+PC9mb3JlaWduLWtleXM+

PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRv

cnM+PGF1dGhvcnM+PGF1dGhvcj5TYW5kZWJyaW5nLCBBLjwvYXV0aG9yPjxhdXRob3I+V2VsYW5k

ZXIsIEguPC9hdXRob3I+PGF1dGhvcj5XaW5ibGFkLCBCLjwvYXV0aG9yPjxhdXRob3I+R3JhZmYs

IEMuPC9hdXRob3I+PGF1dGhvcj5UamVybmJlcmcsIEwuIE8uPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENh

cmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0dXRldCwgS0ktQWx6aGVp

bWVyJmFwb3M7cyBEaXNlYXNlIFJlc2VhcmNoIGNlbnRlciAoS0ktQURSQyksIEh1ZGRpbmdlLCBT

d2VkZW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGhlIHBhdGhvZ2VuaWMgYWJldGE0

MyBpcyBlbnJpY2hlZCBpbiBmYW1pbGlhbCBhbmQgc3BvcmFkaWMgQWx6aGVpbWVyIGRpc2Vhc2U8

L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UExvUyBPbmU8L3NlY29uZGFyeS10aXRsZT48L3RpdGxl

cz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5QTG9TIE9uZTwvZnVsbC10aXRsZT48L3BlcmlvZGlj

YWw+PHBhZ2VzPmU1NTg0NzwvcGFnZXM+PHZvbHVtZT44PC92b2x1bWU+PG51bWJlcj4yPC9udW1i

ZXI+PGVkaXRpb24+MjAxMy8wMi8xNTwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8

L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zl

cjwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qbWV0YWJvbGlzbS9wYXRob2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzLyptZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPkJyYWluL21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPkVuenltZS1MaW5rZWQgSW1tdW5vc29yYmVudCBBc3NheTwva2V5d29yZD48a2V5d29yZD5G

ZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tl

eXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVpbiBJc29m

b3Jtczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEzPC95ZWFyPjwvZGF0ZXM+

PGlzYm4+MTkzMi02MjAzIChFbGVjdHJvbmljKSYjeEQ7MTkzMi02MjAzIChMaW5raW5nKTwvaXNi

bj48YWNjZXNzaW9uLW51bT4yMzQwOTA2MzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11

cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjM0MDkwNjM8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMzU2OTQ2NzwvY3VzdG9tMj48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTM3MS9qb3VybmFsLnBvbmUuMDA1NTg0NzwvZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 31-34. Persons with Down’s syndrome also present an over-production of Aβ and an early onset of AD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYWxhcmlhPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48

UmVjTnVtPjEyNTI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEyNTI8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDQ5NjI1NSI+MTI1Mjwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+S2FsYXJpYSwgUi4gTi48L2F1dGhvcj48

YXV0aG9yPkNvaGVuLCBELiBMLjwvYXV0aG9yPjxhdXRob3I+R3JlZW5iZXJnLCBCLiBELjwvYXV0

aG9yPjxhdXRob3I+U2F2YWdlLCBNLiBKLjwvYXV0aG9yPjxhdXRob3I+Qm9nZGFub3ZpYywgTi4g

RS48L2F1dGhvcj48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5MYW5uZmVsdCwg

TC48L2F1dGhvcj48YXV0aG9yPkFkZW0sIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIENhc2UgV2VzdGVybiBS

ZXNlcnZlIFVuaXZlcnNpdHksIENsZXZlbGFuZCwgT0ggNDQxMDYsIFVTQS48L2F1dGgtYWRkcmVz

cz48dGl0bGVzPjx0aXRsZT5BYnVuZGFuY2Ugb2YgdGhlIGxvbmdlciBBIGJldGEgNDIgaW4gbmVv

Y29ydGljYWwgYW5kIGNlcmVicm92YXNjdWxhciBhbXlsb2lkIGJldGEgZGVwb3NpdHMgaW4gU3dl

ZGlzaCBmYW1pbGlhbCBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgYW5kIERvd24mYXBvcztzIHN5

bmRyb21lPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5ldXJvcmVwb3J0PC9zZWNvbmRhcnktdGl0

bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmV1cm9yZXBvcnQ8L2Z1bGwtdGl0

bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMzc3LTgxPC9wYWdlcz48dm9sdW1lPjc8L3ZvbHVtZT48

bnVtYmVyPjg8L251bWJlcj48ZWRpdGlvbj4xOTk2LzA1LzMxPC9lZGl0aW9uPjxrZXl3b3Jkcz48

a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFn

ZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2dlbmV0

aWNzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy8q

YW5hbHlzaXMvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW4g

UHJlY3Vyc29yL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIENvcnRleC8qY2hl

bWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicm92YXNjdWxhciBDaXJjdWxhdGlvbi8qcGh5

c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5Eb3duIFN5bmRyb21lL2dlbmV0aWNzLyptZXRhYm9s

aXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9oaXN0

b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29y

ZD5NdXRhdGlvbjwva2V5d29yZD48a2V5d29yZD5OZXJ2ZSBUaXNzdWUgUHJvdGVpbnMvKmFuYWx5

c2lzL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPlBlcmlvZGljaXR5PC9rZXl3b3JkPjxrZXl3

b3JkPlN3ZWRlbjwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk2PC95ZWFyPjxw

dWItZGF0ZXM+PGRhdGU+TWF5IDMxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDk1

OS00OTY1IChQcmludCkmI3hEOzA5NTktNDk2NSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1u

dW0+ODg1NjY3OTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6

Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvODg1NjY3OTwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYWxhcmlhPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48

UmVjTnVtPjEyNTI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEyNTI8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDQ5NjI1NSI+MTI1Mjwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+S2FsYXJpYSwgUi4gTi48L2F1dGhvcj48

YXV0aG9yPkNvaGVuLCBELiBMLjwvYXV0aG9yPjxhdXRob3I+R3JlZW5iZXJnLCBCLiBELjwvYXV0

aG9yPjxhdXRob3I+U2F2YWdlLCBNLiBKLjwvYXV0aG9yPjxhdXRob3I+Qm9nZGFub3ZpYywgTi4g

RS48L2F1dGhvcj48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5MYW5uZmVsdCwg

TC48L2F1dGhvcj48YXV0aG9yPkFkZW0sIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIENhc2UgV2VzdGVybiBS

ZXNlcnZlIFVuaXZlcnNpdHksIENsZXZlbGFuZCwgT0ggNDQxMDYsIFVTQS48L2F1dGgtYWRkcmVz

cz48dGl0bGVzPjx0aXRsZT5BYnVuZGFuY2Ugb2YgdGhlIGxvbmdlciBBIGJldGEgNDIgaW4gbmVv

Y29ydGljYWwgYW5kIGNlcmVicm92YXNjdWxhciBhbXlsb2lkIGJldGEgZGVwb3NpdHMgaW4gU3dl

ZGlzaCBmYW1pbGlhbCBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgYW5kIERvd24mYXBvcztzIHN5

bmRyb21lPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5ldXJvcmVwb3J0PC9zZWNvbmRhcnktdGl0

bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmV1cm9yZXBvcnQ8L2Z1bGwtdGl0

bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMzc3LTgxPC9wYWdlcz48dm9sdW1lPjc8L3ZvbHVtZT48

bnVtYmVyPjg8L251bWJlcj48ZWRpdGlvbj4xOTk2LzA1LzMxPC9lZGl0aW9uPjxrZXl3b3Jkcz48

a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFn

ZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2dlbmV0

aWNzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy8q

YW5hbHlzaXMvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW4g

UHJlY3Vyc29yL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIENvcnRleC8qY2hl

bWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicm92YXNjdWxhciBDaXJjdWxhdGlvbi8qcGh5

c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5Eb3duIFN5bmRyb21lL2dlbmV0aWNzLyptZXRhYm9s

aXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9oaXN0

b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29y

ZD5NdXRhdGlvbjwva2V5d29yZD48a2V5d29yZD5OZXJ2ZSBUaXNzdWUgUHJvdGVpbnMvKmFuYWx5

c2lzL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPlBlcmlvZGljaXR5PC9rZXl3b3JkPjxrZXl3

b3JkPlN3ZWRlbjwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk2PC95ZWFyPjxw

dWItZGF0ZXM+PGRhdGU+TWF5IDMxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDk1

OS00OTY1IChQcmludCkmI3hEOzA5NTktNDk2NSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1u

dW0+ODg1NjY3OTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6

Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvODg1NjY3OTwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 31. Transgenic mice overexpressing Aβ are available for the investigation of the AD pathogenic mechanisms. Many of these models develop AD-like lesions and show impaired memory PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdHVyY2hsZXItUGllcnJhdDwvQXV0aG9yPjxZZWFyPjE5

OTc8L1llYXI+PFJlY051bT4xMjcyPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJz

dXBlcnNjcmlwdCI+MzUtMzg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJl

cj4xMjcyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndh

MHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ0OTg3NDUi

PjEyNzI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xl

Ij4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlN0dXJjaGxlci1Q

aWVycmF0LCBDLjwvYXV0aG9yPjxhdXRob3I+QWJyYW1vd3NraSwgRC48L2F1dGhvcj48YXV0aG9y

PkR1a2UsIE0uPC9hdXRob3I+PGF1dGhvcj5XaWVkZXJob2xkLCBLLiBILjwvYXV0aG9yPjxhdXRo

b3I+TWlzdGwsIEMuPC9hdXRob3I+PGF1dGhvcj5Sb3RoYWNoZXIsIFMuPC9hdXRob3I+PGF1dGhv

cj5MZWRlcm1hbm4sIEIuPC9hdXRob3I+PGF1dGhvcj5CdXJraSwgSy48L2F1dGhvcj48YXV0aG9y

PkZyZXksIFAuPC9hdXRob3I+PGF1dGhvcj5QYWdhbmV0dGksIFAuIEEuPC9hdXRob3I+PGF1dGhv

cj5XYXJpZGVsLCBDLjwvYXV0aG9yPjxhdXRob3I+Q2FsaG91biwgTS4gRS48L2F1dGhvcj48YXV0

aG9yPkp1Y2tlciwgTS48L2F1dGhvcj48YXV0aG9yPlByb2JzdCwgQS48L2F1dGhvcj48YXV0aG9y

PlN0YXVmZW5iaWVsLCBNLjwvYXV0aG9yPjxhdXRob3I+U29tbWVyLCBCLjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPk5vdmFydGlzIFBoYXJtYSwgSW5jLiwg

QmFzZWwsIFN3aXR6ZXJsYW5kLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlR3byBhbXls

b2lkIHByZWN1cnNvciBwcm90ZWluIHRyYW5zZ2VuaWMgbW91c2UgbW9kZWxzIHdpdGggQWx6aGVp

bWVyIGRpc2Vhc2UtbGlrZSBwYXRob2xvZ3k8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UHJvYyBO

YXRsIEFjYWQgU2NpIFUgUyBBPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9mdWxsLXRpdGxlPjwvcGVyaW9k

aWNhbD48cGFnZXM+MTMyODctOTI8L3BhZ2VzPjx2b2x1bWU+OTQ8L3ZvbHVtZT48bnVtYmVyPjI0

PC9udW1iZXI+PGVkaXRpb24+MTk5Ny8xMi8xNjwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+

QWx6aGVpbWVyIERpc2Vhc2UvKmdlbmV0aWNzL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5B

bXlsb2lkIGJldGEtUHJvdGVpbiBQcmVjdXJzb3IvKmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3Jk

PkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFuaW1hbDwva2V5d29y

ZD48a2V5d29yZD5IaXBwb2NhbXB1cy9tZXRhYm9saXNtL3BhdGhvbG9neTwva2V5d29yZD48a2V5

d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNl

LCBUcmFuc2dlbmljPC9rZXl3b3JkPjxrZXl3b3JkPk11dGF0aW9uPC9rZXl3b3JkPjxrZXl3b3Jk

Pk5lb2NvcnRleC9tZXRhYm9saXNtL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5OZXVyaXRl

czwva2V5d29yZD48a2V5d29yZD5QaG9zcGhvcnlsYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+UHJv

bW90ZXIgUmVnaW9ucywgR2VuZXRpYzwva2V5d29yZD48a2V5d29yZD5SZWNlcHRvcnMsIENob2xp

bmVyZ2ljL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5zL21ldGFib2xp

c208L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MTk5NzwveWVhcj48cHViLWRhdGVz

PjxkYXRlPk5vdiAyNTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMjctODQyNCAo

UHJpbnQpJiN4RDswMDI3LTg0MjQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjkzNzE4

Mzg8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5j

YmkubmxtLm5paC5nb3YvcHVibWVkLzkzNzE4Mzg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGN1c3RvbTI+UE1DMjQzMDE8L2N1c3RvbTI+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+

SG9sY29tYjwvQXV0aG9yPjxZZWFyPjE5OTg8L1llYXI+PFJlY051bT4xMjcxPC9SZWNOdW0+PHJl

Y29yZD48cmVjLW51bWJlcj4xMjcxPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3Rh

bXA9IjE1MzQ0OTg3MjAiPjEyNzE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkhvbGNvbWIsIEwuPC9hdXRob3I+PGF1dGhvcj5Hb3Jkb24sIE0uIE4uPC9hdXRob3I+PGF1

dGhvcj5NY0dvd2FuLCBFLjwvYXV0aG9yPjxhdXRob3I+WXUsIFguPC9hdXRob3I+PGF1dGhvcj5C

ZW5rb3ZpYywgUy48L2F1dGhvcj48YXV0aG9yPkphbnR6ZW4sIFAuPC9hdXRob3I+PGF1dGhvcj5X

cmlnaHQsIEsuPC9hdXRob3I+PGF1dGhvcj5TYWFkLCBJLjwvYXV0aG9yPjxhdXRob3I+TXVlbGxl

ciwgUi48L2F1dGhvcj48YXV0aG9yPk1vcmdhbiwgRC48L2F1dGhvcj48YXV0aG9yPlNhbmRlcnMs

IFMuPC9hdXRob3I+PGF1dGhvcj5aZWhyLCBDLjwvYXV0aG9yPjxhdXRob3I+TyZhcG9zO0NhbXBv

LCBLLjwvYXV0aG9yPjxhdXRob3I+SGFyZHksIEouPC9hdXRob3I+PGF1dGhvcj5QcmFkYSwgQy4g

TS48L2F1dGhvcj48YXV0aG9yPkVja21hbiwgQy48L2F1dGhvcj48YXV0aG9yPllvdW5raW4sIFMu

PC9hdXRob3I+PGF1dGhvcj5Ic2lhbywgSy48L2F1dGhvcj48YXV0aG9yPkR1ZmYsIEsuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQ

aGFybWFjb2xvZ3ksIFVuaXZlcnNpdHkgb2YgU291dGggRmxvcmlkYSwgVGFtcGEgMzM2MTIsIFVT

QS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BY2NlbGVyYXRlZCBBbHpoZWltZXItdHlw

ZSBwaGVub3R5cGUgaW4gdHJhbnNnZW5pYyBtaWNlIGNhcnJ5aW5nIGJvdGggbXV0YW50IGFteWxv

aWQgcHJlY3Vyc29yIHByb3RlaW4gYW5kIHByZXNlbmlsaW4gMSB0cmFuc2dlbmVzPC90aXRsZT48

c2Vjb25kYXJ5LXRpdGxlPk5hdCBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+

OTctMTAwPC9wYWdlcz48dm9sdW1lPjQ8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlv

bj4xOTk4LzAxLzE0PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFz

ZS8qZ2VuZXRpY3MvcGF0aG9sb2d5LypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZCBiZXRhLVByb3RlaW4gUHJlY3Vyc29yL2Jpb3N5bnRoZXNpcy8qZ2VuZXRpY3M8L2tl

eXdvcmQ+PGtleXdvcmQ+QW5hbHlzaXMgb2YgVmFyaWFuY2U8L2tleXdvcmQ+PGtleXdvcmQ+QW5p

bWFsczwva2V5d29yZD48a2V5d29yZD5CcmFpbi9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

Q2VyZWJyYWwgQ29ydGV4L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5Dcm9zc2VzLCBHZW5l

dGljPC9rZXl3b3JkPjxrZXl3b3JkPkdlbm90eXBlPC9rZXl3b3JkPjxrZXl3b3JkPkdsaWFsIEZp

YnJpbGxhcnkgQWNpZGljIFByb3RlaW4vYW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5z

PC9rZXl3b3JkPjxrZXl3b3JkPk1lbWJyYW5lIFByb3RlaW5zL2Jpb3N5bnRoZXNpcy8qZ2VuZXRp

Y3M8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFuc2dl

bmljPC9rZXl3b3JkPjxrZXl3b3JkPk1vdG9yIEFjdGl2aXR5PC9rZXl3b3JkPjxrZXl3b3JkPlBv

c3R1cmU8L2tleXdvcmQ+PGtleXdvcmQ+UHJlc2VuaWxpbi0xPC9rZXl3b3JkPjxrZXl3b3JkPlBz

eWNob21vdG9yIFBlcmZvcm1hbmNlPC9rZXl3b3JkPjxrZXl3b3JkPlJlZmxleDwva2V5d29yZD48

a2V5d29yZD5TZWl6dXJlczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk4PC95

ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SmFuPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+

MTA3OC04OTU2IChQcmludCkmI3hEOzEwNzgtODk1NiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lv

bi1udW0+OTQyNzYxNDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvOTQyNzYxNDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5HYW1lczwvQXV0aG9yPjxZ

ZWFyPjE5OTU8L1llYXI+PFJlY051bT4xMjcwPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4x

MjcwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4

NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ0OTg2NzciPjEy

NzA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x

NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkdhbWVzLCBELjwvYXV0

aG9yPjxhdXRob3I+QWRhbXMsIEQuPC9hdXRob3I+PGF1dGhvcj5BbGVzc2FuZHJpbmksIFIuPC9h

dXRob3I+PGF1dGhvcj5CYXJib3VyLCBSLjwvYXV0aG9yPjxhdXRob3I+QmVydGhlbGV0dGUsIFAu

PC9hdXRob3I+PGF1dGhvcj5CbGFja3dlbGwsIEMuPC9hdXRob3I+PGF1dGhvcj5DYXJyLCBULjwv

YXV0aG9yPjxhdXRob3I+Q2xlbWVucywgSi48L2F1dGhvcj48YXV0aG9yPkRvbmFsZHNvbiwgVC48

L2F1dGhvcj48YXV0aG9yPkdpbGxlc3BpZSwgRi48L2F1dGhvcj48YXV0aG9yPmV0IGFsLiw8L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5BdGhlbmEgTmV1cm9z

Y2llbmNlcywgSW5jLiwgU291dGggU2FuIEZyYW5jaXNjbywgQ2FsaWZvcm5pYSA5NDA4MC48L2F1

dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BbHpoZWltZXItdHlwZSBuZXVyb3BhdGhvbG9neSBp

biB0cmFuc2dlbmljIG1pY2Ugb3ZlcmV4cHJlc3NpbmcgVjcxN0YgYmV0YS1hbXlsb2lkIHByZWN1

cnNvciBwcm90ZWluPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5hdHVyZTwvc2Vjb25kYXJ5LXRp

dGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5hdHVyZTwvZnVsbC10aXRsZT48

L3BlcmlvZGljYWw+PHBhZ2VzPjUyMy03PC9wYWdlcz48dm9sdW1lPjM3Mzwvdm9sdW1lPjxudW1i

ZXI+NjUxNDwvbnVtYmVyPjxlZGl0aW9uPjE5OTUvMDIvMDk8L2VkaXRpb24+PGtleXdvcmRzPjxr

ZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL21ldGFib2xpc20vKnBhdGhvbG9neTwva2V5d29yZD48

a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvZ2VuZXRpY3MvKm1ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW4gUHJlY3Vyc29yL2dlbmV0aWNzL21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CYXNlIFNl

cXVlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL21ldGFib2xpc20vKnBhdGhvbG9neTwva2V5

d29yZD48a2V5d29yZD5ETkEgUHJpbWVyczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdv

cmQ+PGtleXdvcmQ+SW1tdW5vZW56eW1lIFRlY2huaXF1ZXM8L2tleXdvcmQ+PGtleXdvcmQ+TWlj

ZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFuc2dlbmljPC9rZXl3b3JkPjxrZXl3b3JkPk1p

Y3Jvc2NvcHksIENvbmZvY2FsPC9rZXl3b3JkPjxrZXl3b3JkPk1vbGVjdWxhciBTZXF1ZW5jZSBE

YXRhPC9rZXl3b3JkPjxrZXl3b3JkPk11dGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlBsYXRlbGV0

LURlcml2ZWQgR3Jvd3RoIEZhY3Rvci9nZW5ldGljcy9tZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5

d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5GZWIgOTwvZGF0

ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMjgtMDgzNiAoUHJpbnQpJiN4RDswMDI4LTA4

MzYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjc4NDU0NjU8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVi

bWVkLzc4NDU0NjU8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjEwMzgvMzczNTIzYTA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3Jk

PjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk9kZG88L0F1dGhvcj48WWVhcj4yMDAzPC9ZZWFyPjxSZWNO

dW0+MTM3MjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTM3MjwvcmVjLW51bWJlcj48Zm9y

ZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0

c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0NDk5OTc1Ij4xMzcyPC9rZXk+PC9mb3JlaWduLWtl

eXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmli

dXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5PZGRvLCBTLjwvYXV0aG9yPjxhdXRob3I+Q2FjY2Ftbywg

QS48L2F1dGhvcj48YXV0aG9yPlNoZXBoZXJkLCBKLiBELjwvYXV0aG9yPjxhdXRob3I+TXVycGh5

LCBNLiBQLjwvYXV0aG9yPjxhdXRob3I+R29sZGUsIFQuIEUuPC9hdXRob3I+PGF1dGhvcj5LYXll

ZCwgUi48L2F1dGhvcj48YXV0aG9yPk1ldGhlcmF0ZSwgUi48L2F1dGhvcj48YXV0aG9yPk1hdHRz

b24sIE0uIFAuPC9hdXRob3I+PGF1dGhvcj5Ba2JhcmksIFkuPC9hdXRob3I+PGF1dGhvcj5MYUZl

cmxhLCBGLiBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNz

PkRlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5IGFuZCBCZWhhdmlvciwgVW5pdmVyc2l0eSBvZiBD

YWxpZm9ybmlhLCBJcnZpbmUsIElydmluZSwgQ2FsaWZvcm5pYSA5MjY5NywgVVNBLjwvYXV0aC1h

ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRyaXBsZS10cmFuc2dlbmljIG1vZGVsIG9mIEFsemhlaW1l

ciZhcG9zO3MgZGlzZWFzZSB3aXRoIHBsYXF1ZXMgYW5kIHRhbmdsZXM6IGludHJhY2VsbHVsYXIg

QWJldGEgYW5kIHN5bmFwdGljIGR5c2Z1bmN0aW9uPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5l

dXJvbjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5l

dXJvbjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjQwOS0yMTwvcGFnZXM+PHZvbHVt

ZT4zOTwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxlZGl0aW9uPjIwMDMvMDgvMDU8L2VkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypnZW5ldGljcy9wYXRob2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzLypnZW5ldGljczwva2V5

d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPipEaXNlYXNlIE1vZGVscywg

QW5pbWFsPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbnRyYWNl

bGx1bGFyIEZsdWlkLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+

PGtleXdvcmQ+TWljZSwgSW5icmVkIEM1N0JMPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIFRyYW5z

Z2VuaWM8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9maWJyaWxsYXJ5IFRhbmdsZXMvKmdlbmV0aWNz

L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5QbGFxdWUsIEFteWxvaWQvZ2VuZXRpY3MvcGF0

aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlN5bmFwc2VzLypnZW5ldGljcy8qcGF0aG9sb2d5PC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5KdWwgMzE8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wODk2LTYyNzMgKFByaW50

KSYjeEQ7MDg5Ni02MjczIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xMjg5NTQxNzwv

YWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5u

bG0ubmloLmdvdi9wdWJtZWQvMTI4OTU0MTc8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9y

ZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdHVyY2hsZXItUGllcnJhdDwvQXV0aG9yPjxZZWFyPjE5

OTc8L1llYXI+PFJlY051bT4xMjcyPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJz

dXBlcnNjcmlwdCI+MzUtMzg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJl

cj4xMjcyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndh

MHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ0OTg3NDUi

PjEyNzI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xl

Ij4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlN0dXJjaGxlci1Q

aWVycmF0LCBDLjwvYXV0aG9yPjxhdXRob3I+QWJyYW1vd3NraSwgRC48L2F1dGhvcj48YXV0aG9y

PkR1a2UsIE0uPC9hdXRob3I+PGF1dGhvcj5XaWVkZXJob2xkLCBLLiBILjwvYXV0aG9yPjxhdXRo

b3I+TWlzdGwsIEMuPC9hdXRob3I+PGF1dGhvcj5Sb3RoYWNoZXIsIFMuPC9hdXRob3I+PGF1dGhv

cj5MZWRlcm1hbm4sIEIuPC9hdXRob3I+PGF1dGhvcj5CdXJraSwgSy48L2F1dGhvcj48YXV0aG9y

PkZyZXksIFAuPC9hdXRob3I+PGF1dGhvcj5QYWdhbmV0dGksIFAuIEEuPC9hdXRob3I+PGF1dGhv

cj5XYXJpZGVsLCBDLjwvYXV0aG9yPjxhdXRob3I+Q2FsaG91biwgTS4gRS48L2F1dGhvcj48YXV0

aG9yPkp1Y2tlciwgTS48L2F1dGhvcj48YXV0aG9yPlByb2JzdCwgQS48L2F1dGhvcj48YXV0aG9y

PlN0YXVmZW5iaWVsLCBNLjwvYXV0aG9yPjxhdXRob3I+U29tbWVyLCBCLjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPk5vdmFydGlzIFBoYXJtYSwgSW5jLiwg

QmFzZWwsIFN3aXR6ZXJsYW5kLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlR3byBhbXls

b2lkIHByZWN1cnNvciBwcm90ZWluIHRyYW5zZ2VuaWMgbW91c2UgbW9kZWxzIHdpdGggQWx6aGVp

bWVyIGRpc2Vhc2UtbGlrZSBwYXRob2xvZ3k8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UHJvYyBO

YXRsIEFjYWQgU2NpIFUgUyBBPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9mdWxsLXRpdGxlPjwvcGVyaW9k

aWNhbD48cGFnZXM+MTMyODctOTI8L3BhZ2VzPjx2b2x1bWU+OTQ8L3ZvbHVtZT48bnVtYmVyPjI0

PC9udW1iZXI+PGVkaXRpb24+MTk5Ny8xMi8xNjwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+

QWx6aGVpbWVyIERpc2Vhc2UvKmdlbmV0aWNzL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5B

bXlsb2lkIGJldGEtUHJvdGVpbiBQcmVjdXJzb3IvKmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3Jk

PkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFuaW1hbDwva2V5d29y

ZD48a2V5d29yZD5IaXBwb2NhbXB1cy9tZXRhYm9saXNtL3BhdGhvbG9neTwva2V5d29yZD48a2V5

d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNl

LCBUcmFuc2dlbmljPC9rZXl3b3JkPjxrZXl3b3JkPk11dGF0aW9uPC9rZXl3b3JkPjxrZXl3b3Jk

Pk5lb2NvcnRleC9tZXRhYm9saXNtL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5OZXVyaXRl

czwva2V5d29yZD48a2V5d29yZD5QaG9zcGhvcnlsYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+UHJv

bW90ZXIgUmVnaW9ucywgR2VuZXRpYzwva2V5d29yZD48a2V5d29yZD5SZWNlcHRvcnMsIENob2xp

bmVyZ2ljL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5zL21ldGFib2xp

c208L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MTk5NzwveWVhcj48cHViLWRhdGVz

PjxkYXRlPk5vdiAyNTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMjctODQyNCAo

UHJpbnQpJiN4RDswMDI3LTg0MjQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjkzNzE4

Mzg8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5j

YmkubmxtLm5paC5nb3YvcHVibWVkLzkzNzE4Mzg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGN1c3RvbTI+UE1DMjQzMDE8L2N1c3RvbTI+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+

SG9sY29tYjwvQXV0aG9yPjxZZWFyPjE5OTg8L1llYXI+PFJlY051bT4xMjcxPC9SZWNOdW0+PHJl

Y29yZD48cmVjLW51bWJlcj4xMjcxPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3Rh

bXA9IjE1MzQ0OTg3MjAiPjEyNzE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkhvbGNvbWIsIEwuPC9hdXRob3I+PGF1dGhvcj5Hb3Jkb24sIE0uIE4uPC9hdXRob3I+PGF1

dGhvcj5NY0dvd2FuLCBFLjwvYXV0aG9yPjxhdXRob3I+WXUsIFguPC9hdXRob3I+PGF1dGhvcj5C

ZW5rb3ZpYywgUy48L2F1dGhvcj48YXV0aG9yPkphbnR6ZW4sIFAuPC9hdXRob3I+PGF1dGhvcj5X

cmlnaHQsIEsuPC9hdXRob3I+PGF1dGhvcj5TYWFkLCBJLjwvYXV0aG9yPjxhdXRob3I+TXVlbGxl

ciwgUi48L2F1dGhvcj48YXV0aG9yPk1vcmdhbiwgRC48L2F1dGhvcj48YXV0aG9yPlNhbmRlcnMs

IFMuPC9hdXRob3I+PGF1dGhvcj5aZWhyLCBDLjwvYXV0aG9yPjxhdXRob3I+TyZhcG9zO0NhbXBv

LCBLLjwvYXV0aG9yPjxhdXRob3I+SGFyZHksIEouPC9hdXRob3I+PGF1dGhvcj5QcmFkYSwgQy4g

TS48L2F1dGhvcj48YXV0aG9yPkVja21hbiwgQy48L2F1dGhvcj48YXV0aG9yPllvdW5raW4sIFMu

PC9hdXRob3I+PGF1dGhvcj5Ic2lhbywgSy48L2F1dGhvcj48YXV0aG9yPkR1ZmYsIEsuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQ

aGFybWFjb2xvZ3ksIFVuaXZlcnNpdHkgb2YgU291dGggRmxvcmlkYSwgVGFtcGEgMzM2MTIsIFVT

QS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BY2NlbGVyYXRlZCBBbHpoZWltZXItdHlw

ZSBwaGVub3R5cGUgaW4gdHJhbnNnZW5pYyBtaWNlIGNhcnJ5aW5nIGJvdGggbXV0YW50IGFteWxv

aWQgcHJlY3Vyc29yIHByb3RlaW4gYW5kIHByZXNlbmlsaW4gMSB0cmFuc2dlbmVzPC90aXRsZT48

c2Vjb25kYXJ5LXRpdGxlPk5hdCBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+

OTctMTAwPC9wYWdlcz48dm9sdW1lPjQ8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlv

bj4xOTk4LzAxLzE0PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFz

ZS8qZ2VuZXRpY3MvcGF0aG9sb2d5LypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZCBiZXRhLVByb3RlaW4gUHJlY3Vyc29yL2Jpb3N5bnRoZXNpcy8qZ2VuZXRpY3M8L2tl

eXdvcmQ+PGtleXdvcmQ+QW5hbHlzaXMgb2YgVmFyaWFuY2U8L2tleXdvcmQ+PGtleXdvcmQ+QW5p

bWFsczwva2V5d29yZD48a2V5d29yZD5CcmFpbi9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

Q2VyZWJyYWwgQ29ydGV4L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5Dcm9zc2VzLCBHZW5l

dGljPC9rZXl3b3JkPjxrZXl3b3JkPkdlbm90eXBlPC9rZXl3b3JkPjxrZXl3b3JkPkdsaWFsIEZp

YnJpbGxhcnkgQWNpZGljIFByb3RlaW4vYW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5z

PC9rZXl3b3JkPjxrZXl3b3JkPk1lbWJyYW5lIFByb3RlaW5zL2Jpb3N5bnRoZXNpcy8qZ2VuZXRp

Y3M8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFuc2dl

bmljPC9rZXl3b3JkPjxrZXl3b3JkPk1vdG9yIEFjdGl2aXR5PC9rZXl3b3JkPjxrZXl3b3JkPlBv

c3R1cmU8L2tleXdvcmQ+PGtleXdvcmQ+UHJlc2VuaWxpbi0xPC9rZXl3b3JkPjxrZXl3b3JkPlBz

eWNob21vdG9yIFBlcmZvcm1hbmNlPC9rZXl3b3JkPjxrZXl3b3JkPlJlZmxleDwva2V5d29yZD48

a2V5d29yZD5TZWl6dXJlczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk4PC95

ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SmFuPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+

MTA3OC04OTU2IChQcmludCkmI3hEOzEwNzgtODk1NiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lv

bi1udW0+OTQyNzYxNDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvOTQyNzYxNDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5HYW1lczwvQXV0aG9yPjxZ

ZWFyPjE5OTU8L1llYXI+PFJlY051bT4xMjcwPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4x

MjcwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4

NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ0OTg2NzciPjEy

NzA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x

NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkdhbWVzLCBELjwvYXV0

aG9yPjxhdXRob3I+QWRhbXMsIEQuPC9hdXRob3I+PGF1dGhvcj5BbGVzc2FuZHJpbmksIFIuPC9h

dXRob3I+PGF1dGhvcj5CYXJib3VyLCBSLjwvYXV0aG9yPjxhdXRob3I+QmVydGhlbGV0dGUsIFAu

PC9hdXRob3I+PGF1dGhvcj5CbGFja3dlbGwsIEMuPC9hdXRob3I+PGF1dGhvcj5DYXJyLCBULjwv

YXV0aG9yPjxhdXRob3I+Q2xlbWVucywgSi48L2F1dGhvcj48YXV0aG9yPkRvbmFsZHNvbiwgVC48

L2F1dGhvcj48YXV0aG9yPkdpbGxlc3BpZSwgRi48L2F1dGhvcj48YXV0aG9yPmV0IGFsLiw8L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5BdGhlbmEgTmV1cm9z

Y2llbmNlcywgSW5jLiwgU291dGggU2FuIEZyYW5jaXNjbywgQ2FsaWZvcm5pYSA5NDA4MC48L2F1

dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BbHpoZWltZXItdHlwZSBuZXVyb3BhdGhvbG9neSBp

biB0cmFuc2dlbmljIG1pY2Ugb3ZlcmV4cHJlc3NpbmcgVjcxN0YgYmV0YS1hbXlsb2lkIHByZWN1

cnNvciBwcm90ZWluPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5hdHVyZTwvc2Vjb25kYXJ5LXRp

dGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5hdHVyZTwvZnVsbC10aXRsZT48

L3BlcmlvZGljYWw+PHBhZ2VzPjUyMy03PC9wYWdlcz48dm9sdW1lPjM3Mzwvdm9sdW1lPjxudW1i

ZXI+NjUxNDwvbnVtYmVyPjxlZGl0aW9uPjE5OTUvMDIvMDk8L2VkaXRpb24+PGtleXdvcmRzPjxr

ZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL21ldGFib2xpc20vKnBhdGhvbG9neTwva2V5d29yZD48

a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvZ2VuZXRpY3MvKm1ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW4gUHJlY3Vyc29yL2dlbmV0aWNzL21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CYXNlIFNl

cXVlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL21ldGFib2xpc20vKnBhdGhvbG9neTwva2V5

d29yZD48a2V5d29yZD5ETkEgUHJpbWVyczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdv

cmQ+PGtleXdvcmQ+SW1tdW5vZW56eW1lIFRlY2huaXF1ZXM8L2tleXdvcmQ+PGtleXdvcmQ+TWlj

ZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFuc2dlbmljPC9rZXl3b3JkPjxrZXl3b3JkPk1p

Y3Jvc2NvcHksIENvbmZvY2FsPC9rZXl3b3JkPjxrZXl3b3JkPk1vbGVjdWxhciBTZXF1ZW5jZSBE

YXRhPC9rZXl3b3JkPjxrZXl3b3JkPk11dGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlBsYXRlbGV0

LURlcml2ZWQgR3Jvd3RoIEZhY3Rvci9nZW5ldGljcy9tZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5

d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5GZWIgOTwvZGF0

ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMjgtMDgzNiAoUHJpbnQpJiN4RDswMDI4LTA4

MzYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjc4NDU0NjU8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVi

bWVkLzc4NDU0NjU8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjEwMzgvMzczNTIzYTA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3Jk

PjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk9kZG88L0F1dGhvcj48WWVhcj4yMDAzPC9ZZWFyPjxSZWNO

dW0+MTM3MjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTM3MjwvcmVjLW51bWJlcj48Zm9y

ZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0

c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0NDk5OTc1Ij4xMzcyPC9rZXk+PC9mb3JlaWduLWtl

eXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmli

dXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5PZGRvLCBTLjwvYXV0aG9yPjxhdXRob3I+Q2FjY2Ftbywg

QS48L2F1dGhvcj48YXV0aG9yPlNoZXBoZXJkLCBKLiBELjwvYXV0aG9yPjxhdXRob3I+TXVycGh5

LCBNLiBQLjwvYXV0aG9yPjxhdXRob3I+R29sZGUsIFQuIEUuPC9hdXRob3I+PGF1dGhvcj5LYXll

ZCwgUi48L2F1dGhvcj48YXV0aG9yPk1ldGhlcmF0ZSwgUi48L2F1dGhvcj48YXV0aG9yPk1hdHRz

b24sIE0uIFAuPC9hdXRob3I+PGF1dGhvcj5Ba2JhcmksIFkuPC9hdXRob3I+PGF1dGhvcj5MYUZl

cmxhLCBGLiBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNz

PkRlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5IGFuZCBCZWhhdmlvciwgVW5pdmVyc2l0eSBvZiBD

YWxpZm9ybmlhLCBJcnZpbmUsIElydmluZSwgQ2FsaWZvcm5pYSA5MjY5NywgVVNBLjwvYXV0aC1h

ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRyaXBsZS10cmFuc2dlbmljIG1vZGVsIG9mIEFsemhlaW1l

ciZhcG9zO3MgZGlzZWFzZSB3aXRoIHBsYXF1ZXMgYW5kIHRhbmdsZXM6IGludHJhY2VsbHVsYXIg

QWJldGEgYW5kIHN5bmFwdGljIGR5c2Z1bmN0aW9uPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5l

dXJvbjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5l

dXJvbjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjQwOS0yMTwvcGFnZXM+PHZvbHVt

ZT4zOTwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxlZGl0aW9uPjIwMDMvMDgvMDU8L2VkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypnZW5ldGljcy9wYXRob2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzLypnZW5ldGljczwva2V5

d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPipEaXNlYXNlIE1vZGVscywg

QW5pbWFsPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbnRyYWNl

bGx1bGFyIEZsdWlkLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+

PGtleXdvcmQ+TWljZSwgSW5icmVkIEM1N0JMPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIFRyYW5z

Z2VuaWM8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9maWJyaWxsYXJ5IFRhbmdsZXMvKmdlbmV0aWNz

L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5QbGFxdWUsIEFteWxvaWQvZ2VuZXRpY3MvcGF0

aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlN5bmFwc2VzLypnZW5ldGljcy8qcGF0aG9sb2d5PC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5KdWwgMzE8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wODk2LTYyNzMgKFByaW50

KSYjeEQ7MDg5Ni02MjczIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xMjg5NTQxNzwv

YWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5u

bG0ubmloLmdvdi9wdWJtZWQvMTI4OTU0MTc8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9y

ZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 35-38. Nevertheless, overexpression of APP in mice has received criticism due to the difference from physiological levels observed in human brains PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb2xkZTwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl

Y051bT4xMzczPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MzksNDA8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMzczPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ1MDAwNzciPjEzNzM8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkdvbGRlLCBULiBFLjwvYXV0aG9yPjxh

dXRob3I+RGlja3NvbiwgRC48L2F1dGhvcj48YXV0aG9yPkh1dHRvbiwgTS48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5NYXlvIENsaW5pYyBDb2xsZWdlIG9m

IE1lZGljaW5lLCBEZXBhcnRtZW50IG9mIE5ldXJvc2NpZW5jZSwgTWF5byBDbGluaWMgSmFja3Nv

bnZpbGxlIDQ1MDAgU2FuIFBhYmxvIFJkLiwgSmFja3NvbnZpbGxlLCBGbG9yaWRhIDMyMjI0LCBV

U0EuIHRnb2xkZUBtYXlvLmVkdTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkZpbGxpbmcg

dGhlIGdhcHMgaW4gdGhlIGFiZXRhIGNhc2NhZGUgaHlwb3RoZXNpcyBvZiBBbHpoZWltZXImYXBv

cztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Q3VyciBBbHpoZWltZXIgUmVzPC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q3VyciBBbHpo

ZWltZXIgUmVzPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NDIxLTMwPC9wYWdlcz48

dm9sdW1lPjM8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48ZWRpdGlvbj4yMDA2LzEyLzE2PC9l

ZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2luZzwva2V5d29yZD48a2V5d29yZD5BbHpoZWlt

ZXIgRGlzZWFzZS8qbWV0YWJvbGlzbS8qcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PkFteWxvaWQgYmV0YS1QZXB0aWRlcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5Bbmlt

YWxzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5Nb2RlbHMsIEJp

b2xvZ2ljYWw8L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5zL21ldGFib2xpc208L2tleXdv

cmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkRl

YzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NjctMjA1MCAoUHJpbnQpJiN4RDsx

NTY3LTIwNTAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjE3MTY4NjQxPC9hY2Nlc3Np

b24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWgu

Z292L3B1Ym1lZC8xNzE2ODY0MTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48

L0NpdGU+PENpdGU+PEF1dGhvcj5TYWl0bzwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051

bT4xMzgyPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4xMzgyPC9yZWMtbnVtYmVyPjxmb3Jl

aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRz

enpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ1MDAxOTMiPjEzODI8L2tleT48L2ZvcmVpZ24ta2V5

cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1

dG9ycz48YXV0aG9ycz48YXV0aG9yPlNhaXRvLCBULjwvYXV0aG9yPjxhdXRob3I+TWF0c3ViYSwg

WS48L2F1dGhvcj48YXV0aG9yPllhbWF6YWtpLCBOLjwvYXV0aG9yPjxhdXRob3I+SGFzaGltb3Rv

LCBTLjwvYXV0aG9yPjxhdXRob3I+U2FpZG8sIFQuIEMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+TGFib3JhdG9yeSBmb3IgUHJvdGVvbHl0aWMgTmV1cm9z

Y2llbmNlLCBSSUtFTiBCcmFpbiBTY2llbmNlIEluc3RpdHV0ZSwgV2FrbyAzNTEtMDE5OCwgSmFw

YW4uJiN4RDtMYWJvcmF0b3J5IGZvciBQcm90ZW9seXRpYyBOZXVyb3NjaWVuY2UsIFJJS0VOIEJy

YWluIFNjaWVuY2UgSW5zdGl0dXRlLCBXYWtvIDM1MS0wMTk4LCBKYXBhbiBzYWlkb0BicmFpbi5y

aWtlbi5qcC48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5DYWxwYWluIEFjdGl2YXRpb24g

aW4gQWx6aGVpbWVyJmFwb3M7cyBNb2RlbCBNaWNlIElzIGFuIEFydGlmYWN0IG9mIEFQUCBhbmQg

UHJlc2VuaWxpbiBPdmVyZXhwcmVzc2lvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIE5ldXJv

c2NpPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBO

ZXVyb3NjaTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjk5MzMtNjwvcGFnZXM+PHZv

bHVtZT4zNjwvdm9sdW1lPjxudW1iZXI+Mzg8L251bWJlcj48ZWRpdGlvbj4yMDE2LzA5LzIzPC9l

ZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9nZW5ldGljcy8qbWV0

YWJvbGlzbS8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRl

cy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1Qcm90ZWluIFByZWN1

cnNvci9nZW5ldGljcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3

b3JkPjxrZXl3b3JkPkJyYWluLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkNhbGNpdW0t

QmluZGluZyBQcm90ZWlucy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5EaXNlYXNlIE1v

ZGVscywgQW5pbWFsPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmUgRXhwcmVzc2lvbiBSZWd1bGF0aW9u

L2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NZW1i

cmFuZSBQcm90ZWlucy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29y

ZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgVHJh

bnNnZW5pYzwva2V5d29yZD48a2V5d29yZD5NdXRhdGlvbi9nZW5ldGljczwva2V5d29yZD48a2V5

d29yZD5OQVYxLjEgVm9sdGFnZS1HYXRlZCBTb2RpdW0gQ2hhbm5lbC9nZW5ldGljcy9tZXRhYm9s

aXNtPC9rZXl3b3JkPjxrZXl3b3JkPlBlcHRpZGUgRnJhZ21lbnRzL21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+UHJlc2VuaWxpbi0xL2dlbmV0aWNzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxr

ZXl3b3JkPipOYXYxLjE8L2tleXdvcmQ+PGtleXdvcmQ+KmFteWxvaWQ8L2tleXdvcmQ+PGtleXdv

cmQ+KmNhbHBhaW48L2tleXdvcmQ+PGtleXdvcmQ+KnAyNTwva2V5d29yZD48L2tleXdvcmRzPjxk

YXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwIDIxPC9kYXRlPjwvcHVi

LWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUyOS0yNDAxIChFbGVjdHJvbmljKSYjeEQ7MDI3MC02NDc0

IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNzY1NjAzMDwvYWNjZXNzaW9uLW51bT48

dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMjc2NTYwMzA8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNTAzMDM1

MzwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTUyMy9KTkVVUk9TQ0kuMTkw

Ny0xNi4yMDE2PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmRO

b3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb2xkZTwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl

Y051bT4xMzczPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MzksNDA8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMzczPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ1MDAwNzciPjEzNzM8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkdvbGRlLCBULiBFLjwvYXV0aG9yPjxh

dXRob3I+RGlja3NvbiwgRC48L2F1dGhvcj48YXV0aG9yPkh1dHRvbiwgTS48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5NYXlvIENsaW5pYyBDb2xsZWdlIG9m

IE1lZGljaW5lLCBEZXBhcnRtZW50IG9mIE5ldXJvc2NpZW5jZSwgTWF5byBDbGluaWMgSmFja3Nv

bnZpbGxlIDQ1MDAgU2FuIFBhYmxvIFJkLiwgSmFja3NvbnZpbGxlLCBGbG9yaWRhIDMyMjI0LCBV

U0EuIHRnb2xkZUBtYXlvLmVkdTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkZpbGxpbmcg

dGhlIGdhcHMgaW4gdGhlIGFiZXRhIGNhc2NhZGUgaHlwb3RoZXNpcyBvZiBBbHpoZWltZXImYXBv

cztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Q3VyciBBbHpoZWltZXIgUmVzPC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q3VyciBBbHpo

ZWltZXIgUmVzPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NDIxLTMwPC9wYWdlcz48

dm9sdW1lPjM8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48ZWRpdGlvbj4yMDA2LzEyLzE2PC9l

ZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2luZzwva2V5d29yZD48a2V5d29yZD5BbHpoZWlt

ZXIgRGlzZWFzZS8qbWV0YWJvbGlzbS8qcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PkFteWxvaWQgYmV0YS1QZXB0aWRlcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5Bbmlt

YWxzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5Nb2RlbHMsIEJp

b2xvZ2ljYWw8L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5zL21ldGFib2xpc208L2tleXdv

cmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkRl

YzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NjctMjA1MCAoUHJpbnQpJiN4RDsx

NTY3LTIwNTAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjE3MTY4NjQxPC9hY2Nlc3Np

b24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWgu

Z292L3B1Ym1lZC8xNzE2ODY0MTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48

L0NpdGU+PENpdGU+PEF1dGhvcj5TYWl0bzwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051

bT4xMzgyPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4xMzgyPC9yZWMtbnVtYmVyPjxmb3Jl

aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRz

enpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ1MDAxOTMiPjEzODI8L2tleT48L2ZvcmVpZ24ta2V5

cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1

dG9ycz48YXV0aG9ycz48YXV0aG9yPlNhaXRvLCBULjwvYXV0aG9yPjxhdXRob3I+TWF0c3ViYSwg

WS48L2F1dGhvcj48YXV0aG9yPllhbWF6YWtpLCBOLjwvYXV0aG9yPjxhdXRob3I+SGFzaGltb3Rv

LCBTLjwvYXV0aG9yPjxhdXRob3I+U2FpZG8sIFQuIEMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+TGFib3JhdG9yeSBmb3IgUHJvdGVvbHl0aWMgTmV1cm9z

Y2llbmNlLCBSSUtFTiBCcmFpbiBTY2llbmNlIEluc3RpdHV0ZSwgV2FrbyAzNTEtMDE5OCwgSmFw

YW4uJiN4RDtMYWJvcmF0b3J5IGZvciBQcm90ZW9seXRpYyBOZXVyb3NjaWVuY2UsIFJJS0VOIEJy

YWluIFNjaWVuY2UgSW5zdGl0dXRlLCBXYWtvIDM1MS0wMTk4LCBKYXBhbiBzYWlkb0BicmFpbi5y

aWtlbi5qcC48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5DYWxwYWluIEFjdGl2YXRpb24g

aW4gQWx6aGVpbWVyJmFwb3M7cyBNb2RlbCBNaWNlIElzIGFuIEFydGlmYWN0IG9mIEFQUCBhbmQg

UHJlc2VuaWxpbiBPdmVyZXhwcmVzc2lvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIE5ldXJv

c2NpPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBO

ZXVyb3NjaTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjk5MzMtNjwvcGFnZXM+PHZv

bHVtZT4zNjwvdm9sdW1lPjxudW1iZXI+Mzg8L251bWJlcj48ZWRpdGlvbj4yMDE2LzA5LzIzPC9l

ZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9nZW5ldGljcy8qbWV0

YWJvbGlzbS8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRl

cy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1Qcm90ZWluIFByZWN1

cnNvci9nZW5ldGljcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3

b3JkPjxrZXl3b3JkPkJyYWluLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkNhbGNpdW0t

QmluZGluZyBQcm90ZWlucy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5EaXNlYXNlIE1v

ZGVscywgQW5pbWFsPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmUgRXhwcmVzc2lvbiBSZWd1bGF0aW9u

L2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NZW1i

cmFuZSBQcm90ZWlucy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29y

ZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgVHJh

bnNnZW5pYzwva2V5d29yZD48a2V5d29yZD5NdXRhdGlvbi9nZW5ldGljczwva2V5d29yZD48a2V5

d29yZD5OQVYxLjEgVm9sdGFnZS1HYXRlZCBTb2RpdW0gQ2hhbm5lbC9nZW5ldGljcy9tZXRhYm9s

aXNtPC9rZXl3b3JkPjxrZXl3b3JkPlBlcHRpZGUgRnJhZ21lbnRzL21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+UHJlc2VuaWxpbi0xL2dlbmV0aWNzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxr

ZXl3b3JkPipOYXYxLjE8L2tleXdvcmQ+PGtleXdvcmQ+KmFteWxvaWQ8L2tleXdvcmQ+PGtleXdv

cmQ+KmNhbHBhaW48L2tleXdvcmQ+PGtleXdvcmQ+KnAyNTwva2V5d29yZD48L2tleXdvcmRzPjxk

YXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwIDIxPC9kYXRlPjwvcHVi

LWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUyOS0yNDAxIChFbGVjdHJvbmljKSYjeEQ7MDI3MC02NDc0

IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNzY1NjAzMDwvYWNjZXNzaW9uLW51bT48

dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMjc2NTYwMzA8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNTAzMDM1

MzwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTUyMy9KTkVVUk9TQ0kuMTkw

Ny0xNi4yMDE2PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmRO

b3RlPn==

ADDIN EN.CITE.DATA 39,40. Because of this, novel models closer to human brain biochemistry aim to uncover mechanisms with more translational profiles PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWl0bzwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl

Y051bT4xMzk3PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDEtNDM8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMzk3PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ1MDAzNDQiPjEzOTc8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNhaXRvLCBULjwvYXV0aG9yPjxhdXRo

b3I+TWF0c3ViYSwgWS48L2F1dGhvcj48YXV0aG9yPk1paGlyYSwgTi48L2F1dGhvcj48YXV0aG9y

PlRha2FubywgSi48L2F1dGhvcj48YXV0aG9yPk5pbHNzb24sIFAuPC9hdXRob3I+PGF1dGhvcj5J

dG9oYXJhLCBTLjwvYXV0aG9yPjxhdXRob3I+SXdhdGEsIE4uPC9hdXRob3I+PGF1dGhvcj5TYWlk

bywgVC4gQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz4x

XSBMYWJvcmF0b3J5IGZvciBQcm90ZW9seXRpYyBOZXVyb3NjaWVuY2UsIFJJS0VOIEJyYWluIFNj

aWVuY2UgSW5zdGl0dXRlLCBXYWtvLXNoaSwgU2FpdGFtYSwgSmFwYW4uIFsyXSBKYXBhbiBTY2ll

bmNlIGFuZCBUZWNobm9sb2d5IEFnZW5jeSwgU2FpdGFtYSwgSmFwYW4uJiN4RDtMYWJvcmF0b3J5

IGZvciBQcm90ZW9seXRpYyBOZXVyb3NjaWVuY2UsIFJJS0VOIEJyYWluIFNjaWVuY2UgSW5zdGl0

dXRlLCBXYWtvLXNoaSwgU2FpdGFtYSwgSmFwYW4uJiN4RDtMYWJvcmF0b3J5IGZvciBCZWhhdmlv

cmFsIEdlbmV0aWNzLCBSSUtFTiBCcmFpbiBTY2llbmNlIEluc3RpdHV0ZSwgV2Frby1zaGksIFNh

aXRhbWEsIEphcGFuLiYjeEQ7MV0gTGFib3JhdG9yeSBmb3IgUHJvdGVvbHl0aWMgTmV1cm9zY2ll

bmNlLCBSSUtFTiBCcmFpbiBTY2llbmNlIEluc3RpdHV0ZSwgV2Frby1zaGksIFNhaXRhbWEsIEph

cGFuLiBbMl0gRGVwYXJ0bWVudCBvZiBNb2xlY3VsYXIgTWVkaWNpbmFsIFNjaWVuY2VzLCBEaXZp

c2lvbiBvZiBCaW90ZWNobm9sb2d5LCBOYWdhc2FraSBVbml2ZXJzaXR5IEdyYWR1YXRlIFNjaG9v

bCBvZiBCaW9tZWRpY2FsIFNjaWVuY2VzLCBOYWdhc2FraSwgSmFwYW4uPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+U2luZ2xlIEFwcCBrbm9jay1pbiBtb3VzZSBtb2RlbHMgb2YgQWx6aGVp

bWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5hdCBOZXVyb3NjaTwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz42NjEtMzwvcGFnZXM+PHZvbHVtZT4xNzwv

dm9sdW1lPjxudW1iZXI+NTwvbnVtYmVyPjxlZGl0aW9uPjIwMTQvMDQvMTU8L2VkaXRpb24+PGtl

eXdvcmRzPjxrZXl3b3JkPkFnZSBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBE

aXNlYXNlLypnZW5ldGljcy9tZXRhYm9saXNtLypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZCBiZXRhLVByb3RlaW4gUHJlY3Vyc29yLypnZW5ldGljczwva2V5d29yZD48a2V5d29y

ZD5BbmFseXNpcyBvZiBWYXJpYW5jZTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3Jk

PjxrZXl3b3JkPipEaXNlYXNlIE1vZGVscywgQW5pbWFsPC9rZXl3b3JkPjxrZXl3b3JkPkVuenlt

ZS1MaW5rZWQgSW1tdW5vc29yYmVudCBBc3NheTwva2V5d29yZD48a2V5d29yZD4qR2VuZSBLbm9j

ay1JbiBUZWNobmlxdWVzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29y

ZD5NYXplIExlYXJuaW5nL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29y

ZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgVHJh

bnNnZW5pYzwva2V5d29yZD48a2V5d29yZD5NdXRhdGlvbi9nZW5ldGljczwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDE0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWF5PC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU0Ni0xNzI2IChFbGVjdHJvbmljKSYjeEQ7MTA5

Ny02MjU2IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNDcyODI2OTwvYWNjZXNzaW9u

LW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdv

di9wdWJtZWQvMjQ3MjgyNjk8L3VybD48dXJsPmh0dHBzOi8vd3d3Lm5hdHVyZS5jb20vYXJ0aWNs

ZXMvbm4uMzY5Ny5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjEwLjEwMzgvbm4uMzY5NzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNv

cmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+R2V1bGE8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS

ZWNOdW0+MTc4NTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTc4NTwvcmVjLW51bWJlcj48

Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4

OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0NTA1OTA2Ij4xNzg1PC9rZXk+PC9mb3JlaWdu

LWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250

cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5HZXVsYSwgQy48L2F1dGhvcj48YXV0aG9yPk5hZ3lr

ZXJ5LCBOLjwvYXV0aG9yPjxhdXRob3I+V3UsIEMuIEsuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgSGFydmFyZCBN

ZWRpY2FsIFNjaG9vbCBhbmQgQmV0aCBJc3JhZWwgRGVhY29uZXNzIE1lZGljYWwgQ2VudGVyLCBC

b3N0b24sIE1BIDAyMjE1LCBVU0EuIGNnZXVsYUBjYXJlZ3JvdXAuaGFydmFyZC5lZHU8L2F1dGgt

YWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BbXlsb2lkLWJldGEgZGVwb3NpdHMgaW4gdGhlIGNlcmVi

cmFsIGNvcnRleCBvZiB0aGUgYWdlZCBjb21tb24gbWFybW9zZXQgKENhbGxpdGhyaXggamFjY2h1

cyk6IGluY2lkZW5jZSBhbmQgY2hlbWljYWwgY29tcG9zaXRpb248L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+QWN0YSBOZXVyb3BhdGhvbDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2Rp

Y2FsPjxmdWxsLXRpdGxlPkFjdGEgTmV1cm9wYXRob2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz40OC01ODwvcGFnZXM+PHZvbHVtZT4xMDM8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJl

cj48ZWRpdGlvbj4yMDAyLzAyLzEyPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2luZy8q

cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy8qYW5hbHlz

aXM8L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJv

dGVpbnMgRS9hbmFseXNpczwva2V5d29yZD48a2V5d29yZD5CcmFpbiBEaXNlYXNlcy9lcGlkZW1p

b2xvZ3kvbW9ydGFsaXR5LypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2FsbGl0aHJpeDwv

a2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBDb3J0ZXgvY2hlbWlzdHJ5L2Vuenltb2xvZ3kvKnBh

dGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DaG9saW5lc3RlcmFzZXMvYW5hbHlzaXM8L2tleXdv

cmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFuaW1hbDwva2V5d29yZD48a2V5d29yZD5GZW1h

bGU8L2tleXdvcmQ+PGtleXdvcmQ+SW5jaWRlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tl

eXdvcmQ+PGtleXdvcmQ+TmV1cml0ZXMvY2hlbWlzdHJ5L2Vuenltb2xvZ3kvcGF0aG9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPlBlcHRpZGUgRnJhZ21lbnRzLyphbmFseXNpczwva2V5d29yZD48a2V5

d29yZD5QbGFxdWUsIEFteWxvaWQvY2hlbWlzdHJ5L2Vuenltb2xvZ3kvcGF0aG9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPlN1cnZpdmFsIEFuYWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPlRoaWF6b2xl

cy9hbmFseXNpczwva2V5d29yZD48a2V5d29yZD5hbHBoYSAxLUFudGljaHltb3RyeXBzaW4vYW5h

bHlzaXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMjwveWVhcj48cHViLWRh

dGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMDEtNjMyMiAo

UHJpbnQpJiN4RDswMDAxLTYzMjIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjExODM3

NzQ3PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xMTgzNzc0NzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5TYXNhZ3VyaTwvQXV0aG9yPjxZZWFyPjIw

MTc8L1llYXI+PFJlY051bT4zOTAxPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zOTAxPC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzYwNjg5MjEiPjM5MDE8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNhc2FndXJpLCBILjwvYXV0aG9y

PjxhdXRob3I+Tmlsc3NvbiwgUC48L2F1dGhvcj48YXV0aG9yPkhhc2hpbW90bywgUy48L2F1dGhv

cj48YXV0aG9yPk5hZ2F0YSwgSy48L2F1dGhvcj48YXV0aG9yPlNhaXRvLCBULjwvYXV0aG9yPjxh

dXRob3I+RGUgU3Ryb29wZXIsIEIuPC9hdXRob3I+PGF1dGhvcj5IYXJkeSwgSi48L2F1dGhvcj48

YXV0aG9yPlZhc3NhciwgUi48L2F1dGhvcj48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1

dGhvcj5TYWlkbywgVC4gQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgt

YWRkcmVzcz5MYWJvcmF0b3J5IGZvciBQcm90ZW9seXRpYyBOZXVyb3NjaWVuY2UsIFJJS0VOIEJy

YWluIFNjaWVuY2UgSW5zdGl0dXRlLCBXYWtvLCBKYXBhbiBoaXJva2kuc2FzYWd1cmlAcmlrZW4u

anAgc2FpZG9AYnJhaW4ucmlrZW4uanAuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvbG9neSBhbmQg

TmV1cm9sb2dpY2FsIFNjaWVuY2UsIEdyYWR1YXRlIFNjaG9vbCBvZiBNZWRpY2luZSwgVG9reW8g

TWVkaWNhbCBhbmQgRGVudGFsIFVuaXZlcnNpdHksIFRva3lvLCBKYXBhbi4mI3hEO0xhYm9yYXRv

cnkgZm9yIFByb3Rlb2x5dGljIE5ldXJvc2NpZW5jZSwgUklLRU4gQnJhaW4gU2NpZW5jZSBJbnN0

aXR1dGUsIFdha28sIEphcGFuLiYjeEQ7RGl2aXNpb24gb2YgTmV1cm9nZXJpYXRyaWNzLCBEZXBh

cnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgQ2VudGVy

IGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIEthcm9saW5za2EgSW5zdGl0dXRldCwgSHVkZGluZ2Us

IFN3ZWRlbi4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9zY2llbmNlIGFuZCBQYXRob2Jpb2xvZ3ks

IFJlc2VhcmNoIEluc3RpdHV0ZSBvZiBFbnZpcm9ubWVudGFsIE1lZGljaW5lLCBOYWdveWEgVW5p

dmVyc2l0eSwgTmFnb3lhLCBKYXBhbi4mI3hEO0RlbWVudGlhIFJlc2VhcmNoIEluc3RpdHV0ZSwg

VW5pdmVyc2l0eSBDb2xsZWdlIExvbmRvbiwgTG9uZG9uLCBVSy4mI3hEO0RlcGFydG1lbnQgZm9y

IE5ldXJvc2NpZW5jZXMsIEtVIExldXZlbiwgTGV1dmVuLCBCZWxnaXVtLiYjeEQ7VklCIENlbnRl

ciBmb3IgQnJhaW4gYW5kIERpc2Vhc2UgUmVzZWFyY2gsIExldXZlbiwgQmVsZ2l1bS4mI3hEO1Jl

dGEgTGlsYSBSZXNlYXJjaCBMYWJvcmF0b3JpZXMgYW5kIHRoZSBEZXBhcnRtZW50IG9mIE1vbGVj

dWxhciBOZXVyb3NjaWVuY2UsIFVuaXZlcnNpdHkgQ29sbGVnZSBMb25kb24gSW5zdGl0dXRlIG9m

IE5ldXJvbG9neSwgTG9uZG9uLCBVSy4mI3hEO0RlcGFydG1lbnQgb2YgQ2VsbCBhbmQgTW9sZWN1

bGFyIEJpb2xvZ3ksIEZlaW5iZXJnIFNjaG9vbCBvZiBNZWRpY2luZSwgTm9ydGh3ZXN0ZXJuIFVu

aXZlcnNpdHksIENoaWNhZ28sIElMLCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+

QVBQIG1vdXNlIG1vZGVscyBmb3IgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIHByZWNsaW5pY2Fs

IHN0dWRpZXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+RU1CTyBKPC9zZWNvbmRhcnktdGl0bGU+

PC90aXRsZXM+PHBhZ2VzPjI0NzMtMjQ4NzwvcGFnZXM+PHZvbHVtZT4zNjwvdm9sdW1lPjxudW1i

ZXI+MTc8L251bWJlcj48ZWRpdGlvbj4yMDE3LzA4LzA1PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5

d29yZD4qQWx6aGVpbWVyIERpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBy

b3RlaW4gUHJlY3Vyc29yLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3

b3JkPjxrZXl3b3JkPipEaXNlYXNlIE1vZGVscywgQW5pbWFsPC9rZXl3b3JkPjxrZXl3b3JkPkh1

bWFuczwva2V5d29yZD48a2V5d29yZD4qQVBQIHRyYW5zZ2VuaWM8L2tleXdvcmQ+PGtleXdvcmQ+

KkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD4qQXBwIGtub2NrLWlu

PC9rZXl3b3JkPjxrZXl3b3JkPiphbXlsb2lkIHByZWN1cnNvciBwcm90ZWluPC9rZXl3b3JkPjxr

ZXl3b3JkPiphbXlsb2lkIGJldGEgcGVwdGlkZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4yMDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwIDE8L2RhdGU+PC9wdWItZGF0ZXM+

PC9kYXRlcz48aXNibj4xNDYwLTIwNzUgKEVsZWN0cm9uaWMpJiN4RDswMjYxLTQxODkgKExpbmtp

bmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI4NzY4NzE4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxy

ZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yODc2

ODcxODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM1NTc5MzUwPC9jdXN0

b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTI1Mi9lbWJqLjIwMTc5NzM5NzwvZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWl0bzwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl

Y051bT4xMzk3PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDEtNDM8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMzk3PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ1MDAzNDQiPjEzOTc8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNhaXRvLCBULjwvYXV0aG9yPjxhdXRo

b3I+TWF0c3ViYSwgWS48L2F1dGhvcj48YXV0aG9yPk1paGlyYSwgTi48L2F1dGhvcj48YXV0aG9y

PlRha2FubywgSi48L2F1dGhvcj48YXV0aG9yPk5pbHNzb24sIFAuPC9hdXRob3I+PGF1dGhvcj5J

dG9oYXJhLCBTLjwvYXV0aG9yPjxhdXRob3I+SXdhdGEsIE4uPC9hdXRob3I+PGF1dGhvcj5TYWlk

bywgVC4gQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz4x

XSBMYWJvcmF0b3J5IGZvciBQcm90ZW9seXRpYyBOZXVyb3NjaWVuY2UsIFJJS0VOIEJyYWluIFNj

aWVuY2UgSW5zdGl0dXRlLCBXYWtvLXNoaSwgU2FpdGFtYSwgSmFwYW4uIFsyXSBKYXBhbiBTY2ll

bmNlIGFuZCBUZWNobm9sb2d5IEFnZW5jeSwgU2FpdGFtYSwgSmFwYW4uJiN4RDtMYWJvcmF0b3J5

IGZvciBQcm90ZW9seXRpYyBOZXVyb3NjaWVuY2UsIFJJS0VOIEJyYWluIFNjaWVuY2UgSW5zdGl0

dXRlLCBXYWtvLXNoaSwgU2FpdGFtYSwgSmFwYW4uJiN4RDtMYWJvcmF0b3J5IGZvciBCZWhhdmlv

cmFsIEdlbmV0aWNzLCBSSUtFTiBCcmFpbiBTY2llbmNlIEluc3RpdHV0ZSwgV2Frby1zaGksIFNh

aXRhbWEsIEphcGFuLiYjeEQ7MV0gTGFib3JhdG9yeSBmb3IgUHJvdGVvbHl0aWMgTmV1cm9zY2ll

bmNlLCBSSUtFTiBCcmFpbiBTY2llbmNlIEluc3RpdHV0ZSwgV2Frby1zaGksIFNhaXRhbWEsIEph

cGFuLiBbMl0gRGVwYXJ0bWVudCBvZiBNb2xlY3VsYXIgTWVkaWNpbmFsIFNjaWVuY2VzLCBEaXZp

c2lvbiBvZiBCaW90ZWNobm9sb2d5LCBOYWdhc2FraSBVbml2ZXJzaXR5IEdyYWR1YXRlIFNjaG9v

bCBvZiBCaW9tZWRpY2FsIFNjaWVuY2VzLCBOYWdhc2FraSwgSmFwYW4uPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+U2luZ2xlIEFwcCBrbm9jay1pbiBtb3VzZSBtb2RlbHMgb2YgQWx6aGVp

bWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5hdCBOZXVyb3NjaTwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz42NjEtMzwvcGFnZXM+PHZvbHVtZT4xNzwv

dm9sdW1lPjxudW1iZXI+NTwvbnVtYmVyPjxlZGl0aW9uPjIwMTQvMDQvMTU8L2VkaXRpb24+PGtl

eXdvcmRzPjxrZXl3b3JkPkFnZSBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBE

aXNlYXNlLypnZW5ldGljcy9tZXRhYm9saXNtLypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZCBiZXRhLVByb3RlaW4gUHJlY3Vyc29yLypnZW5ldGljczwva2V5d29yZD48a2V5d29y

ZD5BbmFseXNpcyBvZiBWYXJpYW5jZTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3Jk

PjxrZXl3b3JkPipEaXNlYXNlIE1vZGVscywgQW5pbWFsPC9rZXl3b3JkPjxrZXl3b3JkPkVuenlt

ZS1MaW5rZWQgSW1tdW5vc29yYmVudCBBc3NheTwva2V5d29yZD48a2V5d29yZD4qR2VuZSBLbm9j

ay1JbiBUZWNobmlxdWVzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29y

ZD5NYXplIExlYXJuaW5nL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29y

ZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgVHJh

bnNnZW5pYzwva2V5d29yZD48a2V5d29yZD5NdXRhdGlvbi9nZW5ldGljczwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDE0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWF5PC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU0Ni0xNzI2IChFbGVjdHJvbmljKSYjeEQ7MTA5

Ny02MjU2IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNDcyODI2OTwvYWNjZXNzaW9u

LW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdv

di9wdWJtZWQvMjQ3MjgyNjk8L3VybD48dXJsPmh0dHBzOi8vd3d3Lm5hdHVyZS5jb20vYXJ0aWNs

ZXMvbm4uMzY5Ny5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjEwLjEwMzgvbm4uMzY5NzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNv

cmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+R2V1bGE8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS

ZWNOdW0+MTc4NTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTc4NTwvcmVjLW51bWJlcj48

Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4

OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0NTA1OTA2Ij4xNzg1PC9rZXk+PC9mb3JlaWdu

LWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250

cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5HZXVsYSwgQy48L2F1dGhvcj48YXV0aG9yPk5hZ3lr

ZXJ5LCBOLjwvYXV0aG9yPjxhdXRob3I+V3UsIEMuIEsuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgSGFydmFyZCBN

ZWRpY2FsIFNjaG9vbCBhbmQgQmV0aCBJc3JhZWwgRGVhY29uZXNzIE1lZGljYWwgQ2VudGVyLCBC

b3N0b24sIE1BIDAyMjE1LCBVU0EuIGNnZXVsYUBjYXJlZ3JvdXAuaGFydmFyZC5lZHU8L2F1dGgt

YWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BbXlsb2lkLWJldGEgZGVwb3NpdHMgaW4gdGhlIGNlcmVi

cmFsIGNvcnRleCBvZiB0aGUgYWdlZCBjb21tb24gbWFybW9zZXQgKENhbGxpdGhyaXggamFjY2h1

cyk6IGluY2lkZW5jZSBhbmQgY2hlbWljYWwgY29tcG9zaXRpb248L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+QWN0YSBOZXVyb3BhdGhvbDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2Rp

Y2FsPjxmdWxsLXRpdGxlPkFjdGEgTmV1cm9wYXRob2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz40OC01ODwvcGFnZXM+PHZvbHVtZT4xMDM8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJl

cj48ZWRpdGlvbj4yMDAyLzAyLzEyPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2luZy8q

cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy8qYW5hbHlz

aXM8L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJv

dGVpbnMgRS9hbmFseXNpczwva2V5d29yZD48a2V5d29yZD5CcmFpbiBEaXNlYXNlcy9lcGlkZW1p

b2xvZ3kvbW9ydGFsaXR5LypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2FsbGl0aHJpeDwv

a2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBDb3J0ZXgvY2hlbWlzdHJ5L2Vuenltb2xvZ3kvKnBh

dGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DaG9saW5lc3RlcmFzZXMvYW5hbHlzaXM8L2tleXdv

cmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFuaW1hbDwva2V5d29yZD48a2V5d29yZD5GZW1h

bGU8L2tleXdvcmQ+PGtleXdvcmQ+SW5jaWRlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tl

eXdvcmQ+PGtleXdvcmQ+TmV1cml0ZXMvY2hlbWlzdHJ5L2Vuenltb2xvZ3kvcGF0aG9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPlBlcHRpZGUgRnJhZ21lbnRzLyphbmFseXNpczwva2V5d29yZD48a2V5

d29yZD5QbGFxdWUsIEFteWxvaWQvY2hlbWlzdHJ5L2Vuenltb2xvZ3kvcGF0aG9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPlN1cnZpdmFsIEFuYWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPlRoaWF6b2xl

cy9hbmFseXNpczwva2V5d29yZD48a2V5d29yZD5hbHBoYSAxLUFudGljaHltb3RyeXBzaW4vYW5h

bHlzaXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMjwveWVhcj48cHViLWRh

dGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMDEtNjMyMiAo

UHJpbnQpJiN4RDswMDAxLTYzMjIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjExODM3

NzQ3PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xMTgzNzc0NzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5TYXNhZ3VyaTwvQXV0aG9yPjxZZWFyPjIw

MTc8L1llYXI+PFJlY051bT4zOTAxPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zOTAxPC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzYwNjg5MjEiPjM5MDE8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNhc2FndXJpLCBILjwvYXV0aG9y

PjxhdXRob3I+Tmlsc3NvbiwgUC48L2F1dGhvcj48YXV0aG9yPkhhc2hpbW90bywgUy48L2F1dGhv

cj48YXV0aG9yPk5hZ2F0YSwgSy48L2F1dGhvcj48YXV0aG9yPlNhaXRvLCBULjwvYXV0aG9yPjxh

dXRob3I+RGUgU3Ryb29wZXIsIEIuPC9hdXRob3I+PGF1dGhvcj5IYXJkeSwgSi48L2F1dGhvcj48

YXV0aG9yPlZhc3NhciwgUi48L2F1dGhvcj48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1

dGhvcj5TYWlkbywgVC4gQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgt

YWRkcmVzcz5MYWJvcmF0b3J5IGZvciBQcm90ZW9seXRpYyBOZXVyb3NjaWVuY2UsIFJJS0VOIEJy

YWluIFNjaWVuY2UgSW5zdGl0dXRlLCBXYWtvLCBKYXBhbiBoaXJva2kuc2FzYWd1cmlAcmlrZW4u

anAgc2FpZG9AYnJhaW4ucmlrZW4uanAuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvbG9neSBhbmQg

TmV1cm9sb2dpY2FsIFNjaWVuY2UsIEdyYWR1YXRlIFNjaG9vbCBvZiBNZWRpY2luZSwgVG9reW8g

TWVkaWNhbCBhbmQgRGVudGFsIFVuaXZlcnNpdHksIFRva3lvLCBKYXBhbi4mI3hEO0xhYm9yYXRv

cnkgZm9yIFByb3Rlb2x5dGljIE5ldXJvc2NpZW5jZSwgUklLRU4gQnJhaW4gU2NpZW5jZSBJbnN0

aXR1dGUsIFdha28sIEphcGFuLiYjeEQ7RGl2aXNpb24gb2YgTmV1cm9nZXJpYXRyaWNzLCBEZXBh

cnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgQ2VudGVy

IGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIEthcm9saW5za2EgSW5zdGl0dXRldCwgSHVkZGluZ2Us

IFN3ZWRlbi4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9zY2llbmNlIGFuZCBQYXRob2Jpb2xvZ3ks

IFJlc2VhcmNoIEluc3RpdHV0ZSBvZiBFbnZpcm9ubWVudGFsIE1lZGljaW5lLCBOYWdveWEgVW5p

dmVyc2l0eSwgTmFnb3lhLCBKYXBhbi4mI3hEO0RlbWVudGlhIFJlc2VhcmNoIEluc3RpdHV0ZSwg

VW5pdmVyc2l0eSBDb2xsZWdlIExvbmRvbiwgTG9uZG9uLCBVSy4mI3hEO0RlcGFydG1lbnQgZm9y

IE5ldXJvc2NpZW5jZXMsIEtVIExldXZlbiwgTGV1dmVuLCBCZWxnaXVtLiYjeEQ7VklCIENlbnRl

ciBmb3IgQnJhaW4gYW5kIERpc2Vhc2UgUmVzZWFyY2gsIExldXZlbiwgQmVsZ2l1bS4mI3hEO1Jl

dGEgTGlsYSBSZXNlYXJjaCBMYWJvcmF0b3JpZXMgYW5kIHRoZSBEZXBhcnRtZW50IG9mIE1vbGVj

dWxhciBOZXVyb3NjaWVuY2UsIFVuaXZlcnNpdHkgQ29sbGVnZSBMb25kb24gSW5zdGl0dXRlIG9m

IE5ldXJvbG9neSwgTG9uZG9uLCBVSy4mI3hEO0RlcGFydG1lbnQgb2YgQ2VsbCBhbmQgTW9sZWN1

bGFyIEJpb2xvZ3ksIEZlaW5iZXJnIFNjaG9vbCBvZiBNZWRpY2luZSwgTm9ydGh3ZXN0ZXJuIFVu

aXZlcnNpdHksIENoaWNhZ28sIElMLCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+

QVBQIG1vdXNlIG1vZGVscyBmb3IgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIHByZWNsaW5pY2Fs

IHN0dWRpZXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+RU1CTyBKPC9zZWNvbmRhcnktdGl0bGU+

PC90aXRsZXM+PHBhZ2VzPjI0NzMtMjQ4NzwvcGFnZXM+PHZvbHVtZT4zNjwvdm9sdW1lPjxudW1i

ZXI+MTc8L251bWJlcj48ZWRpdGlvbj4yMDE3LzA4LzA1PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5

d29yZD4qQWx6aGVpbWVyIERpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBy

b3RlaW4gUHJlY3Vyc29yLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3

b3JkPjxrZXl3b3JkPipEaXNlYXNlIE1vZGVscywgQW5pbWFsPC9rZXl3b3JkPjxrZXl3b3JkPkh1

bWFuczwva2V5d29yZD48a2V5d29yZD4qQVBQIHRyYW5zZ2VuaWM8L2tleXdvcmQ+PGtleXdvcmQ+

KkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD4qQXBwIGtub2NrLWlu

PC9rZXl3b3JkPjxrZXl3b3JkPiphbXlsb2lkIHByZWN1cnNvciBwcm90ZWluPC9rZXl3b3JkPjxr

ZXl3b3JkPiphbXlsb2lkIGJldGEgcGVwdGlkZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4yMDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwIDE8L2RhdGU+PC9wdWItZGF0ZXM+

PC9kYXRlcz48aXNibj4xNDYwLTIwNzUgKEVsZWN0cm9uaWMpJiN4RDswMjYxLTQxODkgKExpbmtp

bmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI4NzY4NzE4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxy

ZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yODc2

ODcxODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM1NTc5MzUwPC9jdXN0

b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTI1Mi9lbWJqLjIwMTc5NzM5NzwvZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 41-43. In the amyloid cascade model, Aβ42 aggregates in the presence of binding proteins such as ApoE, as well as with metal ions, leading to plaque formation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJkeTwvQXV0aG9yPjxZZWFyPjE5OTI8L1llYXI+PFJl

Y051bT4yMDY0PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTUsNDQsNDU8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDY0PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ3Nzk4NTMiPjIwNjQ8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhhcmR5LCBKLiBBLjwvYXV0aG9y

PjxhdXRob3I+SGlnZ2lucywgRy4gQS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+

PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIEJpb2NoZW1pc3RyeSwgU3QuIE1hcnkmYXBvcztz

IEhvc3BpdGFsIE1lZGljYWwgU2Nob29sLCBMb25kb24sIFUuSy48L2F1dGgtYWRkcmVzcz48dGl0

bGVzPjx0aXRsZT5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IHRoZSBhbXlsb2lkIGNhc2NhZGUg

aHlwb3RoZXNpczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5TY2llbmNlPC9zZWNvbmRhcnktdGl0

bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+U2NpZW5jZTwvZnVsbC10aXRsZT48

L3BlcmlvZGljYWw+PHBhZ2VzPjE4NC01PC9wYWdlcz48dm9sdW1lPjI1Njwvdm9sdW1lPjxudW1i

ZXI+NTA1NDwvbnVtYmVyPjxlZGl0aW9uPjE5OTIvMDQvMTA8L2VkaXRpb24+PGtleXdvcmRzPjxr

ZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypldGlvbG9neS9nZW5ldGljcy9waHlzaW9wYXRob2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZC8qZ2VuZXRpY3MvbWV0YWJvbGlzbS9waHlzaW9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1Qcm90ZWluIFByZWN1cnNvci9nZW5l

dGljczwva2V5d29yZD48a2V5d29yZD5CcmFpbi9wYXRob2xvZ3kvcGh5c2lvcGF0aG9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPkNlbGwgRGVhdGg8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3

b3JkPjxrZXl3b3JkPipNdXRhdGlvbjwva2V5d29yZD48a2V5d29yZD5OZXVyb2ZpYnJpbGxhcnkg

VGFuZ2xlcy9waHlzaW9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTI8

L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BcHIgMTA8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4wMDM2LTgwNzUgKFByaW50KSYjeEQ7MDAzNi04MDc1IChMaW5raW5nKTwvaXNibj48YWNj

ZXNzaW9uLW51bT4xNTY2MDY3PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy

bD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNTY2MDY3PC91cmw+PC9yZWxh

dGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkpvbmVzPC9BdXRo

b3I+PFllYXI+MjAxMDwvWWVhcj48UmVjTnVtPjIwNjU8L1JlY051bT48cmVjb3JkPjxyZWMtbnVt

YmVyPjIwNjU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJm

d2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDc3OTk2

MSI+MjA2NTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj

bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Sm9uZXMsIEwu

PC9hdXRob3I+PGF1dGhvcj5Ib2xtYW5zLCBQLiBBLjwvYXV0aG9yPjxhdXRob3I+SGFtc2hlcmUs

IE0uIEwuPC9hdXRob3I+PGF1dGhvcj5IYXJvbGQsIEQuPC9hdXRob3I+PGF1dGhvcj5Nb3Nrdmlu

YSwgVi48L2F1dGhvcj48YXV0aG9yPkl2YW5vdiwgRC48L2F1dGhvcj48YXV0aG9yPlBvY2tsaW5n

dG9uLCBBLjwvYXV0aG9yPjxhdXRob3I+QWJyYWhhbSwgUi48L2F1dGhvcj48YXV0aG9yPkhvbGxp

bmd3b3J0aCwgUC48L2F1dGhvcj48YXV0aG9yPlNpbXMsIFIuPC9hdXRob3I+PGF1dGhvcj5HZXJy

aXNoLCBBLjwvYXV0aG9yPjxhdXRob3I+UGFod2EsIEouIFMuPC9hdXRob3I+PGF1dGhvcj5Kb25l

cywgTi48L2F1dGhvcj48YXV0aG9yPlN0cmV0dG9uLCBBLjwvYXV0aG9yPjxhdXRob3I+TW9yZ2Fu

LCBBLiBSLjwvYXV0aG9yPjxhdXRob3I+TG92ZXN0b25lLCBTLjwvYXV0aG9yPjxhdXRob3I+UG93

ZWxsLCBKLjwvYXV0aG9yPjxhdXRob3I+UHJvaXRzaSwgUC48L2F1dGhvcj48YXV0aG9yPkx1cHRv

biwgTS4gSy48L2F1dGhvcj48YXV0aG9yPkJyYXluZSwgQy48L2F1dGhvcj48YXV0aG9yPlJ1Ymlu

c3p0ZWluLCBELiBDLjwvYXV0aG9yPjxhdXRob3I+R2lsbCwgTS48L2F1dGhvcj48YXV0aG9yPkxh

d2xvciwgQi48L2F1dGhvcj48YXV0aG9yPkx5bmNoLCBBLjwvYXV0aG9yPjxhdXRob3I+TW9yZ2Fu

LCBLLjwvYXV0aG9yPjxhdXRob3I+QnJvd24sIEsuIFMuPC9hdXRob3I+PGF1dGhvcj5QYXNzbW9y

ZSwgUC4gQS48L2F1dGhvcj48YXV0aG9yPkNyYWlnLCBELjwvYXV0aG9yPjxhdXRob3I+TWNHdWlu

bmVzcywgQi48L2F1dGhvcj48YXV0aG9yPlRvZGQsIFMuPC9hdXRob3I+PGF1dGhvcj5Ib2xtZXMs

IEMuPC9hdXRob3I+PGF1dGhvcj5NYW5uLCBELjwvYXV0aG9yPjxhdXRob3I+U21pdGgsIEEuIEQu

PC9hdXRob3I+PGF1dGhvcj5Mb3ZlLCBTLjwvYXV0aG9yPjxhdXRob3I+S2Vob2UsIFAuIEcuPC9h

dXRob3I+PGF1dGhvcj5NZWFkLCBTLjwvYXV0aG9yPjxhdXRob3I+Rm94LCBOLjwvYXV0aG9yPjxh

dXRob3I+Um9zc29yLCBNLjwvYXV0aG9yPjxhdXRob3I+Q29sbGluZ2UsIEouPC9hdXRob3I+PGF1

dGhvcj5NYWllciwgVy48L2F1dGhvcj48YXV0aG9yPkplc3NlbiwgRi48L2F1dGhvcj48YXV0aG9y

PlNjaHVybWFubiwgQi48L2F1dGhvcj48YXV0aG9yPkhldW4sIFIuPC9hdXRob3I+PGF1dGhvcj5L

b2xzY2gsIEguPC9hdXRob3I+PGF1dGhvcj52YW4gZGVuIEJ1c3NjaGUsIEguPC9hdXRob3I+PGF1

dGhvcj5IZXVzZXIsIEkuPC9hdXRob3I+PGF1dGhvcj5QZXRlcnMsIE8uPC9hdXRob3I+PGF1dGhv

cj5Lb3JuaHViZXIsIEouPC9hdXRob3I+PGF1dGhvcj5XaWx0ZmFuZywgSi48L2F1dGhvcj48YXV0

aG9yPkRpY2hnYW5zLCBNLjwvYXV0aG9yPjxhdXRob3I+RnJvbGljaCwgTC48L2F1dGhvcj48YXV0

aG9yPkhhbXBlbCwgSC48L2F1dGhvcj48YXV0aG9yPkh1bGwsIE0uPC9hdXRob3I+PGF1dGhvcj5S

dWplc2N1LCBELjwvYXV0aG9yPjxhdXRob3I+R29hdGUsIEEuIE0uPC9hdXRob3I+PGF1dGhvcj5L

YXV3ZSwgSi4gUy48L2F1dGhvcj48YXV0aG9yPkNydWNoYWdhLCBDLjwvYXV0aG9yPjxhdXRob3I+

Tm93b3RueSwgUC48L2F1dGhvcj48YXV0aG9yPk1vcnJpcywgSi4gQy48L2F1dGhvcj48YXV0aG9y

Pk1heW8sIEsuPC9hdXRob3I+PGF1dGhvcj5MaXZpbmdzdG9uLCBHLjwvYXV0aG9yPjxhdXRob3I+

QmFzcywgTi4gSi48L2F1dGhvcj48YXV0aG9yPkd1cmxpbmcsIEguPC9hdXRob3I+PGF1dGhvcj5N

Y1F1aWxsaW4sIEEuPC9hdXRob3I+PGF1dGhvcj5Hd2lsbGlhbSwgUi48L2F1dGhvcj48YXV0aG9y

PkRlbG91a2FzLCBQLjwvYXV0aG9yPjxhdXRob3I+QWwtQ2hhbGFiaSwgQS48L2F1dGhvcj48YXV0

aG9yPlNoYXcsIEMuIEUuPC9hdXRob3I+PGF1dGhvcj5TaW5nbGV0b24sIEEuIEIuPC9hdXRob3I+

PGF1dGhvcj5HdWVycmVpcm8sIFIuPC9hdXRob3I+PGF1dGhvcj5NdWhsZWlzZW4sIFQuIFcuPC9h

dXRob3I+PGF1dGhvcj5Ob3RoZW4sIE0uIE0uPC9hdXRob3I+PGF1dGhvcj5Nb2VidXMsIFMuPC9h

dXRob3I+PGF1dGhvcj5Kb2NrZWwsIEsuIEguPC9hdXRob3I+PGF1dGhvcj5LbG9wcCwgTi48L2F1

dGhvcj48YXV0aG9yPldpY2htYW5uLCBILiBFLjwvYXV0aG9yPjxhdXRob3I+UnV0aGVyLCBFLjwv

YXV0aG9yPjxhdXRob3I+Q2FycmFzcXVpbGxvLCBNLiBNLjwvYXV0aG9yPjxhdXRob3I+UGFua3Jh

dHosIFYuIFMuPC9hdXRob3I+PGF1dGhvcj5Zb3Vua2luLCBTLiBHLjwvYXV0aG9yPjxhdXRob3I+

SGFyZHksIEouPC9hdXRob3I+PGF1dGhvcj5PJmFwb3M7RG9ub3ZhbiwgTS4gQy48L2F1dGhvcj48

YXV0aG9yPk93ZW4sIE0uIEouPC9hdXRob3I+PGF1dGhvcj5XaWxsaWFtcywgSi48L2F1dGhvcj48

L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIFBzeWNo

b2xvZ2ljYWwgTWVkaWNpbmUgYW5kIE5ldXJvbG9neSwgU2Nob29sIG9mIE1lZGljaW5lLCBDYXJk

aWZmIFVuaXZlcnNpdHksIE1lZGljYWwgUmVzZWFyY2ggQ291bmNpbCBDZW50cmUgZm9yIE5ldXJv

cHN5Y2hpYXRyaWMgR2VuZXRpY3MgYW5kIEdlbm9taWNzLCBDYXJkaWZmLCBVbml0ZWQgS2luZ2Rv

bS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5HZW5ldGljIGV2aWRlbmNlIGltcGxpY2F0

ZXMgdGhlIGltbXVuZSBzeXN0ZW0gYW5kIGNob2xlc3Rlcm9sIG1ldGFib2xpc20gaW4gdGhlIGFl

dGlvbG9neSBvZiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0

bGU+UExvUyBPbmU8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10

aXRsZT5QTG9TIE9uZTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPmUxMzk1MDwvcGFn

ZXM+PHZvbHVtZT41PC92b2x1bWU+PG51bWJlcj4xMTwvbnVtYmVyPjxlZGl0aW9uPjIwMTAvMTEv

MTk8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypnZW5ldGlj

cy9pbW11bm9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QXBvbGlwb3Byb3RlaW5z

IEUvZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0ZXJvbC8qbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DaHJvbW9zb21lIE1hcHBpbmc8L2tleXdvcmQ+PGtl

eXdvcmQ+R2VuZXRpYyBQcmVkaXNwb3NpdGlvbiB0byBEaXNlYXNlL2dlbmV0aWNzPC9rZXl3b3Jk

PjxrZXl3b3JkPkdlbm9tZSwgSHVtYW48L2tleXdvcmQ+PGtleXdvcmQ+Kkdlbm9tZS1XaWRlIEFz

c29jaWF0aW9uIFN0dWR5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29y

ZD5JbW11bmUgU3lzdGVtLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlBvbHltb3JwaGlz

bSwgU2luZ2xlIE51Y2xlb3RpZGU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAx

MDwveWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdiAxNTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVz

Pjxpc2JuPjE5MzItNjIwMyAoRWxlY3Ryb25pYykmI3hEOzE5MzItNjIwMyAoTGlua2luZyk8L2lz

Ym4+PGFjY2Vzc2lvbi1udW0+MjEwODU1NzA8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQt

dXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIxMDg1NTcwPC91

cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzI5ODE1MjY8L2N1c3RvbTI+PGVs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEzNzEvam91cm5hbC5wb25lLjAwMTM5NTA8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkNhc3RlbGxh

bm88L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxSZWNOdW0+MjA2NjwvUmVjTnVtPjxyZWNvcmQ+

PHJlYy1udW1iZXI+MjA2NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIg

ZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIx

NTM0NzgwMDc2Ij4yMDY2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5D

YXN0ZWxsYW5vLCBKLiBNLjwvYXV0aG9yPjxhdXRob3I+S2ltLCBKLjwvYXV0aG9yPjxhdXRob3I+

U3Rld2FydCwgRi4gUi48L2F1dGhvcj48YXV0aG9yPkppYW5nLCBILjwvYXV0aG9yPjxhdXRob3I+

RGVNYXR0b3MsIFIuIEIuPC9hdXRob3I+PGF1dGhvcj5QYXR0ZXJzb24sIEIuIFcuPC9hdXRob3I+

PGF1dGhvcj5GYWdhbiwgQS4gTS48L2F1dGhvcj48YXV0aG9yPk1vcnJpcywgSi4gQy48L2F1dGhv

cj48YXV0aG9yPk1hd3VlbnllZ2EsIEsuIEcuPC9hdXRob3I+PGF1dGhvcj5DcnVjaGFnYSwgQy48

L2F1dGhvcj48YXV0aG9yPkdvYXRlLCBBLiBNLjwvYXV0aG9yPjxhdXRob3I+QmFsZXMsIEsuIFIu

PC9hdXRob3I+PGF1dGhvcj5QYXVsLCBTLiBNLjwvYXV0aG9yPjxhdXRob3I+QmF0ZW1hbiwgUi4g

Si48L2F1dGhvcj48YXV0aG9yPkhvbHR6bWFuLCBELiBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2Nv

bnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBXYXNoaW5n

dG9uIFVuaXZlcnNpdHkgU2Nob29sIG9mIE1lZGljaW5lLCBTdC4gTG91aXMsIE1PIDYzMTEwLCBV

U0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+SHVtYW4gYXBvRSBpc29mb3JtcyBkaWZm

ZXJlbnRpYWxseSByZWd1bGF0ZSBicmFpbiBhbXlsb2lkLWJldGEgcGVwdGlkZSBjbGVhcmFuY2U8

L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+U2NpIFRyYW5zbCBNZWQ8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5TY2kgVHJhbnNsIE1lZDwvZnVsbC10aXRs

ZT48L3BlcmlvZGljYWw+PHBhZ2VzPjg5cmE1NzwvcGFnZXM+PHZvbHVtZT4zPC92b2x1bWU+PG51

bWJlcj44OTwvbnVtYmVyPjxlZGl0aW9uPjIwMTEvMDcvMDE8L2VkaXRpb24+PGtleXdvcmRzPjxr

ZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWxs

ZWxlczwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9nZW5ldGljcy9tZXRhYm9s

aXNtL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvKmNl

cmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5

d29yZD5BcG9saXBvcHJvdGVpbiBFNC9nZW5ldGljcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5CaW9tYXJrZXJzL2NlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+QnJh

aW4vKm1ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29y

ZD48a2V5d29yZD5HZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtl

eXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2Us

IEluYnJlZCBDNTdCTDwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFuc2dlbmljPC9rZXl3b3Jk

PjxrZXl3b3JkPk1pY3JvZGlhbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tl

eXdvcmQ+PGtleXdvcmQ+UHJvdGVpbiBJc29mb3Jtcy9nZW5ldGljcy8qbWV0YWJvbGlzbTwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

SnVuIDI5PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTk0Ni02MjQyIChFbGVjdHJv

bmljKSYjeEQ7MTk0Ni02MjM0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMTcxNTY3

ODwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNi

aS5ubG0ubmloLmdvdi9wdWJtZWQvMjE3MTU2Nzg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGN1c3RvbTI+UE1DMzE5MjM2NDwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu

MTEyNi9zY2l0cmFuc2xtZWQuMzAwMjE1NjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNv

cmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJkeTwvQXV0aG9yPjxZZWFyPjE5OTI8L1llYXI+PFJl

Y051bT4yMDY0PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTUsNDQsNDU8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDY0PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ3Nzk4NTMiPjIwNjQ8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhhcmR5LCBKLiBBLjwvYXV0aG9y

PjxhdXRob3I+SGlnZ2lucywgRy4gQS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+

PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIEJpb2NoZW1pc3RyeSwgU3QuIE1hcnkmYXBvcztz

IEhvc3BpdGFsIE1lZGljYWwgU2Nob29sLCBMb25kb24sIFUuSy48L2F1dGgtYWRkcmVzcz48dGl0

bGVzPjx0aXRsZT5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IHRoZSBhbXlsb2lkIGNhc2NhZGUg

aHlwb3RoZXNpczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5TY2llbmNlPC9zZWNvbmRhcnktdGl0

bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+U2NpZW5jZTwvZnVsbC10aXRsZT48

L3BlcmlvZGljYWw+PHBhZ2VzPjE4NC01PC9wYWdlcz48dm9sdW1lPjI1Njwvdm9sdW1lPjxudW1i

ZXI+NTA1NDwvbnVtYmVyPjxlZGl0aW9uPjE5OTIvMDQvMTA8L2VkaXRpb24+PGtleXdvcmRzPjxr

ZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypldGlvbG9neS9nZW5ldGljcy9waHlzaW9wYXRob2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZC8qZ2VuZXRpY3MvbWV0YWJvbGlzbS9waHlzaW9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1Qcm90ZWluIFByZWN1cnNvci9nZW5l

dGljczwva2V5d29yZD48a2V5d29yZD5CcmFpbi9wYXRob2xvZ3kvcGh5c2lvcGF0aG9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPkNlbGwgRGVhdGg8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3

b3JkPjxrZXl3b3JkPipNdXRhdGlvbjwva2V5d29yZD48a2V5d29yZD5OZXVyb2ZpYnJpbGxhcnkg

VGFuZ2xlcy9waHlzaW9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTI8

L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BcHIgMTA8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4wMDM2LTgwNzUgKFByaW50KSYjeEQ7MDAzNi04MDc1IChMaW5raW5nKTwvaXNibj48YWNj

ZXNzaW9uLW51bT4xNTY2MDY3PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy

bD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNTY2MDY3PC91cmw+PC9yZWxh

dGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkpvbmVzPC9BdXRo

b3I+PFllYXI+MjAxMDwvWWVhcj48UmVjTnVtPjIwNjU8L1JlY051bT48cmVjb3JkPjxyZWMtbnVt

YmVyPjIwNjU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJm

d2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDc3OTk2

MSI+MjA2NTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj

bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Sm9uZXMsIEwu

PC9hdXRob3I+PGF1dGhvcj5Ib2xtYW5zLCBQLiBBLjwvYXV0aG9yPjxhdXRob3I+SGFtc2hlcmUs

IE0uIEwuPC9hdXRob3I+PGF1dGhvcj5IYXJvbGQsIEQuPC9hdXRob3I+PGF1dGhvcj5Nb3Nrdmlu

YSwgVi48L2F1dGhvcj48YXV0aG9yPkl2YW5vdiwgRC48L2F1dGhvcj48YXV0aG9yPlBvY2tsaW5n

dG9uLCBBLjwvYXV0aG9yPjxhdXRob3I+QWJyYWhhbSwgUi48L2F1dGhvcj48YXV0aG9yPkhvbGxp

bmd3b3J0aCwgUC48L2F1dGhvcj48YXV0aG9yPlNpbXMsIFIuPC9hdXRob3I+PGF1dGhvcj5HZXJy

aXNoLCBBLjwvYXV0aG9yPjxhdXRob3I+UGFod2EsIEouIFMuPC9hdXRob3I+PGF1dGhvcj5Kb25l

cywgTi48L2F1dGhvcj48YXV0aG9yPlN0cmV0dG9uLCBBLjwvYXV0aG9yPjxhdXRob3I+TW9yZ2Fu

LCBBLiBSLjwvYXV0aG9yPjxhdXRob3I+TG92ZXN0b25lLCBTLjwvYXV0aG9yPjxhdXRob3I+UG93

ZWxsLCBKLjwvYXV0aG9yPjxhdXRob3I+UHJvaXRzaSwgUC48L2F1dGhvcj48YXV0aG9yPkx1cHRv

biwgTS4gSy48L2F1dGhvcj48YXV0aG9yPkJyYXluZSwgQy48L2F1dGhvcj48YXV0aG9yPlJ1Ymlu

c3p0ZWluLCBELiBDLjwvYXV0aG9yPjxhdXRob3I+R2lsbCwgTS48L2F1dGhvcj48YXV0aG9yPkxh

d2xvciwgQi48L2F1dGhvcj48YXV0aG9yPkx5bmNoLCBBLjwvYXV0aG9yPjxhdXRob3I+TW9yZ2Fu

LCBLLjwvYXV0aG9yPjxhdXRob3I+QnJvd24sIEsuIFMuPC9hdXRob3I+PGF1dGhvcj5QYXNzbW9y

ZSwgUC4gQS48L2F1dGhvcj48YXV0aG9yPkNyYWlnLCBELjwvYXV0aG9yPjxhdXRob3I+TWNHdWlu

bmVzcywgQi48L2F1dGhvcj48YXV0aG9yPlRvZGQsIFMuPC9hdXRob3I+PGF1dGhvcj5Ib2xtZXMs

IEMuPC9hdXRob3I+PGF1dGhvcj5NYW5uLCBELjwvYXV0aG9yPjxhdXRob3I+U21pdGgsIEEuIEQu

PC9hdXRob3I+PGF1dGhvcj5Mb3ZlLCBTLjwvYXV0aG9yPjxhdXRob3I+S2Vob2UsIFAuIEcuPC9h

dXRob3I+PGF1dGhvcj5NZWFkLCBTLjwvYXV0aG9yPjxhdXRob3I+Rm94LCBOLjwvYXV0aG9yPjxh

dXRob3I+Um9zc29yLCBNLjwvYXV0aG9yPjxhdXRob3I+Q29sbGluZ2UsIEouPC9hdXRob3I+PGF1

dGhvcj5NYWllciwgVy48L2F1dGhvcj48YXV0aG9yPkplc3NlbiwgRi48L2F1dGhvcj48YXV0aG9y

PlNjaHVybWFubiwgQi48L2F1dGhvcj48YXV0aG9yPkhldW4sIFIuPC9hdXRob3I+PGF1dGhvcj5L

b2xzY2gsIEguPC9hdXRob3I+PGF1dGhvcj52YW4gZGVuIEJ1c3NjaGUsIEguPC9hdXRob3I+PGF1

dGhvcj5IZXVzZXIsIEkuPC9hdXRob3I+PGF1dGhvcj5QZXRlcnMsIE8uPC9hdXRob3I+PGF1dGhv

cj5Lb3JuaHViZXIsIEouPC9hdXRob3I+PGF1dGhvcj5XaWx0ZmFuZywgSi48L2F1dGhvcj48YXV0

aG9yPkRpY2hnYW5zLCBNLjwvYXV0aG9yPjxhdXRob3I+RnJvbGljaCwgTC48L2F1dGhvcj48YXV0

aG9yPkhhbXBlbCwgSC48L2F1dGhvcj48YXV0aG9yPkh1bGwsIE0uPC9hdXRob3I+PGF1dGhvcj5S

dWplc2N1LCBELjwvYXV0aG9yPjxhdXRob3I+R29hdGUsIEEuIE0uPC9hdXRob3I+PGF1dGhvcj5L

YXV3ZSwgSi4gUy48L2F1dGhvcj48YXV0aG9yPkNydWNoYWdhLCBDLjwvYXV0aG9yPjxhdXRob3I+

Tm93b3RueSwgUC48L2F1dGhvcj48YXV0aG9yPk1vcnJpcywgSi4gQy48L2F1dGhvcj48YXV0aG9y

Pk1heW8sIEsuPC9hdXRob3I+PGF1dGhvcj5MaXZpbmdzdG9uLCBHLjwvYXV0aG9yPjxhdXRob3I+

QmFzcywgTi4gSi48L2F1dGhvcj48YXV0aG9yPkd1cmxpbmcsIEguPC9hdXRob3I+PGF1dGhvcj5N

Y1F1aWxsaW4sIEEuPC9hdXRob3I+PGF1dGhvcj5Hd2lsbGlhbSwgUi48L2F1dGhvcj48YXV0aG9y

PkRlbG91a2FzLCBQLjwvYXV0aG9yPjxhdXRob3I+QWwtQ2hhbGFiaSwgQS48L2F1dGhvcj48YXV0

aG9yPlNoYXcsIEMuIEUuPC9hdXRob3I+PGF1dGhvcj5TaW5nbGV0b24sIEEuIEIuPC9hdXRob3I+

PGF1dGhvcj5HdWVycmVpcm8sIFIuPC9hdXRob3I+PGF1dGhvcj5NdWhsZWlzZW4sIFQuIFcuPC9h

dXRob3I+PGF1dGhvcj5Ob3RoZW4sIE0uIE0uPC9hdXRob3I+PGF1dGhvcj5Nb2VidXMsIFMuPC9h

dXRob3I+PGF1dGhvcj5Kb2NrZWwsIEsuIEguPC9hdXRob3I+PGF1dGhvcj5LbG9wcCwgTi48L2F1

dGhvcj48YXV0aG9yPldpY2htYW5uLCBILiBFLjwvYXV0aG9yPjxhdXRob3I+UnV0aGVyLCBFLjwv

YXV0aG9yPjxhdXRob3I+Q2FycmFzcXVpbGxvLCBNLiBNLjwvYXV0aG9yPjxhdXRob3I+UGFua3Jh

dHosIFYuIFMuPC9hdXRob3I+PGF1dGhvcj5Zb3Vua2luLCBTLiBHLjwvYXV0aG9yPjxhdXRob3I+

SGFyZHksIEouPC9hdXRob3I+PGF1dGhvcj5PJmFwb3M7RG9ub3ZhbiwgTS4gQy48L2F1dGhvcj48

YXV0aG9yPk93ZW4sIE0uIEouPC9hdXRob3I+PGF1dGhvcj5XaWxsaWFtcywgSi48L2F1dGhvcj48

L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIFBzeWNo

b2xvZ2ljYWwgTWVkaWNpbmUgYW5kIE5ldXJvbG9neSwgU2Nob29sIG9mIE1lZGljaW5lLCBDYXJk

aWZmIFVuaXZlcnNpdHksIE1lZGljYWwgUmVzZWFyY2ggQ291bmNpbCBDZW50cmUgZm9yIE5ldXJv

cHN5Y2hpYXRyaWMgR2VuZXRpY3MgYW5kIEdlbm9taWNzLCBDYXJkaWZmLCBVbml0ZWQgS2luZ2Rv

bS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5HZW5ldGljIGV2aWRlbmNlIGltcGxpY2F0

ZXMgdGhlIGltbXVuZSBzeXN0ZW0gYW5kIGNob2xlc3Rlcm9sIG1ldGFib2xpc20gaW4gdGhlIGFl

dGlvbG9neSBvZiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0

bGU+UExvUyBPbmU8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10

aXRsZT5QTG9TIE9uZTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPmUxMzk1MDwvcGFn

ZXM+PHZvbHVtZT41PC92b2x1bWU+PG51bWJlcj4xMTwvbnVtYmVyPjxlZGl0aW9uPjIwMTAvMTEv

MTk8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypnZW5ldGlj

cy9pbW11bm9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QXBvbGlwb3Byb3RlaW5z

IEUvZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0ZXJvbC8qbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DaHJvbW9zb21lIE1hcHBpbmc8L2tleXdvcmQ+PGtl

eXdvcmQ+R2VuZXRpYyBQcmVkaXNwb3NpdGlvbiB0byBEaXNlYXNlL2dlbmV0aWNzPC9rZXl3b3Jk

PjxrZXl3b3JkPkdlbm9tZSwgSHVtYW48L2tleXdvcmQ+PGtleXdvcmQ+Kkdlbm9tZS1XaWRlIEFz

c29jaWF0aW9uIFN0dWR5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29y

ZD5JbW11bmUgU3lzdGVtLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlBvbHltb3JwaGlz

bSwgU2luZ2xlIE51Y2xlb3RpZGU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAx

MDwveWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdiAxNTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVz

Pjxpc2JuPjE5MzItNjIwMyAoRWxlY3Ryb25pYykmI3hEOzE5MzItNjIwMyAoTGlua2luZyk8L2lz

Ym4+PGFjY2Vzc2lvbi1udW0+MjEwODU1NzA8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQt

dXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIxMDg1NTcwPC91

cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzI5ODE1MjY8L2N1c3RvbTI+PGVs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEzNzEvam91cm5hbC5wb25lLjAwMTM5NTA8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkNhc3RlbGxh

bm88L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxSZWNOdW0+MjA2NjwvUmVjTnVtPjxyZWNvcmQ+

PHJlYy1udW1iZXI+MjA2NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIg

ZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIx

NTM0NzgwMDc2Ij4yMDY2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5D

YXN0ZWxsYW5vLCBKLiBNLjwvYXV0aG9yPjxhdXRob3I+S2ltLCBKLjwvYXV0aG9yPjxhdXRob3I+

U3Rld2FydCwgRi4gUi48L2F1dGhvcj48YXV0aG9yPkppYW5nLCBILjwvYXV0aG9yPjxhdXRob3I+

RGVNYXR0b3MsIFIuIEIuPC9hdXRob3I+PGF1dGhvcj5QYXR0ZXJzb24sIEIuIFcuPC9hdXRob3I+

PGF1dGhvcj5GYWdhbiwgQS4gTS48L2F1dGhvcj48YXV0aG9yPk1vcnJpcywgSi4gQy48L2F1dGhv

cj48YXV0aG9yPk1hd3VlbnllZ2EsIEsuIEcuPC9hdXRob3I+PGF1dGhvcj5DcnVjaGFnYSwgQy48

L2F1dGhvcj48YXV0aG9yPkdvYXRlLCBBLiBNLjwvYXV0aG9yPjxhdXRob3I+QmFsZXMsIEsuIFIu

PC9hdXRob3I+PGF1dGhvcj5QYXVsLCBTLiBNLjwvYXV0aG9yPjxhdXRob3I+QmF0ZW1hbiwgUi4g

Si48L2F1dGhvcj48YXV0aG9yPkhvbHR6bWFuLCBELiBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2Nv

bnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBXYXNoaW5n

dG9uIFVuaXZlcnNpdHkgU2Nob29sIG9mIE1lZGljaW5lLCBTdC4gTG91aXMsIE1PIDYzMTEwLCBV

U0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+SHVtYW4gYXBvRSBpc29mb3JtcyBkaWZm

ZXJlbnRpYWxseSByZWd1bGF0ZSBicmFpbiBhbXlsb2lkLWJldGEgcGVwdGlkZSBjbGVhcmFuY2U8

L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+U2NpIFRyYW5zbCBNZWQ8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5TY2kgVHJhbnNsIE1lZDwvZnVsbC10aXRs

ZT48L3BlcmlvZGljYWw+PHBhZ2VzPjg5cmE1NzwvcGFnZXM+PHZvbHVtZT4zPC92b2x1bWU+PG51

bWJlcj44OTwvbnVtYmVyPjxlZGl0aW9uPjIwMTEvMDcvMDE8L2VkaXRpb24+PGtleXdvcmRzPjxr

ZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWxs

ZWxlczwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9nZW5ldGljcy9tZXRhYm9s

aXNtL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvKmNl

cmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5

d29yZD5BcG9saXBvcHJvdGVpbiBFNC9nZW5ldGljcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5CaW9tYXJrZXJzL2NlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+QnJh

aW4vKm1ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29y

ZD48a2V5d29yZD5HZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtl

eXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2Us

IEluYnJlZCBDNTdCTDwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFuc2dlbmljPC9rZXl3b3Jk

PjxrZXl3b3JkPk1pY3JvZGlhbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tl

eXdvcmQ+PGtleXdvcmQ+UHJvdGVpbiBJc29mb3Jtcy9nZW5ldGljcy8qbWV0YWJvbGlzbTwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

SnVuIDI5PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTk0Ni02MjQyIChFbGVjdHJv

bmljKSYjeEQ7MTk0Ni02MjM0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMTcxNTY3

ODwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNi

aS5ubG0ubmloLmdvdi9wdWJtZWQvMjE3MTU2Nzg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGN1c3RvbTI+UE1DMzE5MjM2NDwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu

MTEyNi9zY2l0cmFuc2xtZWQuMzAwMjE1NjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNv

cmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 15,44,45. Downstream, the cascade leads to Tau aggregation, inflammation, oxidative stress and ultimately neuronal death ADDIN EN.CITE <EndNote><Cite><Author>Hardy</Author><Year>2014</Year><RecNum>283</RecNum><DisplayText><style face="superscript">46</style></DisplayText><record><rec-number>283</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1531775273">283</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hardy, J.</author><author>Bogdanovic, N.</author><author>Winblad, B.</author><author>Portelius, E.</author><author>Andreasen, N.</author><author>Cedazo-Minguez, A.</author><author>Zetterberg, H.</author></authors></contributors><titles><title>Pathways to Alzheimer&apos;s disease</title><secondary-title>J Intern Med</secondary-title></titles><periodical><full-title>J Intern Med</full-title></periodical><pages>296-303</pages><volume>275</volume><number>3</number><keywords><keyword>*Alzheimer Disease/genetics/metabolism</keyword><keyword>*Amyloid/genetics/metabolism</keyword><keyword>Amyloid beta-Peptides/*antagonists &amp; inhibitors</keyword><keyword>Brain/metabolism</keyword><keyword>Early Medical Intervention</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Humans</keyword><keyword>Immunotherapy/methods</keyword></keywords><dates><year>2014</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1365-2796 (Electronic)&#xD;0954-6820 (Linking)</isbn><accession-num>24749173</accession-num><urls><related-urls><url>. These pathways are rather clear at least for the familial cases. Now with the genome-wide association studies (GWAS), we have several new prospects coming up, but still, it is a scientific consensus that Aβ processing and Tau hyperphosphorylation are key components of AD pathology ADDIN EN.CITE <EndNote><Cite><Author>Hardy</Author><Year>2006</Year><RecNum>132</RecNum><DisplayText><style face="superscript">47</style></DisplayText><record><rec-number>132</rec-number><foreign-keys><key app="EN" db-id="swwr55ss42rv2ze9w2s50t9sx29tta02p5te" timestamp="1536227420">132</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hardy, J.</author></authors></contributors><auth-address>Laboratory of Neurogenetics, National Institute on Aging, Porter Neuroscience Building, 35, Convent Drive, Bethesda, MD20892, USA. hardyj@mail.</auth-address><titles><title>Alzheimer&apos;s disease: the amyloid cascade hypothesis: an update and reappraisal</title><secondary-title>J Alzheimers Dis</secondary-title></titles><periodical><full-title>J Alzheimers Dis</full-title></periodical><pages>151-3</pages><volume>9</volume><number>3 Suppl</number><edition>2006/08/18</edition><keywords><keyword>Alzheimer Disease/*metabolism/*pathology</keyword><keyword>Amyloid beta-Peptides/*metabolism</keyword><keyword>Brain/*metabolism/*pathology</keyword><keyword>Humans</keyword></keywords><dates><year>2006</year></dates><isbn>1387-2877 (Print)&#xD;1387-2877 (Linking)</isbn><accession-num>16914853</accession-num><urls><related-urls><url>. Upstream, we have more new pathways that have been elucidated, mainly by the GWAS PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Kb25lczwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl

Y051bT4yMDY1PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDY1PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ3Nzk5NjEiPjIwNjU8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkpvbmVzLCBMLjwvYXV0aG9yPjxhdXRob3I+

SG9sbWFucywgUC4gQS48L2F1dGhvcj48YXV0aG9yPkhhbXNoZXJlLCBNLiBMLjwvYXV0aG9yPjxh

dXRob3I+SGFyb2xkLCBELjwvYXV0aG9yPjxhdXRob3I+TW9za3ZpbmEsIFYuPC9hdXRob3I+PGF1

dGhvcj5JdmFub3YsIEQuPC9hdXRob3I+PGF1dGhvcj5Qb2NrbGluZ3RvbiwgQS48L2F1dGhvcj48

YXV0aG9yPkFicmFoYW0sIFIuPC9hdXRob3I+PGF1dGhvcj5Ib2xsaW5nd29ydGgsIFAuPC9hdXRo

b3I+PGF1dGhvcj5TaW1zLCBSLjwvYXV0aG9yPjxhdXRob3I+R2VycmlzaCwgQS48L2F1dGhvcj48

YXV0aG9yPlBhaHdhLCBKLiBTLjwvYXV0aG9yPjxhdXRob3I+Sm9uZXMsIE4uPC9hdXRob3I+PGF1

dGhvcj5TdHJldHRvbiwgQS48L2F1dGhvcj48YXV0aG9yPk1vcmdhbiwgQS4gUi48L2F1dGhvcj48

YXV0aG9yPkxvdmVzdG9uZSwgUy48L2F1dGhvcj48YXV0aG9yPlBvd2VsbCwgSi48L2F1dGhvcj48

YXV0aG9yPlByb2l0c2ksIFAuPC9hdXRob3I+PGF1dGhvcj5MdXB0b24sIE0uIEsuPC9hdXRob3I+

PGF1dGhvcj5CcmF5bmUsIEMuPC9hdXRob3I+PGF1dGhvcj5SdWJpbnN6dGVpbiwgRC4gQy48L2F1

dGhvcj48YXV0aG9yPkdpbGwsIE0uPC9hdXRob3I+PGF1dGhvcj5MYXdsb3IsIEIuPC9hdXRob3I+

PGF1dGhvcj5MeW5jaCwgQS48L2F1dGhvcj48YXV0aG9yPk1vcmdhbiwgSy48L2F1dGhvcj48YXV0

aG9yPkJyb3duLCBLLiBTLjwvYXV0aG9yPjxhdXRob3I+UGFzc21vcmUsIFAuIEEuPC9hdXRob3I+

PGF1dGhvcj5DcmFpZywgRC48L2F1dGhvcj48YXV0aG9yPk1jR3Vpbm5lc3MsIEIuPC9hdXRob3I+

PGF1dGhvcj5Ub2RkLCBTLjwvYXV0aG9yPjxhdXRob3I+SG9sbWVzLCBDLjwvYXV0aG9yPjxhdXRo

b3I+TWFubiwgRC48L2F1dGhvcj48YXV0aG9yPlNtaXRoLCBBLiBELjwvYXV0aG9yPjxhdXRob3I+

TG92ZSwgUy48L2F1dGhvcj48YXV0aG9yPktlaG9lLCBQLiBHLjwvYXV0aG9yPjxhdXRob3I+TWVh

ZCwgUy48L2F1dGhvcj48YXV0aG9yPkZveCwgTi48L2F1dGhvcj48YXV0aG9yPlJvc3NvciwgTS48

L2F1dGhvcj48YXV0aG9yPkNvbGxpbmdlLCBKLjwvYXV0aG9yPjxhdXRob3I+TWFpZXIsIFcuPC9h

dXRob3I+PGF1dGhvcj5KZXNzZW4sIEYuPC9hdXRob3I+PGF1dGhvcj5TY2h1cm1hbm4sIEIuPC9h

dXRob3I+PGF1dGhvcj5IZXVuLCBSLjwvYXV0aG9yPjxhdXRob3I+S29sc2NoLCBILjwvYXV0aG9y

PjxhdXRob3I+dmFuIGRlbiBCdXNzY2hlLCBILjwvYXV0aG9yPjxhdXRob3I+SGV1c2VyLCBJLjwv

YXV0aG9yPjxhdXRob3I+UGV0ZXJzLCBPLjwvYXV0aG9yPjxhdXRob3I+S29ybmh1YmVyLCBKLjwv

YXV0aG9yPjxhdXRob3I+V2lsdGZhbmcsIEouPC9hdXRob3I+PGF1dGhvcj5EaWNoZ2FucywgTS48

L2F1dGhvcj48YXV0aG9yPkZyb2xpY2gsIEwuPC9hdXRob3I+PGF1dGhvcj5IYW1wZWwsIEguPC9h

dXRob3I+PGF1dGhvcj5IdWxsLCBNLjwvYXV0aG9yPjxhdXRob3I+UnVqZXNjdSwgRC48L2F1dGhv

cj48YXV0aG9yPkdvYXRlLCBBLiBNLjwvYXV0aG9yPjxhdXRob3I+S2F1d2UsIEouIFMuPC9hdXRo

b3I+PGF1dGhvcj5DcnVjaGFnYSwgQy48L2F1dGhvcj48YXV0aG9yPk5vd290bnksIFAuPC9hdXRo

b3I+PGF1dGhvcj5Nb3JyaXMsIEouIEMuPC9hdXRob3I+PGF1dGhvcj5NYXlvLCBLLjwvYXV0aG9y

PjxhdXRob3I+TGl2aW5nc3RvbiwgRy48L2F1dGhvcj48YXV0aG9yPkJhc3MsIE4uIEouPC9hdXRo

b3I+PGF1dGhvcj5HdXJsaW5nLCBILjwvYXV0aG9yPjxhdXRob3I+TWNRdWlsbGluLCBBLjwvYXV0

aG9yPjxhdXRob3I+R3dpbGxpYW0sIFIuPC9hdXRob3I+PGF1dGhvcj5EZWxvdWthcywgUC48L2F1

dGhvcj48YXV0aG9yPkFsLUNoYWxhYmksIEEuPC9hdXRob3I+PGF1dGhvcj5TaGF3LCBDLiBFLjwv

YXV0aG9yPjxhdXRob3I+U2luZ2xldG9uLCBBLiBCLjwvYXV0aG9yPjxhdXRob3I+R3VlcnJlaXJv

LCBSLjwvYXV0aG9yPjxhdXRob3I+TXVobGVpc2VuLCBULiBXLjwvYXV0aG9yPjxhdXRob3I+Tm90

aGVuLCBNLiBNLjwvYXV0aG9yPjxhdXRob3I+TW9lYnVzLCBTLjwvYXV0aG9yPjxhdXRob3I+Sm9j

a2VsLCBLLiBILjwvYXV0aG9yPjxhdXRob3I+S2xvcHAsIE4uPC9hdXRob3I+PGF1dGhvcj5XaWNo

bWFubiwgSC4gRS48L2F1dGhvcj48YXV0aG9yPlJ1dGhlciwgRS48L2F1dGhvcj48YXV0aG9yPkNh

cnJhc3F1aWxsbywgTS4gTS48L2F1dGhvcj48YXV0aG9yPlBhbmtyYXR6LCBWLiBTLjwvYXV0aG9y

PjxhdXRob3I+WW91bmtpbiwgUy4gRy48L2F1dGhvcj48YXV0aG9yPkhhcmR5LCBKLjwvYXV0aG9y

PjxhdXRob3I+TyZhcG9zO0Rvbm92YW4sIE0uIEMuPC9hdXRob3I+PGF1dGhvcj5Pd2VuLCBNLiBK

LjwvYXV0aG9yPjxhdXRob3I+V2lsbGlhbXMsIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp

YnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQc3ljaG9sb2dpY2FsIE1lZGljaW5l

IGFuZCBOZXVyb2xvZ3ksIFNjaG9vbCBvZiBNZWRpY2luZSwgQ2FyZGlmZiBVbml2ZXJzaXR5LCBN

ZWRpY2FsIFJlc2VhcmNoIENvdW5jaWwgQ2VudHJlIGZvciBOZXVyb3BzeWNoaWF0cmljIEdlbmV0

aWNzIGFuZCBHZW5vbWljcywgQ2FyZGlmZiwgVW5pdGVkIEtpbmdkb20uPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+R2VuZXRpYyBldmlkZW5jZSBpbXBsaWNhdGVzIHRoZSBpbW11bmUgc3lz

dGVtIGFuZCBjaG9sZXN0ZXJvbCBtZXRhYm9saXNtIGluIHRoZSBhZXRpb2xvZ3kgb2YgQWx6aGVp

bWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlBMb1MgT25lPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UExvUyBPbmU8L2Z1

bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz5lMTM5NTA8L3BhZ2VzPjx2b2x1bWU+NTwvdm9s

dW1lPjxudW1iZXI+MTE8L251bWJlcj48ZWRpdGlvbj4yMDEwLzExLzE5PC9lZGl0aW9uPjxrZXl3

b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qZ2VuZXRpY3MvaW1tdW5vbG9neS9tZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWlucyBFL2dlbmV0aWNzL21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGVzdGVyb2wvKm1ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+Q2hyb21vc29tZSBNYXBwaW5nPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmV0aWMgUHJl

ZGlzcG9zaXRpb24gdG8gRGlzZWFzZS9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5HZW5vbWUs

IEh1bWFuPC9rZXl3b3JkPjxrZXl3b3JkPipHZW5vbWUtV2lkZSBBc3NvY2lhdGlvbiBTdHVkeTwv

a2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5lIFN5c3RlbS8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5Qb2x5bW9ycGhpc20sIFNpbmdsZSBOdWNsZW90

aWRlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTA8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT5Ob3YgMTU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xOTMyLTYyMDMg

KEVsZWN0cm9uaWMpJiN4RDsxOTMyLTYyMDMgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVt

PjIxMDg1NTcwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczov

L3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMTA4NTU3MDwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48Y3VzdG9tMj5QTUMyOTgxNTI2PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNl

LW51bT4xMC4xMzcxL2pvdXJuYWwucG9uZS4wMDEzOTUwPC9lbGVjdHJvbmljLXJlc291cmNlLW51

bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Kb25lczwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl

Y051bT4yMDY1PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDY1PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ3Nzk5NjEiPjIwNjU8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkpvbmVzLCBMLjwvYXV0aG9yPjxhdXRob3I+

SG9sbWFucywgUC4gQS48L2F1dGhvcj48YXV0aG9yPkhhbXNoZXJlLCBNLiBMLjwvYXV0aG9yPjxh

dXRob3I+SGFyb2xkLCBELjwvYXV0aG9yPjxhdXRob3I+TW9za3ZpbmEsIFYuPC9hdXRob3I+PGF1

dGhvcj5JdmFub3YsIEQuPC9hdXRob3I+PGF1dGhvcj5Qb2NrbGluZ3RvbiwgQS48L2F1dGhvcj48

YXV0aG9yPkFicmFoYW0sIFIuPC9hdXRob3I+PGF1dGhvcj5Ib2xsaW5nd29ydGgsIFAuPC9hdXRo

b3I+PGF1dGhvcj5TaW1zLCBSLjwvYXV0aG9yPjxhdXRob3I+R2VycmlzaCwgQS48L2F1dGhvcj48

YXV0aG9yPlBhaHdhLCBKLiBTLjwvYXV0aG9yPjxhdXRob3I+Sm9uZXMsIE4uPC9hdXRob3I+PGF1

dGhvcj5TdHJldHRvbiwgQS48L2F1dGhvcj48YXV0aG9yPk1vcmdhbiwgQS4gUi48L2F1dGhvcj48

YXV0aG9yPkxvdmVzdG9uZSwgUy48L2F1dGhvcj48YXV0aG9yPlBvd2VsbCwgSi48L2F1dGhvcj48

YXV0aG9yPlByb2l0c2ksIFAuPC9hdXRob3I+PGF1dGhvcj5MdXB0b24sIE0uIEsuPC9hdXRob3I+

PGF1dGhvcj5CcmF5bmUsIEMuPC9hdXRob3I+PGF1dGhvcj5SdWJpbnN6dGVpbiwgRC4gQy48L2F1

dGhvcj48YXV0aG9yPkdpbGwsIE0uPC9hdXRob3I+PGF1dGhvcj5MYXdsb3IsIEIuPC9hdXRob3I+

PGF1dGhvcj5MeW5jaCwgQS48L2F1dGhvcj48YXV0aG9yPk1vcmdhbiwgSy48L2F1dGhvcj48YXV0

aG9yPkJyb3duLCBLLiBTLjwvYXV0aG9yPjxhdXRob3I+UGFzc21vcmUsIFAuIEEuPC9hdXRob3I+

PGF1dGhvcj5DcmFpZywgRC48L2F1dGhvcj48YXV0aG9yPk1jR3Vpbm5lc3MsIEIuPC9hdXRob3I+

PGF1dGhvcj5Ub2RkLCBTLjwvYXV0aG9yPjxhdXRob3I+SG9sbWVzLCBDLjwvYXV0aG9yPjxhdXRo

b3I+TWFubiwgRC48L2F1dGhvcj48YXV0aG9yPlNtaXRoLCBBLiBELjwvYXV0aG9yPjxhdXRob3I+

TG92ZSwgUy48L2F1dGhvcj48YXV0aG9yPktlaG9lLCBQLiBHLjwvYXV0aG9yPjxhdXRob3I+TWVh

ZCwgUy48L2F1dGhvcj48YXV0aG9yPkZveCwgTi48L2F1dGhvcj48YXV0aG9yPlJvc3NvciwgTS48

L2F1dGhvcj48YXV0aG9yPkNvbGxpbmdlLCBKLjwvYXV0aG9yPjxhdXRob3I+TWFpZXIsIFcuPC9h

dXRob3I+PGF1dGhvcj5KZXNzZW4sIEYuPC9hdXRob3I+PGF1dGhvcj5TY2h1cm1hbm4sIEIuPC9h

dXRob3I+PGF1dGhvcj5IZXVuLCBSLjwvYXV0aG9yPjxhdXRob3I+S29sc2NoLCBILjwvYXV0aG9y

PjxhdXRob3I+dmFuIGRlbiBCdXNzY2hlLCBILjwvYXV0aG9yPjxhdXRob3I+SGV1c2VyLCBJLjwv

YXV0aG9yPjxhdXRob3I+UGV0ZXJzLCBPLjwvYXV0aG9yPjxhdXRob3I+S29ybmh1YmVyLCBKLjwv

YXV0aG9yPjxhdXRob3I+V2lsdGZhbmcsIEouPC9hdXRob3I+PGF1dGhvcj5EaWNoZ2FucywgTS48

L2F1dGhvcj48YXV0aG9yPkZyb2xpY2gsIEwuPC9hdXRob3I+PGF1dGhvcj5IYW1wZWwsIEguPC9h

dXRob3I+PGF1dGhvcj5IdWxsLCBNLjwvYXV0aG9yPjxhdXRob3I+UnVqZXNjdSwgRC48L2F1dGhv

cj48YXV0aG9yPkdvYXRlLCBBLiBNLjwvYXV0aG9yPjxhdXRob3I+S2F1d2UsIEouIFMuPC9hdXRo

b3I+PGF1dGhvcj5DcnVjaGFnYSwgQy48L2F1dGhvcj48YXV0aG9yPk5vd290bnksIFAuPC9hdXRo

b3I+PGF1dGhvcj5Nb3JyaXMsIEouIEMuPC9hdXRob3I+PGF1dGhvcj5NYXlvLCBLLjwvYXV0aG9y

PjxhdXRob3I+TGl2aW5nc3RvbiwgRy48L2F1dGhvcj48YXV0aG9yPkJhc3MsIE4uIEouPC9hdXRo

b3I+PGF1dGhvcj5HdXJsaW5nLCBILjwvYXV0aG9yPjxhdXRob3I+TWNRdWlsbGluLCBBLjwvYXV0

aG9yPjxhdXRob3I+R3dpbGxpYW0sIFIuPC9hdXRob3I+PGF1dGhvcj5EZWxvdWthcywgUC48L2F1

dGhvcj48YXV0aG9yPkFsLUNoYWxhYmksIEEuPC9hdXRob3I+PGF1dGhvcj5TaGF3LCBDLiBFLjwv

YXV0aG9yPjxhdXRob3I+U2luZ2xldG9uLCBBLiBCLjwvYXV0aG9yPjxhdXRob3I+R3VlcnJlaXJv

LCBSLjwvYXV0aG9yPjxhdXRob3I+TXVobGVpc2VuLCBULiBXLjwvYXV0aG9yPjxhdXRob3I+Tm90

aGVuLCBNLiBNLjwvYXV0aG9yPjxhdXRob3I+TW9lYnVzLCBTLjwvYXV0aG9yPjxhdXRob3I+Sm9j

a2VsLCBLLiBILjwvYXV0aG9yPjxhdXRob3I+S2xvcHAsIE4uPC9hdXRob3I+PGF1dGhvcj5XaWNo

bWFubiwgSC4gRS48L2F1dGhvcj48YXV0aG9yPlJ1dGhlciwgRS48L2F1dGhvcj48YXV0aG9yPkNh

cnJhc3F1aWxsbywgTS4gTS48L2F1dGhvcj48YXV0aG9yPlBhbmtyYXR6LCBWLiBTLjwvYXV0aG9y

PjxhdXRob3I+WW91bmtpbiwgUy4gRy48L2F1dGhvcj48YXV0aG9yPkhhcmR5LCBKLjwvYXV0aG9y

PjxhdXRob3I+TyZhcG9zO0Rvbm92YW4sIE0uIEMuPC9hdXRob3I+PGF1dGhvcj5Pd2VuLCBNLiBK

LjwvYXV0aG9yPjxhdXRob3I+V2lsbGlhbXMsIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp

YnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQc3ljaG9sb2dpY2FsIE1lZGljaW5l

IGFuZCBOZXVyb2xvZ3ksIFNjaG9vbCBvZiBNZWRpY2luZSwgQ2FyZGlmZiBVbml2ZXJzaXR5LCBN

ZWRpY2FsIFJlc2VhcmNoIENvdW5jaWwgQ2VudHJlIGZvciBOZXVyb3BzeWNoaWF0cmljIEdlbmV0

aWNzIGFuZCBHZW5vbWljcywgQ2FyZGlmZiwgVW5pdGVkIEtpbmdkb20uPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+R2VuZXRpYyBldmlkZW5jZSBpbXBsaWNhdGVzIHRoZSBpbW11bmUgc3lz

dGVtIGFuZCBjaG9sZXN0ZXJvbCBtZXRhYm9saXNtIGluIHRoZSBhZXRpb2xvZ3kgb2YgQWx6aGVp

bWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlBMb1MgT25lPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UExvUyBPbmU8L2Z1

bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz5lMTM5NTA8L3BhZ2VzPjx2b2x1bWU+NTwvdm9s

dW1lPjxudW1iZXI+MTE8L251bWJlcj48ZWRpdGlvbj4yMDEwLzExLzE5PC9lZGl0aW9uPjxrZXl3

b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qZ2VuZXRpY3MvaW1tdW5vbG9neS9tZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWlucyBFL2dlbmV0aWNzL21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGVzdGVyb2wvKm1ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+Q2hyb21vc29tZSBNYXBwaW5nPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmV0aWMgUHJl

ZGlzcG9zaXRpb24gdG8gRGlzZWFzZS9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5HZW5vbWUs

IEh1bWFuPC9rZXl3b3JkPjxrZXl3b3JkPipHZW5vbWUtV2lkZSBBc3NvY2lhdGlvbiBTdHVkeTwv

a2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5lIFN5c3RlbS8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5Qb2x5bW9ycGhpc20sIFNpbmdsZSBOdWNsZW90

aWRlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTA8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT5Ob3YgMTU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xOTMyLTYyMDMg

KEVsZWN0cm9uaWMpJiN4RDsxOTMyLTYyMDMgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVt

PjIxMDg1NTcwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczov

L3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMTA4NTU3MDwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48Y3VzdG9tMj5QTUMyOTgxNTI2PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNl

LW51bT4xMC4xMzcxL2pvdXJuYWwucG9uZS4wMDEzOTUwPC9lbGVjdHJvbmljLXJlc291cmNlLW51

bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 44. These are the glucose metabolism, the cholesterol metabolism, inflammation, intracellular membrane, and vesicle recycling and oxidative stress PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJvbGQ8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS

ZWNOdW0+MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjQs

NDQsNDgsNDk8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0icDkyYWFwdDUwMGY5MDVl

MmRmNDU1cGU2dnpmcnRzOWF0ZXA1IiB0aW1lc3RhbXA9IjE1MTU1MTE1MTQiPjI8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhhcm9sZCwgRGVuaXNlPC9hdXRob3I+PGF1

dGhvcj5BYnJhaGFtLCBSaWNoYXJkPC9hdXRob3I+PGF1dGhvcj5Ib2xsaW5nd29ydGgsIFBhdWw8

L2F1dGhvcj48YXV0aG9yPlNpbXMsIFJlYmVjY2E8L2F1dGhvcj48YXV0aG9yPkdlcnJpc2gsIEFt

eTwvYXV0aG9yPjxhdXRob3I+SGFtc2hlcmUsIE1hcmlhbiBMLjwvYXV0aG9yPjxhdXRob3I+UGFo

d2EsIEphc3ByZWV0IFNpbmdoPC9hdXRob3I+PGF1dGhvcj5Nb3NrdmluYSwgVmFsZW50aW5hPC9h

dXRob3I+PGF1dGhvcj5Eb3d6ZWxsLCBLaW1iZXJsZXk8L2F1dGhvcj48YXV0aG9yPldpbGxpYW1z

LCBBbXk8L2F1dGhvcj48YXV0aG9yPkpvbmVzLCBOaWNvbGE8L2F1dGhvcj48YXV0aG9yPlRob21h

cywgQ2hhcmxlbmU8L2F1dGhvcj48YXV0aG9yPlN0cmV0dG9uLCBBbGV4YW5kcmE8L2F1dGhvcj48

YXV0aG9yPk1vcmdhbiwgQW5naGFyYWQgUi48L2F1dGhvcj48YXV0aG9yPkxvdmVzdG9uZSwgU2lt

b248L2F1dGhvcj48YXV0aG9yPlBvd2VsbCwgSm9objwvYXV0aG9yPjxhdXRob3I+UHJvaXRzaSwg

UGV0cm91bGE8L2F1dGhvcj48YXV0aG9yPkx1cHRvbiwgTWljaGVsbGUgSy48L2F1dGhvcj48YXV0

aG9yPkJyYXluZSwgQ2Fyb2w8L2F1dGhvcj48YXV0aG9yPlJ1Ymluc3p0ZWluLCBEYXZpZCBDLjwv

YXV0aG9yPjxhdXRob3I+R2lsbCwgTWljaGFlbDwvYXV0aG9yPjxhdXRob3I+TGF3bG9yLCBCcmlh

bjwvYXV0aG9yPjxhdXRob3I+THluY2gsIEFvaWJoaW5uPC9hdXRob3I+PGF1dGhvcj5Nb3JnYW4s

IEtldmluPC9hdXRob3I+PGF1dGhvcj5Ccm93biwgS3Jpc3RlbGxlIFMuPC9hdXRob3I+PGF1dGhv

cj5QYXNzbW9yZSwgUGV0ZXIgQS48L2F1dGhvcj48YXV0aG9yPkNyYWlnLCBEYXZpZDwvYXV0aG9y

PjxhdXRob3I+TWNHdWlubmVzcywgQmVybmFkZXR0ZTwvYXV0aG9yPjxhdXRob3I+VG9kZCwgU3Rl

cGhlbjwvYXV0aG9yPjxhdXRob3I+SG9sbWVzLCBDbGl2ZTwvYXV0aG9yPjxhdXRob3I+TWFubiwg

RGF2aWQ8L2F1dGhvcj48YXV0aG9yPlNtaXRoLCBBLiBEYXZpZDwvYXV0aG9yPjxhdXRob3I+TG92

ZSwgU2V0aDwvYXV0aG9yPjxhdXRob3I+S2Vob2UsIFBhdHJpY2sgRy48L2F1dGhvcj48YXV0aG9y

PkhhcmR5LCBKb2huPC9hdXRob3I+PGF1dGhvcj5NZWFkLCBTaW1vbjwvYXV0aG9yPjxhdXRob3I+

Rm94LCBOaWNrPC9hdXRob3I+PGF1dGhvcj5Sb3Nzb3IsIE1hcnRpbjwvYXV0aG9yPjxhdXRob3I+

Q29sbGluZ2UsIEpvaG48L2F1dGhvcj48YXV0aG9yPk1haWVyLCBXb2xmZ2FuZzwvYXV0aG9yPjxh

dXRob3I+SmVzc2VuLCBGcmFuazwvYXV0aG9yPjxhdXRob3I+U2NodXJtYW5uLCBCcml0dGE8L2F1

dGhvcj48YXV0aG9yPkhldW4sIFJlaW5oYXJkPC9hdXRob3I+PGF1dGhvcj52YW4gZGVuIEJ1c3Nj

aGUsIEhlbmRyaWs8L2F1dGhvcj48YXV0aG9yPkhldXNlciwgSXNhYmVsbGE8L2F1dGhvcj48YXV0

aG9yPktvcm5odWJlciwgSm9oYW5uZXM8L2F1dGhvcj48YXV0aG9yPldpbHRmYW5nLCBKZW5zPC9h

dXRob3I+PGF1dGhvcj5EaWNoZ2FucywgTWFydGluPC9hdXRob3I+PGF1dGhvcj5Gcm9saWNoLCBM

dXR6PC9hdXRob3I+PGF1dGhvcj5IYW1wZWwsIEhhcmFsZDwvYXV0aG9yPjxhdXRob3I+SHVsbCwg

TWljaGFlbDwvYXV0aG9yPjxhdXRob3I+UnVqZXNjdSwgRGFuPC9hdXRob3I+PGF1dGhvcj5Hb2F0

ZSwgQWxpc29uIE0uPC9hdXRob3I+PGF1dGhvcj5LYXV3ZSwgSm9obiBTLiBLLjwvYXV0aG9yPjxh

dXRob3I+Q3J1Y2hhZ2EsIENhcmxvczwvYXV0aG9yPjxhdXRob3I+Tm93b3RueSwgUGV0cmE8L2F1

dGhvcj48YXV0aG9yPk1vcnJpcywgSm9obiBDLjwvYXV0aG9yPjxhdXRob3I+TWF5bywgS2V2aW48

L2F1dGhvcj48YXV0aG9yPlNsZWVnZXJzLCBLcmlzdGVsPC9hdXRob3I+PGF1dGhvcj5CZXR0ZW5z

LCBLYXJvbGllbjwvYXV0aG9yPjxhdXRob3I+RW5nZWxib3JnaHMsIFNlYmFzdGlhYW48L2F1dGhv

cj48YXV0aG9yPkRlIERleW4sIFBldGVyIFAuPC9hdXRob3I+PGF1dGhvcj5WYW4gQnJvZWNraG92

ZW4sIENocmlzdGluZTwvYXV0aG9yPjxhdXRob3I+TGl2aW5nc3RvbiwgR2lsbDwvYXV0aG9yPjxh

dXRob3I+QmFzcywgTmljaG9sYXMgSi48L2F1dGhvcj48YXV0aG9yPkd1cmxpbmcsIEh1Z2g8L2F1

dGhvcj48YXV0aG9yPk1jUXVpbGxpbiwgQW5kcmV3PC9hdXRob3I+PGF1dGhvcj5Hd2lsbGlhbSwg

UmhpYW48L2F1dGhvcj48YXV0aG9yPkRlbG91a2FzLCBQYW5hZ2lvdGlzPC9hdXRob3I+PGF1dGhv

cj5BbC1DaGFsYWJpLCBBbW1hcjwvYXV0aG9yPjxhdXRob3I+U2hhdywgQ2hyaXN0b3BoZXIgRS48

L2F1dGhvcj48YXV0aG9yPlRzb2xha2ksIE1hZ2RhPC9hdXRob3I+PGF1dGhvcj5TaW5nbGV0b24s

IEFuZHJldyBCLjwvYXV0aG9yPjxhdXRob3I+R3VlcnJlaXJvLCBSaXRhPC9hdXRob3I+PGF1dGhv

cj5NdWhsZWlzZW4sIFRob21hcyBXLjwvYXV0aG9yPjxhdXRob3I+Tm90aGVuLCBNYXJrdXMgTS48

L2F1dGhvcj48YXV0aG9yPk1vZWJ1cywgU3VzYW5uZTwvYXV0aG9yPjxhdXRob3I+Sm9ja2VsLCBL

YXJsLUhlaW56PC9hdXRob3I+PGF1dGhvcj5LbG9wcCwgTm9ybWFuPC9hdXRob3I+PGF1dGhvcj5X

aWNobWFubiwgSC4gRXJpY2g8L2F1dGhvcj48YXV0aG9yPkNhcnJhc3F1aWxsbywgTWluZXJ2YSBN

LjwvYXV0aG9yPjxhdXRob3I+UGFua3JhdHosIFYuIFNoYW5lPC9hdXRob3I+PGF1dGhvcj5Zb3Vu

a2luLCBTdGV2ZW4gRy48L2F1dGhvcj48YXV0aG9yPkhvbG1hbnMsIFBldGVyIEEuPC9hdXRob3I+

PGF1dGhvcj5PJmFwb3M7RG9ub3ZhbiwgTWljaGFlbDwvYXV0aG9yPjxhdXRob3I+T3dlbiwgTWlj

aGFlbCBKLjwvYXV0aG9yPjxhdXRob3I+V2lsbGlhbXMsIEp1bGllPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkdlbm9tZS13aWRlIGFzc29jaWF0aW9uIHN0

dWR5IGlkZW50aWZpZXMgdmFyaWFudHMgYXQgQ0xVIGFuZCBQSUNBTE0gYXNzb2NpYXRlZCB3aXRo

IEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OYXQgR2Vu

ZXQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OYXQg

R2VuZXQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMDg4LTEwOTM8L3BhZ2VzPjx2

b2x1bWU+NDE8L3ZvbHVtZT48bnVtYmVyPjEwPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMDk8L3ll

YXI+PHB1Yi1kYXRlcz48ZGF0ZT4xMC8vcHJpbnQ8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

cHVibGlzaGVyPk5hdHVyZSBQdWJsaXNoaW5nIEdyb3VwPC9wdWJsaXNoZXI+PGlzYm4+MTA2MS00

MDM2PC9pc2JuPjx3b3JrLXR5cGU+TGV0dGVyPC93b3JrLXR5cGU+PHVybHM+PHJlbGF0ZWQtdXJs

cz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjEwMzgvbmcuNDQwPC91cmw+PC9yZWxhdGVkLXVy

bHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDM4L25nLjQ0MDwvZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Sm9uZXM8L0F1

dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNOdW0+NjYyPC9SZWNOdW0+PHJlY29yZD48cmVjLW51

bWJlcj42NjI8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJk

dncyZmFwZnRzMDVzZ2VyenM2eDBmNXB0cjU5eHB3OTlhMGEiIHRpbWVzdGFtcD0iMTUxODQ1ODY0

OSI+NjYyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs

ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Kb25lcywgQi48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QWx6aGVpbWVy

IGRpc2Vhc2U6IFRSRU0yIGxpbmtlZCB0byBsYXRlLW9uc2V0IEFEPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPk5hdCBSZXYgTmV1cm9sPC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5OYXR1cmUg

cmV2aWV3cy4gTmV1cm9sb2d5PC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwt

dGl0bGU+TmF0IFJldiBOZXVyb2w8L2Z1bGwtdGl0bGU+PGFiYnItMT5OYXR1cmUgcmV2aWV3cy4g

TmV1cm9sb2d5PC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRs

ZT5OYXQgUmV2IE5ldXJvbDwvZnVsbC10aXRsZT48YWJici0xPk5hdHVyZSByZXZpZXdzLiBOZXVy

b2xvZ3k8L2FiYnItMT48L2FsdC1wZXJpb2RpY2FsPjxwYWdlcz41PC9wYWdlcz48dm9sdW1lPjk8

L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4yMDEyLzEyLzA1PC9lZGl0aW9uPjxk

YXRlcz48eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SmFuPC9kYXRlPjwvcHViLWRh

dGVzPjwvZGF0ZXM+PGlzYm4+MTc1OS00NzY2IChFbGVjdHJvbmljKSYjeEQ7MTc1OS00NzU4IChM

aW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzIwODExNDwvYWNjZXNzaW9uLW51bT48d29y

ay10eXBlPkNvbW1lbnQ8L3dvcmstdHlwZT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDov

L3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMzIwODExNDwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9ucm5ldXJvbC4yMDEyLjI1

NDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+PC9yZWNv

cmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Sm9uZXM8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

ZWNOdW0+MjA2NTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MjA2NTwvcmVjLW51bWJlcj48

Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4

OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0Nzc5OTYxIj4yMDY1PC9rZXk+PC9mb3JlaWdu

LWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250

cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Kb25lcywgTC48L2F1dGhvcj48YXV0aG9yPkhvbG1h

bnMsIFAuIEEuPC9hdXRob3I+PGF1dGhvcj5IYW1zaGVyZSwgTS4gTC48L2F1dGhvcj48YXV0aG9y

Pkhhcm9sZCwgRC48L2F1dGhvcj48YXV0aG9yPk1vc2t2aW5hLCBWLjwvYXV0aG9yPjxhdXRob3I+

SXZhbm92LCBELjwvYXV0aG9yPjxhdXRob3I+UG9ja2xpbmd0b24sIEEuPC9hdXRob3I+PGF1dGhv

cj5BYnJhaGFtLCBSLjwvYXV0aG9yPjxhdXRob3I+SG9sbGluZ3dvcnRoLCBQLjwvYXV0aG9yPjxh

dXRob3I+U2ltcywgUi48L2F1dGhvcj48YXV0aG9yPkdlcnJpc2gsIEEuPC9hdXRob3I+PGF1dGhv

cj5QYWh3YSwgSi4gUy48L2F1dGhvcj48YXV0aG9yPkpvbmVzLCBOLjwvYXV0aG9yPjxhdXRob3I+

U3RyZXR0b24sIEEuPC9hdXRob3I+PGF1dGhvcj5Nb3JnYW4sIEEuIFIuPC9hdXRob3I+PGF1dGhv

cj5Mb3Zlc3RvbmUsIFMuPC9hdXRob3I+PGF1dGhvcj5Qb3dlbGwsIEouPC9hdXRob3I+PGF1dGhv

cj5Qcm9pdHNpLCBQLjwvYXV0aG9yPjxhdXRob3I+THVwdG9uLCBNLiBLLjwvYXV0aG9yPjxhdXRo

b3I+QnJheW5lLCBDLjwvYXV0aG9yPjxhdXRob3I+UnViaW5zenRlaW4sIEQuIEMuPC9hdXRob3I+

PGF1dGhvcj5HaWxsLCBNLjwvYXV0aG9yPjxhdXRob3I+TGF3bG9yLCBCLjwvYXV0aG9yPjxhdXRo

b3I+THluY2gsIEEuPC9hdXRob3I+PGF1dGhvcj5Nb3JnYW4sIEsuPC9hdXRob3I+PGF1dGhvcj5C

cm93biwgSy4gUy48L2F1dGhvcj48YXV0aG9yPlBhc3Ntb3JlLCBQLiBBLjwvYXV0aG9yPjxhdXRo

b3I+Q3JhaWcsIEQuPC9hdXRob3I+PGF1dGhvcj5NY0d1aW5uZXNzLCBCLjwvYXV0aG9yPjxhdXRo

b3I+VG9kZCwgUy48L2F1dGhvcj48YXV0aG9yPkhvbG1lcywgQy48L2F1dGhvcj48YXV0aG9yPk1h

bm4sIEQuPC9hdXRob3I+PGF1dGhvcj5TbWl0aCwgQS4gRC48L2F1dGhvcj48YXV0aG9yPkxvdmUs

IFMuPC9hdXRob3I+PGF1dGhvcj5LZWhvZSwgUC4gRy48L2F1dGhvcj48YXV0aG9yPk1lYWQsIFMu

PC9hdXRob3I+PGF1dGhvcj5Gb3gsIE4uPC9hdXRob3I+PGF1dGhvcj5Sb3Nzb3IsIE0uPC9hdXRo

b3I+PGF1dGhvcj5Db2xsaW5nZSwgSi48L2F1dGhvcj48YXV0aG9yPk1haWVyLCBXLjwvYXV0aG9y

PjxhdXRob3I+SmVzc2VuLCBGLjwvYXV0aG9yPjxhdXRob3I+U2NodXJtYW5uLCBCLjwvYXV0aG9y

PjxhdXRob3I+SGV1biwgUi48L2F1dGhvcj48YXV0aG9yPktvbHNjaCwgSC48L2F1dGhvcj48YXV0

aG9yPnZhbiBkZW4gQnVzc2NoZSwgSC48L2F1dGhvcj48YXV0aG9yPkhldXNlciwgSS48L2F1dGhv

cj48YXV0aG9yPlBldGVycywgTy48L2F1dGhvcj48YXV0aG9yPktvcm5odWJlciwgSi48L2F1dGhv

cj48YXV0aG9yPldpbHRmYW5nLCBKLjwvYXV0aG9yPjxhdXRob3I+RGljaGdhbnMsIE0uPC9hdXRo

b3I+PGF1dGhvcj5Gcm9saWNoLCBMLjwvYXV0aG9yPjxhdXRob3I+SGFtcGVsLCBILjwvYXV0aG9y

PjxhdXRob3I+SHVsbCwgTS48L2F1dGhvcj48YXV0aG9yPlJ1amVzY3UsIEQuPC9hdXRob3I+PGF1

dGhvcj5Hb2F0ZSwgQS4gTS48L2F1dGhvcj48YXV0aG9yPkthdXdlLCBKLiBTLjwvYXV0aG9yPjxh

dXRob3I+Q3J1Y2hhZ2EsIEMuPC9hdXRob3I+PGF1dGhvcj5Ob3dvdG55LCBQLjwvYXV0aG9yPjxh

dXRob3I+TW9ycmlzLCBKLiBDLjwvYXV0aG9yPjxhdXRob3I+TWF5bywgSy48L2F1dGhvcj48YXV0

aG9yPkxpdmluZ3N0b24sIEcuPC9hdXRob3I+PGF1dGhvcj5CYXNzLCBOLiBKLjwvYXV0aG9yPjxh

dXRob3I+R3VybGluZywgSC48L2F1dGhvcj48YXV0aG9yPk1jUXVpbGxpbiwgQS48L2F1dGhvcj48

YXV0aG9yPkd3aWxsaWFtLCBSLjwvYXV0aG9yPjxhdXRob3I+RGVsb3VrYXMsIFAuPC9hdXRob3I+

PGF1dGhvcj5BbC1DaGFsYWJpLCBBLjwvYXV0aG9yPjxhdXRob3I+U2hhdywgQy4gRS48L2F1dGhv

cj48YXV0aG9yPlNpbmdsZXRvbiwgQS4gQi48L2F1dGhvcj48YXV0aG9yPkd1ZXJyZWlybywgUi48

L2F1dGhvcj48YXV0aG9yPk11aGxlaXNlbiwgVC4gVy48L2F1dGhvcj48YXV0aG9yPk5vdGhlbiwg

TS4gTS48L2F1dGhvcj48YXV0aG9yPk1vZWJ1cywgUy48L2F1dGhvcj48YXV0aG9yPkpvY2tlbCwg

Sy4gSC48L2F1dGhvcj48YXV0aG9yPktsb3BwLCBOLjwvYXV0aG9yPjxhdXRob3I+V2ljaG1hbm4s

IEguIEUuPC9hdXRob3I+PGF1dGhvcj5SdXRoZXIsIEUuPC9hdXRob3I+PGF1dGhvcj5DYXJyYXNx

dWlsbG8sIE0uIE0uPC9hdXRob3I+PGF1dGhvcj5QYW5rcmF0eiwgVi4gUy48L2F1dGhvcj48YXV0

aG9yPllvdW5raW4sIFMuIEcuPC9hdXRob3I+PGF1dGhvcj5IYXJkeSwgSi48L2F1dGhvcj48YXV0

aG9yPk8mYXBvcztEb25vdmFuLCBNLiBDLjwvYXV0aG9yPjxhdXRob3I+T3dlbiwgTS4gSi48L2F1

dGhvcj48YXV0aG9yPldpbGxpYW1zLCBKLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgUHN5Y2hvbG9naWNhbCBNZWRpY2luZSBhbmQg

TmV1cm9sb2d5LCBTY2hvb2wgb2YgTWVkaWNpbmUsIENhcmRpZmYgVW5pdmVyc2l0eSwgTWVkaWNh

bCBSZXNlYXJjaCBDb3VuY2lsIENlbnRyZSBmb3IgTmV1cm9wc3ljaGlhdHJpYyBHZW5ldGljcyBh

bmQgR2Vub21pY3MsIENhcmRpZmYsIFVuaXRlZCBLaW5nZG9tLjwvYXV0aC1hZGRyZXNzPjx0aXRs

ZXM+PHRpdGxlPkdlbmV0aWMgZXZpZGVuY2UgaW1wbGljYXRlcyB0aGUgaW1tdW5lIHN5c3RlbSBh

bmQgY2hvbGVzdGVyb2wgbWV0YWJvbGlzbSBpbiB0aGUgYWV0aW9sb2d5IG9mIEFsemhlaW1lciZh

cG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5QTG9TIE9uZTwvc2Vjb25kYXJ5

LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlBMb1MgT25lPC9mdWxsLXRp

dGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+ZTEzOTUwPC9wYWdlcz48dm9sdW1lPjU8L3ZvbHVtZT48

bnVtYmVyPjExPC9udW1iZXI+PGVkaXRpb24+MjAxMC8xMS8xOTwvZWRpdGlvbj48a2V5d29yZHM+

PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmdlbmV0aWNzL2ltbXVub2xvZ3kvbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMgRS9nZW5ldGljcy9tZXRhYm9saXNt

PC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3

b3JkPkNocm9tb3NvbWUgTWFwcGluZzwva2V5d29yZD48a2V5d29yZD5HZW5ldGljIFByZWRpc3Bv

c2l0aW9uIHRvIERpc2Vhc2UvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+R2Vub21lLCBIdW1h

bjwva2V5d29yZD48a2V5d29yZD4qR2Vub21lLVdpZGUgQXNzb2NpYXRpb24gU3R1ZHk8L2tleXdv

cmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVuZSBTeXN0ZW0vKm1ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UG9seW1vcnBoaXNtLCBTaW5nbGUgTnVjbGVvdGlkZTwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+Tm92IDE1PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTkzMi02MjAzIChFbGVj

dHJvbmljKSYjeEQ7MTkzMi02MjAzIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMTA4

NTU3MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjEwODU1NzA8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGN1c3RvbTI+UE1DMjk4MTUyNjwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

MTAuMTM3MS9qb3VybmFsLnBvbmUuMDAxMzk1MDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9y

ZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+V2luYmxhZDwvQXV0aG9yPjxZZWFyPjIwMTY8L1ll

YXI+PFJlY051bT4yNzI8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjI3MjwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhw

Znd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMxNzc1MjcxIj4yNzI8L2tleT48L2ZvcmVp

Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv

bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5B

bW91eWVsLCBQLjwvYXV0aG9yPjxhdXRob3I+QW5kcmlldSwgUy48L2F1dGhvcj48YXV0aG9yPkJh

bGxhcmQsIEMuPC9hdXRob3I+PGF1dGhvcj5CcmF5bmUsIEMuPC9hdXRob3I+PGF1dGhvcj5Ccm9k

YXR5LCBILjwvYXV0aG9yPjxhdXRob3I+Q2VkYXpvLU1pbmd1ZXosIEEuPC9hdXRob3I+PGF1dGhv

cj5EdWJvaXMsIEIuPC9hdXRob3I+PGF1dGhvcj5FZHZhcmRzc29uLCBELjwvYXV0aG9yPjxhdXRo

b3I+RmVsZG1hbiwgSC48L2F1dGhvcj48YXV0aG9yPkZyYXRpZ2xpb25pLCBMLjwvYXV0aG9yPjxh

dXRob3I+RnJpc29uaSwgRy4gQi48L2F1dGhvcj48YXV0aG9yPkdhdXRoaWVyLCBTLjwvYXV0aG9y

PjxhdXRob3I+R2VvcmdlcywgSi48L2F1dGhvcj48YXV0aG9yPkdyYWZmLCBDLjwvYXV0aG9yPjxh

dXRob3I+SXFiYWwsIEsuPC9hdXRob3I+PGF1dGhvcj5KZXNzZW4sIEYuPC9hdXRob3I+PGF1dGhv

cj5Kb2hhbnNzb24sIEcuPC9hdXRob3I+PGF1dGhvcj5Kb25zc29uLCBMLjwvYXV0aG9yPjxhdXRo

b3I+S2l2aXBlbHRvLCBNLjwvYXV0aG9yPjxhdXRob3I+S25hcHAsIE0uPC9hdXRob3I+PGF1dGhv

cj5NYW5naWFsYXNjaGUsIEYuPC9hdXRob3I+PGF1dGhvcj5NZWxpcywgUi48L2F1dGhvcj48YXV0

aG9yPk5vcmRiZXJnLCBBLjwvYXV0aG9yPjxhdXRob3I+Umlra2VydCwgTS4gTy48L2F1dGhvcj48

YXV0aG9yPlFpdSwgQy48L2F1dGhvcj48YXV0aG9yPlNha21hciwgVC4gUC48L2F1dGhvcj48YXV0

aG9yPlNjaGVsdGVucywgUC48L2F1dGhvcj48YXV0aG9yPlNjaG5laWRlciwgTC4gUy48L2F1dGhv

cj48YXV0aG9yPlNwZXJsaW5nLCBSLjwvYXV0aG9yPjxhdXRob3I+VGplcm5iZXJnLCBMLiBPLjwv

YXV0aG9yPjxhdXRob3I+V2FsZGVtYXIsIEcuPC9hdXRob3I+PGF1dGhvcj5XaW1vLCBBLjwvYXV0

aG9yPjxhdXRob3I+WmV0dGVyYmVyZywgSC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNl

cyBhbmQgU29jaWV0eSwgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9m

IE5ldXJvZ2VyaWF0cmljcywgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBIdWRkaW5nZSwgU3dlZGVu

OyBEZXBhcnRtZW50IG9mIEdlcmlhdHJpYyBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5

IEhvc3BpdGFsLCBIdWRkaW5nZSwgU3dlZGVuLiBFbGVjdHJvbmljIGFkZHJlc3M6IGJlbmd0LXdp

bmJsYWQtc3dlZGlzaGJyYWlucG93ZXJAa2kuc2UuJiN4RDtDZW50cmUgSG9zcGl0YWxpZXIgUmVn

aW9uYWwgVW5pdmVyc2l0YWlyZSBkZSBMaWxsZSwgSW5zdGl0dXQgUGFzdGV1ciBkZSBMaWxsZSwg

SU5TRVJNIFUxMTY3IFJJRC1BR0UsIFVuaXRlIGQmYXBvcztFcGlkZW1pb2xvZ2llIGV0IGRlIFNh

bnRlIFB1YmxpcXVlLCBMYWJleCBESVNUQUxaLCBMaWxsZSwgRnJhbmNlLiYjeEQ7RGVwYXJ0bWVu

dCBvZiBFcGlkZW1pb2xvZ3kgYW5kIFB1YmxpYyBIZWFsdGgsIEZhY3VsdHkgb2YgTWVkaWNpbmUs

IFRvdWxvdXNlIFVuaXZlcnNpdHkgSG9zcGl0YWwsIFRvdWxvdXNlLCBGcmFuY2UuJiN4RDtXb2xm

c29uIENlbnRyZSBmb3IgQWdlLVJlbGF0ZWQgRGlzZWFzZXMsIEtpbmcmYXBvcztzIENvbGxlZ2Ug

TG9uZG9uLCBMb25kb24sIFVLLiYjeEQ7Q2FtYnJpZGdlIEluc3RpdHV0ZSBvZiBQdWJsaWMgSGVh

bHRoLCBVbml2ZXJzaXR5IG9mIENhbWJyaWRnZSwgQ2FtYnJpZGdlLCBVSy4mI3hEO0NlbnRyZSBm

b3IgSGVhbHRoeSBCcmFpbiBBZ2VpbmcgYW5kIERlbWVudGlhIENvbGxhYm9yYXRpdmUgUmVzZWFy

Y2ggQ2VudHJlLCBVbml2ZXJzaXR5IG9mIE5ldyBTb3V0aCBXYWxlcywgU3lkbmV5LCBOU1csIEF1

c3RyYWxpYS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFu

ZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2YgTmV1

cm9nZXJpYXRyaWNzLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIEh1ZGRpbmdlLCBTd2VkZW4uJiN4

RDtJbnN0aXR1dCBkZSBsYSBNZW1vaXJlIGV0IGRlIGxhIE1hbGFkaWUgZCZhcG9zO0FsemhlaW1l

ciwgSU0yQSwgSU5TRVJNLCBJbnN0aXR1dCBkdSBDZXJ2ZWF1IGV0IGRlIGxhIE1vZWxsZSBFcGlu

aWVyZSwgVU1SLVM5NzUsIEdyb3VwZSBIb3NwaXRhbGllciBQaXRpZS1TYWxwZXRyaWVyZSwgVW5p

dmVyc2l0ZSBQaWVycmUgZXQgTWFyaWUgQ3VyaWUtUGFyaXMgNiwgUGFyaXMsIEZyYW5jZS4mI3hE

O1NjaG9vbCBvZiBOdXJzaW5nIGFuZCBNaWR3aWZlcnksIExhIFRyb2JlIFVuaXZlcnNpdHksIE1l

bGJvdXJuZSwgVklDLCBBdXN0cmFsaWE7IERlcGFydG1lbnQgb2YgTnVyc2luZywgVW1lYSBVbml2

ZXJzaXR5LCBVbWVhLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBOZXVyb2xvZ3ksIEZhY3VsdHkg

b2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQnJpdGlzaCBDb2x1bWJpYSwgVmFuY291dmVyLCBC

QywgQ2FuYWRhLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMg

YW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBBZ2luZyBSZXNlYXJj

aCBDZW50ZXIsIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtH

ZW5ldmEgVW5pdmVyc2l0eSBIb3NwaXRhbHMgYW5kIFVuaXZlcnNpdHkgb2YgR2VuZXZhLCBHZW5l

dmEsIFN3aXR6ZXJsYW5kOyBJUkNDUyBDZW50cm8gU2FuIEdpb3Zhbm5pIGRpIERpbyBGYXRlYmVu

ZWZyYXRlbGxpLCBCcmVzY2lhLCBJdGFseS4mI3hEO01jR2lsbCBDZW50ZXIgZm9yIFN0dWRpZXMg

aW4gQWdpbmcsIEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZSBSZXNlYXJjaCBVbml0LCBhbmQgRG91

Z2xhcyBNZW50YWwgSGVhbHRoIFVuaXZlcnNpdHkgSW5zdGl0dXRlLCBNb250cmVhbCwgUUMsIENh

bmFkYS4mI3hEO0FsemhlaW1lciBFdXJvcGUsIEx1eGVtYm91cmcgQ2l0eSwgTHV4ZW1ib3VyZy4m

I3hEO0RlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5

LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2YgTmV1cm9nZXJpYXRy

aWNzLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIEh1ZGRpbmdlLCBTd2VkZW47IERlcGFydG1lbnQg

b2YgR2VyaWF0cmljIE1lZGljaW5lLCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1

ZGRpbmdlLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvY2hlbWlzdHJ5LCBJbmdlIEdy

dW5ka2UtSXFiYWwgUmVzZWFyY2ggRmxvb3IsIE5ldyBZb3JrIFN0YXRlIEluc3RpdHV0ZSBmb3Ig

QmFzaWMgUmVzZWFyY2gsIFN0YXRlbiBJc2xhbmQsIE5ZLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9m

IFBzeWNoaWF0cnksIFVuaXZlcnNpdHkgb2YgQ29sb2duZSwgQ29sb2duZSwgR2VybWFueTsgR2Vy

bWFuIENlbnRlciBmb3IgTmV1cm9kZWdlbmVyYXRpdmUgRGlzZWFzZXMgKERaTkUpLCBCb25uLCBH

ZXJtYW55LiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5k

IFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEaXZpc2lvbiBvZiBOZXVy

b2dlcmlhdHJpY3MsIEthcm9saW5za2EgSW5zdGl0dXRldCwgSHVkZGluZ2UsIFN3ZWRlbjsgRGVw

YXJ0bWVudCBvZiBHZXJpYXRyaWMgTWVkaWNpbmUsIEthcm9saW5za2EgVW5pdmVyc2l0eSBIb3Nw

aXRhbCwgSHVkZGluZ2UsIFN3ZWRlbjsgRGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUg

U2NpZW5jZXMgYW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBBZ2lu

ZyBSZXNlYXJjaCBDZW50ZXIsIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2Vk

ZW4uJiN4RDtQZXJzb25hbCBTb2NpYWwgU2VydmljZXMgUmVzZWFyY2ggVW5pdCwgTG9uZG9uIFNj

aG9vbCBvZiBFY29ub21pY3MgYW5kIFBvbGl0aWNhbCBTY2llbmNlLCBMb25kb24sIFVLLiYjeEQ7

UmFkYm91ZHVtYyBBbHpoZWltZXIgQ2VudHJlIGFuZCBEZXBhcnRtZW50IG9mIEdlcmlhdHJpYyBN

ZWRpY2luZSwgUmFkYm91ZCBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBOaWptZWdlbiwgTmV0

aGVybGFuZHMuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBh

bmQgU29jaWV0eSwgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIFRy

YW5zbGF0aW9uYWwgQWx6aGVpbWVyIEJpb2xvZ3ksIEthcm9saW5za2EgSW5zdGl0dXRldCwgSHVk

ZGluZ2UsIFN3ZWRlbjsgRGVwYXJ0bWVudCBvZiBHZXJpYXRyaWMgTWVkaWNpbmUsIEthcm9saW5z

a2EgVW5pdmVyc2l0eSBIb3NwaXRhbCwgSHVkZGluZ2UsIFN3ZWRlbi4mI3hEO0RlcGFydG1lbnQg

b2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFs

emhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2YgTmV1cm9nZXJpYXRyaWNzLCBLYXJvbGluc2th

IEluc3RpdHV0ZXQsIEh1ZGRpbmdlLCBTd2VkZW47IExhYm9yYXRvcnkgb2YgQ2hlbWljYWwgQmlv

bG9neSAmYW1wOyBTaWduYWwgVHJhbnNkdWN0aW9uLCBUaGUgUm9ja2VmZWxsZXIgVW5pdmVyc2l0

eSwgTmV3IFlvcmssIE5ZLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvbG9neSBhbmQgQWx6

aGVpbWVyIENlbnRlciwgVlUgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRlciwgTmV1cm9zY2llbmNl

IENhbXB1cywgQW1zdGVyZGFtLCBOZXRoZXJsYW5kcy4mI3hEO0RlcGFydG1lbnQgb2YgUHN5Y2hp

YXRyeSBhbmQgdGhlIEJlaGF2aW9yYWwgU2NpZW5jZXMgYW5kIERlcGFydG1lbnQgb2YgTmV1cm9s

b2d5LCBLZWNrIFNjaG9vbCBvZiBNZWRpY2luZSwgTGVvbmFyZCBEYXZpcyBTY2hvb2wgb2YgR2Vy

b250b2xvZ3kgb2YgdGhlIFVuaXZlcnNpdHkgb2YgU291dGhlcm4gQ2FsaWZvcm5pYSwgTG9zIEFu

Z2VsZXMsIENBLCBVU0EuJiN4RDtDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCBhbmQgVHJl

YXRtZW50LCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgQnJpZ2hhbSBhbmQgV29tZW4mYXBvcztz

IEhvc3BpdGFsIGFuZCBNYXNzYWNodXNldHRzIEdlbmVyYWwgSG9zcGl0YWwsIEhhcnZhcmQgTWVk

aWNhbCBTY2hvb2wsIEJvc3RvbiwgTUEsIFVTQS4mI3hEO0RhbmlzaCBEZW1lbnRpYSBSZXNlYXJj

aCBDZW50cmUsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBSaWdzaG9zcGl0YWxldCwgVW5pdmVy

c2l0eSBvZiBDb3BlbmhhZ2VuLCBDb3BlbmhhZ2VuLCBEZW5tYXJrLiYjeEQ7Q2xpbmljYWwgTmV1

cm9jaGVtaXN0cnkgTGFib3JhdG9yeSwgRGVwYXJ0bWVudCBvZiBOZXVyb3NjaWVuY2UgYW5kIFBo

eXNpb2xvZ3ksIFRoZSBTYWhsZ3JlbnNrYSBBY2FkZW15IGF0IHRoZSBVbml2ZXJzaXR5IG9mIEdv

dGhlbmJ1cmcsIE1vbG5kYWwsIFN3ZWRlbjsgVUNMIEluc3RpdHV0ZSBvZiBOZXVyb2xvZ3ksIFF1

ZWVuIFNxdWFyZSwgTG9uZG9uLCBVSy48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5EZWZl

YXRpbmcgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGFuZCBvdGhlciBkZW1lbnRpYXM6IGEgcHJp

b3JpdHkgZm9yIEV1cm9wZWFuIHNjaWVuY2UgYW5kIHNvY2lldHk8L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+TGFuY2V0IE5ldXJvbDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz40NTUt

NTMyPC9wYWdlcz48dm9sdW1lPjE1PC92b2x1bWU+PG51bWJlcj41PC9udW1iZXI+PGtleXdvcmRz

PjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLyp0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkJp

b21lZGljYWwgUmVzZWFyY2gvZWNvbm9taWNzLypvcmdhbml6YXRpb24gJmFtcDsgYWRtaW5pc3Ry

YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+RGVtZW50aWEvKnRoZXJhcHk8L2tleXdvcmQ+PGtleXdv

cmQ+RXVyb3BlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48L2tleXdvcmRzPjxk

YXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXByPC9kYXRlPjwvcHViLWRh

dGVzPjwvZGF0ZXM+PGlzYm4+MTQ3NC00NDY1IChFbGVjdHJvbmljKSYjeEQ7MTQ3NC00NDIyIChM

aW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNjk4NzcwMTwvYWNjZXNzaW9uLW51bT48dXJs

cz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8y

Njk4NzcwMTwvdXJsPjx1cmw+aHR0cHM6Ly9hYy5lbHMtY2RuLmNvbS9TMTQ3NDQ0MjIxNjAwMDYy

NC8xLXMyLjAtUzE0NzQ0NDIyMTYwMDA2MjQtbWFpbi5wZGY/X3RpZD0wNzdmMDgxNS1jYjU2LTQw

YzUtYWRiZi1mOGJmYWE1YmM5YTcmYW1wO2FjZG5hdD0xNTM0NDk1MjYwXzgxZjAyYTNkZmI4ZGJj

YjAxY2NjZWMxMmUyOWY2Y2VlPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmlj

LXJlc291cmNlLW51bT4xMC4xMDE2L1MxNDc0LTQ0MjIoMTYpMDAwNjItNDwvZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJvbGQ8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS

ZWNOdW0+MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjQs

NDQsNDgsNDk8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0icDkyYWFwdDUwMGY5MDVl

MmRmNDU1cGU2dnpmcnRzOWF0ZXA1IiB0aW1lc3RhbXA9IjE1MTU1MTE1MTQiPjI8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhhcm9sZCwgRGVuaXNlPC9hdXRob3I+PGF1

dGhvcj5BYnJhaGFtLCBSaWNoYXJkPC9hdXRob3I+PGF1dGhvcj5Ib2xsaW5nd29ydGgsIFBhdWw8

L2F1dGhvcj48YXV0aG9yPlNpbXMsIFJlYmVjY2E8L2F1dGhvcj48YXV0aG9yPkdlcnJpc2gsIEFt

eTwvYXV0aG9yPjxhdXRob3I+SGFtc2hlcmUsIE1hcmlhbiBMLjwvYXV0aG9yPjxhdXRob3I+UGFo

d2EsIEphc3ByZWV0IFNpbmdoPC9hdXRob3I+PGF1dGhvcj5Nb3NrdmluYSwgVmFsZW50aW5hPC9h

dXRob3I+PGF1dGhvcj5Eb3d6ZWxsLCBLaW1iZXJsZXk8L2F1dGhvcj48YXV0aG9yPldpbGxpYW1z

LCBBbXk8L2F1dGhvcj48YXV0aG9yPkpvbmVzLCBOaWNvbGE8L2F1dGhvcj48YXV0aG9yPlRob21h

cywgQ2hhcmxlbmU8L2F1dGhvcj48YXV0aG9yPlN0cmV0dG9uLCBBbGV4YW5kcmE8L2F1dGhvcj48

YXV0aG9yPk1vcmdhbiwgQW5naGFyYWQgUi48L2F1dGhvcj48YXV0aG9yPkxvdmVzdG9uZSwgU2lt

b248L2F1dGhvcj48YXV0aG9yPlBvd2VsbCwgSm9objwvYXV0aG9yPjxhdXRob3I+UHJvaXRzaSwg

UGV0cm91bGE8L2F1dGhvcj48YXV0aG9yPkx1cHRvbiwgTWljaGVsbGUgSy48L2F1dGhvcj48YXV0

aG9yPkJyYXluZSwgQ2Fyb2w8L2F1dGhvcj48YXV0aG9yPlJ1Ymluc3p0ZWluLCBEYXZpZCBDLjwv

YXV0aG9yPjxhdXRob3I+R2lsbCwgTWljaGFlbDwvYXV0aG9yPjxhdXRob3I+TGF3bG9yLCBCcmlh

bjwvYXV0aG9yPjxhdXRob3I+THluY2gsIEFvaWJoaW5uPC9hdXRob3I+PGF1dGhvcj5Nb3JnYW4s

IEtldmluPC9hdXRob3I+PGF1dGhvcj5Ccm93biwgS3Jpc3RlbGxlIFMuPC9hdXRob3I+PGF1dGhv

cj5QYXNzbW9yZSwgUGV0ZXIgQS48L2F1dGhvcj48YXV0aG9yPkNyYWlnLCBEYXZpZDwvYXV0aG9y

PjxhdXRob3I+TWNHdWlubmVzcywgQmVybmFkZXR0ZTwvYXV0aG9yPjxhdXRob3I+VG9kZCwgU3Rl

cGhlbjwvYXV0aG9yPjxhdXRob3I+SG9sbWVzLCBDbGl2ZTwvYXV0aG9yPjxhdXRob3I+TWFubiwg

RGF2aWQ8L2F1dGhvcj48YXV0aG9yPlNtaXRoLCBBLiBEYXZpZDwvYXV0aG9yPjxhdXRob3I+TG92

ZSwgU2V0aDwvYXV0aG9yPjxhdXRob3I+S2Vob2UsIFBhdHJpY2sgRy48L2F1dGhvcj48YXV0aG9y

PkhhcmR5LCBKb2huPC9hdXRob3I+PGF1dGhvcj5NZWFkLCBTaW1vbjwvYXV0aG9yPjxhdXRob3I+

Rm94LCBOaWNrPC9hdXRob3I+PGF1dGhvcj5Sb3Nzb3IsIE1hcnRpbjwvYXV0aG9yPjxhdXRob3I+

Q29sbGluZ2UsIEpvaG48L2F1dGhvcj48YXV0aG9yPk1haWVyLCBXb2xmZ2FuZzwvYXV0aG9yPjxh

dXRob3I+SmVzc2VuLCBGcmFuazwvYXV0aG9yPjxhdXRob3I+U2NodXJtYW5uLCBCcml0dGE8L2F1

dGhvcj48YXV0aG9yPkhldW4sIFJlaW5oYXJkPC9hdXRob3I+PGF1dGhvcj52YW4gZGVuIEJ1c3Nj

aGUsIEhlbmRyaWs8L2F1dGhvcj48YXV0aG9yPkhldXNlciwgSXNhYmVsbGE8L2F1dGhvcj48YXV0

aG9yPktvcm5odWJlciwgSm9oYW5uZXM8L2F1dGhvcj48YXV0aG9yPldpbHRmYW5nLCBKZW5zPC9h

dXRob3I+PGF1dGhvcj5EaWNoZ2FucywgTWFydGluPC9hdXRob3I+PGF1dGhvcj5Gcm9saWNoLCBM

dXR6PC9hdXRob3I+PGF1dGhvcj5IYW1wZWwsIEhhcmFsZDwvYXV0aG9yPjxhdXRob3I+SHVsbCwg

TWljaGFlbDwvYXV0aG9yPjxhdXRob3I+UnVqZXNjdSwgRGFuPC9hdXRob3I+PGF1dGhvcj5Hb2F0

ZSwgQWxpc29uIE0uPC9hdXRob3I+PGF1dGhvcj5LYXV3ZSwgSm9obiBTLiBLLjwvYXV0aG9yPjxh

dXRob3I+Q3J1Y2hhZ2EsIENhcmxvczwvYXV0aG9yPjxhdXRob3I+Tm93b3RueSwgUGV0cmE8L2F1

dGhvcj48YXV0aG9yPk1vcnJpcywgSm9obiBDLjwvYXV0aG9yPjxhdXRob3I+TWF5bywgS2V2aW48

L2F1dGhvcj48YXV0aG9yPlNsZWVnZXJzLCBLcmlzdGVsPC9hdXRob3I+PGF1dGhvcj5CZXR0ZW5z

LCBLYXJvbGllbjwvYXV0aG9yPjxhdXRob3I+RW5nZWxib3JnaHMsIFNlYmFzdGlhYW48L2F1dGhv

cj48YXV0aG9yPkRlIERleW4sIFBldGVyIFAuPC9hdXRob3I+PGF1dGhvcj5WYW4gQnJvZWNraG92

ZW4sIENocmlzdGluZTwvYXV0aG9yPjxhdXRob3I+TGl2aW5nc3RvbiwgR2lsbDwvYXV0aG9yPjxh

dXRob3I+QmFzcywgTmljaG9sYXMgSi48L2F1dGhvcj48YXV0aG9yPkd1cmxpbmcsIEh1Z2g8L2F1

dGhvcj48YXV0aG9yPk1jUXVpbGxpbiwgQW5kcmV3PC9hdXRob3I+PGF1dGhvcj5Hd2lsbGlhbSwg

UmhpYW48L2F1dGhvcj48YXV0aG9yPkRlbG91a2FzLCBQYW5hZ2lvdGlzPC9hdXRob3I+PGF1dGhv

cj5BbC1DaGFsYWJpLCBBbW1hcjwvYXV0aG9yPjxhdXRob3I+U2hhdywgQ2hyaXN0b3BoZXIgRS48

L2F1dGhvcj48YXV0aG9yPlRzb2xha2ksIE1hZ2RhPC9hdXRob3I+PGF1dGhvcj5TaW5nbGV0b24s

IEFuZHJldyBCLjwvYXV0aG9yPjxhdXRob3I+R3VlcnJlaXJvLCBSaXRhPC9hdXRob3I+PGF1dGhv

cj5NdWhsZWlzZW4sIFRob21hcyBXLjwvYXV0aG9yPjxhdXRob3I+Tm90aGVuLCBNYXJrdXMgTS48

L2F1dGhvcj48YXV0aG9yPk1vZWJ1cywgU3VzYW5uZTwvYXV0aG9yPjxhdXRob3I+Sm9ja2VsLCBL

YXJsLUhlaW56PC9hdXRob3I+PGF1dGhvcj5LbG9wcCwgTm9ybWFuPC9hdXRob3I+PGF1dGhvcj5X

aWNobWFubiwgSC4gRXJpY2g8L2F1dGhvcj48YXV0aG9yPkNhcnJhc3F1aWxsbywgTWluZXJ2YSBN

LjwvYXV0aG9yPjxhdXRob3I+UGFua3JhdHosIFYuIFNoYW5lPC9hdXRob3I+PGF1dGhvcj5Zb3Vu

a2luLCBTdGV2ZW4gRy48L2F1dGhvcj48YXV0aG9yPkhvbG1hbnMsIFBldGVyIEEuPC9hdXRob3I+

PGF1dGhvcj5PJmFwb3M7RG9ub3ZhbiwgTWljaGFlbDwvYXV0aG9yPjxhdXRob3I+T3dlbiwgTWlj

aGFlbCBKLjwvYXV0aG9yPjxhdXRob3I+V2lsbGlhbXMsIEp1bGllPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkdlbm9tZS13aWRlIGFzc29jaWF0aW9uIHN0

dWR5IGlkZW50aWZpZXMgdmFyaWFudHMgYXQgQ0xVIGFuZCBQSUNBTE0gYXNzb2NpYXRlZCB3aXRo

IEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OYXQgR2Vu

ZXQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OYXQg

R2VuZXQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMDg4LTEwOTM8L3BhZ2VzPjx2

b2x1bWU+NDE8L3ZvbHVtZT48bnVtYmVyPjEwPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMDk8L3ll

YXI+PHB1Yi1kYXRlcz48ZGF0ZT4xMC8vcHJpbnQ8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

cHVibGlzaGVyPk5hdHVyZSBQdWJsaXNoaW5nIEdyb3VwPC9wdWJsaXNoZXI+PGlzYm4+MTA2MS00

MDM2PC9pc2JuPjx3b3JrLXR5cGU+TGV0dGVyPC93b3JrLXR5cGU+PHVybHM+PHJlbGF0ZWQtdXJs

cz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjEwMzgvbmcuNDQwPC91cmw+PC9yZWxhdGVkLXVy

bHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDM4L25nLjQ0MDwvZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Sm9uZXM8L0F1

dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNOdW0+NjYyPC9SZWNOdW0+PHJlY29yZD48cmVjLW51

bWJlcj42NjI8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJk

dncyZmFwZnRzMDVzZ2VyenM2eDBmNXB0cjU5eHB3OTlhMGEiIHRpbWVzdGFtcD0iMTUxODQ1ODY0

OSI+NjYyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs

ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Kb25lcywgQi48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QWx6aGVpbWVy

IGRpc2Vhc2U6IFRSRU0yIGxpbmtlZCB0byBsYXRlLW9uc2V0IEFEPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPk5hdCBSZXYgTmV1cm9sPC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5OYXR1cmUg

cmV2aWV3cy4gTmV1cm9sb2d5PC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwt

dGl0bGU+TmF0IFJldiBOZXVyb2w8L2Z1bGwtdGl0bGU+PGFiYnItMT5OYXR1cmUgcmV2aWV3cy4g

TmV1cm9sb2d5PC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRs

ZT5OYXQgUmV2IE5ldXJvbDwvZnVsbC10aXRsZT48YWJici0xPk5hdHVyZSByZXZpZXdzLiBOZXVy

b2xvZ3k8L2FiYnItMT48L2FsdC1wZXJpb2RpY2FsPjxwYWdlcz41PC9wYWdlcz48dm9sdW1lPjk8

L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4yMDEyLzEyLzA1PC9lZGl0aW9uPjxk

YXRlcz48eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SmFuPC9kYXRlPjwvcHViLWRh

dGVzPjwvZGF0ZXM+PGlzYm4+MTc1OS00NzY2IChFbGVjdHJvbmljKSYjeEQ7MTc1OS00NzU4IChM

aW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzIwODExNDwvYWNjZXNzaW9uLW51bT48d29y

ay10eXBlPkNvbW1lbnQ8L3dvcmstdHlwZT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDov

L3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMzIwODExNDwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9ucm5ldXJvbC4yMDEyLjI1

NDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+PC9yZWNv

cmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Sm9uZXM8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

ZWNOdW0+MjA2NTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MjA2NTwvcmVjLW51bWJlcj48

Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4

OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0Nzc5OTYxIj4yMDY1PC9rZXk+PC9mb3JlaWdu

LWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250

cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Kb25lcywgTC48L2F1dGhvcj48YXV0aG9yPkhvbG1h

bnMsIFAuIEEuPC9hdXRob3I+PGF1dGhvcj5IYW1zaGVyZSwgTS4gTC48L2F1dGhvcj48YXV0aG9y

Pkhhcm9sZCwgRC48L2F1dGhvcj48YXV0aG9yPk1vc2t2aW5hLCBWLjwvYXV0aG9yPjxhdXRob3I+

SXZhbm92LCBELjwvYXV0aG9yPjxhdXRob3I+UG9ja2xpbmd0b24sIEEuPC9hdXRob3I+PGF1dGhv

cj5BYnJhaGFtLCBSLjwvYXV0aG9yPjxhdXRob3I+SG9sbGluZ3dvcnRoLCBQLjwvYXV0aG9yPjxh

dXRob3I+U2ltcywgUi48L2F1dGhvcj48YXV0aG9yPkdlcnJpc2gsIEEuPC9hdXRob3I+PGF1dGhv

cj5QYWh3YSwgSi4gUy48L2F1dGhvcj48YXV0aG9yPkpvbmVzLCBOLjwvYXV0aG9yPjxhdXRob3I+

U3RyZXR0b24sIEEuPC9hdXRob3I+PGF1dGhvcj5Nb3JnYW4sIEEuIFIuPC9hdXRob3I+PGF1dGhv

cj5Mb3Zlc3RvbmUsIFMuPC9hdXRob3I+PGF1dGhvcj5Qb3dlbGwsIEouPC9hdXRob3I+PGF1dGhv

cj5Qcm9pdHNpLCBQLjwvYXV0aG9yPjxhdXRob3I+THVwdG9uLCBNLiBLLjwvYXV0aG9yPjxhdXRo

b3I+QnJheW5lLCBDLjwvYXV0aG9yPjxhdXRob3I+UnViaW5zenRlaW4sIEQuIEMuPC9hdXRob3I+

PGF1dGhvcj5HaWxsLCBNLjwvYXV0aG9yPjxhdXRob3I+TGF3bG9yLCBCLjwvYXV0aG9yPjxhdXRo

b3I+THluY2gsIEEuPC9hdXRob3I+PGF1dGhvcj5Nb3JnYW4sIEsuPC9hdXRob3I+PGF1dGhvcj5C

cm93biwgSy4gUy48L2F1dGhvcj48YXV0aG9yPlBhc3Ntb3JlLCBQLiBBLjwvYXV0aG9yPjxhdXRo

b3I+Q3JhaWcsIEQuPC9hdXRob3I+PGF1dGhvcj5NY0d1aW5uZXNzLCBCLjwvYXV0aG9yPjxhdXRo

b3I+VG9kZCwgUy48L2F1dGhvcj48YXV0aG9yPkhvbG1lcywgQy48L2F1dGhvcj48YXV0aG9yPk1h

bm4sIEQuPC9hdXRob3I+PGF1dGhvcj5TbWl0aCwgQS4gRC48L2F1dGhvcj48YXV0aG9yPkxvdmUs

IFMuPC9hdXRob3I+PGF1dGhvcj5LZWhvZSwgUC4gRy48L2F1dGhvcj48YXV0aG9yPk1lYWQsIFMu

PC9hdXRob3I+PGF1dGhvcj5Gb3gsIE4uPC9hdXRob3I+PGF1dGhvcj5Sb3Nzb3IsIE0uPC9hdXRo

b3I+PGF1dGhvcj5Db2xsaW5nZSwgSi48L2F1dGhvcj48YXV0aG9yPk1haWVyLCBXLjwvYXV0aG9y

PjxhdXRob3I+SmVzc2VuLCBGLjwvYXV0aG9yPjxhdXRob3I+U2NodXJtYW5uLCBCLjwvYXV0aG9y

PjxhdXRob3I+SGV1biwgUi48L2F1dGhvcj48YXV0aG9yPktvbHNjaCwgSC48L2F1dGhvcj48YXV0

aG9yPnZhbiBkZW4gQnVzc2NoZSwgSC48L2F1dGhvcj48YXV0aG9yPkhldXNlciwgSS48L2F1dGhv

cj48YXV0aG9yPlBldGVycywgTy48L2F1dGhvcj48YXV0aG9yPktvcm5odWJlciwgSi48L2F1dGhv

cj48YXV0aG9yPldpbHRmYW5nLCBKLjwvYXV0aG9yPjxhdXRob3I+RGljaGdhbnMsIE0uPC9hdXRo

b3I+PGF1dGhvcj5Gcm9saWNoLCBMLjwvYXV0aG9yPjxhdXRob3I+SGFtcGVsLCBILjwvYXV0aG9y

PjxhdXRob3I+SHVsbCwgTS48L2F1dGhvcj48YXV0aG9yPlJ1amVzY3UsIEQuPC9hdXRob3I+PGF1

dGhvcj5Hb2F0ZSwgQS4gTS48L2F1dGhvcj48YXV0aG9yPkthdXdlLCBKLiBTLjwvYXV0aG9yPjxh

dXRob3I+Q3J1Y2hhZ2EsIEMuPC9hdXRob3I+PGF1dGhvcj5Ob3dvdG55LCBQLjwvYXV0aG9yPjxh

dXRob3I+TW9ycmlzLCBKLiBDLjwvYXV0aG9yPjxhdXRob3I+TWF5bywgSy48L2F1dGhvcj48YXV0

aG9yPkxpdmluZ3N0b24sIEcuPC9hdXRob3I+PGF1dGhvcj5CYXNzLCBOLiBKLjwvYXV0aG9yPjxh

dXRob3I+R3VybGluZywgSC48L2F1dGhvcj48YXV0aG9yPk1jUXVpbGxpbiwgQS48L2F1dGhvcj48

YXV0aG9yPkd3aWxsaWFtLCBSLjwvYXV0aG9yPjxhdXRob3I+RGVsb3VrYXMsIFAuPC9hdXRob3I+

PGF1dGhvcj5BbC1DaGFsYWJpLCBBLjwvYXV0aG9yPjxhdXRob3I+U2hhdywgQy4gRS48L2F1dGhv

cj48YXV0aG9yPlNpbmdsZXRvbiwgQS4gQi48L2F1dGhvcj48YXV0aG9yPkd1ZXJyZWlybywgUi48

L2F1dGhvcj48YXV0aG9yPk11aGxlaXNlbiwgVC4gVy48L2F1dGhvcj48YXV0aG9yPk5vdGhlbiwg

TS4gTS48L2F1dGhvcj48YXV0aG9yPk1vZWJ1cywgUy48L2F1dGhvcj48YXV0aG9yPkpvY2tlbCwg

Sy4gSC48L2F1dGhvcj48YXV0aG9yPktsb3BwLCBOLjwvYXV0aG9yPjxhdXRob3I+V2ljaG1hbm4s

IEguIEUuPC9hdXRob3I+PGF1dGhvcj5SdXRoZXIsIEUuPC9hdXRob3I+PGF1dGhvcj5DYXJyYXNx

dWlsbG8sIE0uIE0uPC9hdXRob3I+PGF1dGhvcj5QYW5rcmF0eiwgVi4gUy48L2F1dGhvcj48YXV0

aG9yPllvdW5raW4sIFMuIEcuPC9hdXRob3I+PGF1dGhvcj5IYXJkeSwgSi48L2F1dGhvcj48YXV0

aG9yPk8mYXBvcztEb25vdmFuLCBNLiBDLjwvYXV0aG9yPjxhdXRob3I+T3dlbiwgTS4gSi48L2F1

dGhvcj48YXV0aG9yPldpbGxpYW1zLCBKLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgUHN5Y2hvbG9naWNhbCBNZWRpY2luZSBhbmQg

TmV1cm9sb2d5LCBTY2hvb2wgb2YgTWVkaWNpbmUsIENhcmRpZmYgVW5pdmVyc2l0eSwgTWVkaWNh

bCBSZXNlYXJjaCBDb3VuY2lsIENlbnRyZSBmb3IgTmV1cm9wc3ljaGlhdHJpYyBHZW5ldGljcyBh

bmQgR2Vub21pY3MsIENhcmRpZmYsIFVuaXRlZCBLaW5nZG9tLjwvYXV0aC1hZGRyZXNzPjx0aXRs

ZXM+PHRpdGxlPkdlbmV0aWMgZXZpZGVuY2UgaW1wbGljYXRlcyB0aGUgaW1tdW5lIHN5c3RlbSBh

bmQgY2hvbGVzdGVyb2wgbWV0YWJvbGlzbSBpbiB0aGUgYWV0aW9sb2d5IG9mIEFsemhlaW1lciZh

cG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5QTG9TIE9uZTwvc2Vjb25kYXJ5

LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlBMb1MgT25lPC9mdWxsLXRp

dGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+ZTEzOTUwPC9wYWdlcz48dm9sdW1lPjU8L3ZvbHVtZT48

bnVtYmVyPjExPC9udW1iZXI+PGVkaXRpb24+MjAxMC8xMS8xOTwvZWRpdGlvbj48a2V5d29yZHM+

PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmdlbmV0aWNzL2ltbXVub2xvZ3kvbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMgRS9nZW5ldGljcy9tZXRhYm9saXNt

PC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3

b3JkPkNocm9tb3NvbWUgTWFwcGluZzwva2V5d29yZD48a2V5d29yZD5HZW5ldGljIFByZWRpc3Bv

c2l0aW9uIHRvIERpc2Vhc2UvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+R2Vub21lLCBIdW1h

bjwva2V5d29yZD48a2V5d29yZD4qR2Vub21lLVdpZGUgQXNzb2NpYXRpb24gU3R1ZHk8L2tleXdv

cmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVuZSBTeXN0ZW0vKm1ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UG9seW1vcnBoaXNtLCBTaW5nbGUgTnVjbGVvdGlkZTwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+Tm92IDE1PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTkzMi02MjAzIChFbGVj

dHJvbmljKSYjeEQ7MTkzMi02MjAzIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMTA4

NTU3MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjEwODU1NzA8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGN1c3RvbTI+UE1DMjk4MTUyNjwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

MTAuMTM3MS9qb3VybmFsLnBvbmUuMDAxMzk1MDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9y

ZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+V2luYmxhZDwvQXV0aG9yPjxZZWFyPjIwMTY8L1ll

YXI+PFJlY051bT4yNzI8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjI3MjwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhw

Znd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMxNzc1MjcxIj4yNzI8L2tleT48L2ZvcmVp

Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv

bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5B

bW91eWVsLCBQLjwvYXV0aG9yPjxhdXRob3I+QW5kcmlldSwgUy48L2F1dGhvcj48YXV0aG9yPkJh

bGxhcmQsIEMuPC9hdXRob3I+PGF1dGhvcj5CcmF5bmUsIEMuPC9hdXRob3I+PGF1dGhvcj5Ccm9k

YXR5LCBILjwvYXV0aG9yPjxhdXRob3I+Q2VkYXpvLU1pbmd1ZXosIEEuPC9hdXRob3I+PGF1dGhv

cj5EdWJvaXMsIEIuPC9hdXRob3I+PGF1dGhvcj5FZHZhcmRzc29uLCBELjwvYXV0aG9yPjxhdXRo

b3I+RmVsZG1hbiwgSC48L2F1dGhvcj48YXV0aG9yPkZyYXRpZ2xpb25pLCBMLjwvYXV0aG9yPjxh

dXRob3I+RnJpc29uaSwgRy4gQi48L2F1dGhvcj48YXV0aG9yPkdhdXRoaWVyLCBTLjwvYXV0aG9y

PjxhdXRob3I+R2VvcmdlcywgSi48L2F1dGhvcj48YXV0aG9yPkdyYWZmLCBDLjwvYXV0aG9yPjxh

dXRob3I+SXFiYWwsIEsuPC9hdXRob3I+PGF1dGhvcj5KZXNzZW4sIEYuPC9hdXRob3I+PGF1dGhv

cj5Kb2hhbnNzb24sIEcuPC9hdXRob3I+PGF1dGhvcj5Kb25zc29uLCBMLjwvYXV0aG9yPjxhdXRo

b3I+S2l2aXBlbHRvLCBNLjwvYXV0aG9yPjxhdXRob3I+S25hcHAsIE0uPC9hdXRob3I+PGF1dGhv

cj5NYW5naWFsYXNjaGUsIEYuPC9hdXRob3I+PGF1dGhvcj5NZWxpcywgUi48L2F1dGhvcj48YXV0

aG9yPk5vcmRiZXJnLCBBLjwvYXV0aG9yPjxhdXRob3I+Umlra2VydCwgTS4gTy48L2F1dGhvcj48

YXV0aG9yPlFpdSwgQy48L2F1dGhvcj48YXV0aG9yPlNha21hciwgVC4gUC48L2F1dGhvcj48YXV0

aG9yPlNjaGVsdGVucywgUC48L2F1dGhvcj48YXV0aG9yPlNjaG5laWRlciwgTC4gUy48L2F1dGhv

cj48YXV0aG9yPlNwZXJsaW5nLCBSLjwvYXV0aG9yPjxhdXRob3I+VGplcm5iZXJnLCBMLiBPLjwv

YXV0aG9yPjxhdXRob3I+V2FsZGVtYXIsIEcuPC9hdXRob3I+PGF1dGhvcj5XaW1vLCBBLjwvYXV0

aG9yPjxhdXRob3I+WmV0dGVyYmVyZywgSC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNl

cyBhbmQgU29jaWV0eSwgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9m

IE5ldXJvZ2VyaWF0cmljcywgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBIdWRkaW5nZSwgU3dlZGVu

OyBEZXBhcnRtZW50IG9mIEdlcmlhdHJpYyBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5

IEhvc3BpdGFsLCBIdWRkaW5nZSwgU3dlZGVuLiBFbGVjdHJvbmljIGFkZHJlc3M6IGJlbmd0LXdp

bmJsYWQtc3dlZGlzaGJyYWlucG93ZXJAa2kuc2UuJiN4RDtDZW50cmUgSG9zcGl0YWxpZXIgUmVn

aW9uYWwgVW5pdmVyc2l0YWlyZSBkZSBMaWxsZSwgSW5zdGl0dXQgUGFzdGV1ciBkZSBMaWxsZSwg

SU5TRVJNIFUxMTY3IFJJRC1BR0UsIFVuaXRlIGQmYXBvcztFcGlkZW1pb2xvZ2llIGV0IGRlIFNh

bnRlIFB1YmxpcXVlLCBMYWJleCBESVNUQUxaLCBMaWxsZSwgRnJhbmNlLiYjeEQ7RGVwYXJ0bWVu

dCBvZiBFcGlkZW1pb2xvZ3kgYW5kIFB1YmxpYyBIZWFsdGgsIEZhY3VsdHkgb2YgTWVkaWNpbmUs

IFRvdWxvdXNlIFVuaXZlcnNpdHkgSG9zcGl0YWwsIFRvdWxvdXNlLCBGcmFuY2UuJiN4RDtXb2xm

c29uIENlbnRyZSBmb3IgQWdlLVJlbGF0ZWQgRGlzZWFzZXMsIEtpbmcmYXBvcztzIENvbGxlZ2Ug

TG9uZG9uLCBMb25kb24sIFVLLiYjeEQ7Q2FtYnJpZGdlIEluc3RpdHV0ZSBvZiBQdWJsaWMgSGVh

bHRoLCBVbml2ZXJzaXR5IG9mIENhbWJyaWRnZSwgQ2FtYnJpZGdlLCBVSy4mI3hEO0NlbnRyZSBm

b3IgSGVhbHRoeSBCcmFpbiBBZ2VpbmcgYW5kIERlbWVudGlhIENvbGxhYm9yYXRpdmUgUmVzZWFy

Y2ggQ2VudHJlLCBVbml2ZXJzaXR5IG9mIE5ldyBTb3V0aCBXYWxlcywgU3lkbmV5LCBOU1csIEF1

c3RyYWxpYS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFu

ZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2YgTmV1

cm9nZXJpYXRyaWNzLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIEh1ZGRpbmdlLCBTd2VkZW4uJiN4

RDtJbnN0aXR1dCBkZSBsYSBNZW1vaXJlIGV0IGRlIGxhIE1hbGFkaWUgZCZhcG9zO0FsemhlaW1l

ciwgSU0yQSwgSU5TRVJNLCBJbnN0aXR1dCBkdSBDZXJ2ZWF1IGV0IGRlIGxhIE1vZWxsZSBFcGlu

aWVyZSwgVU1SLVM5NzUsIEdyb3VwZSBIb3NwaXRhbGllciBQaXRpZS1TYWxwZXRyaWVyZSwgVW5p

dmVyc2l0ZSBQaWVycmUgZXQgTWFyaWUgQ3VyaWUtUGFyaXMgNiwgUGFyaXMsIEZyYW5jZS4mI3hE

O1NjaG9vbCBvZiBOdXJzaW5nIGFuZCBNaWR3aWZlcnksIExhIFRyb2JlIFVuaXZlcnNpdHksIE1l

bGJvdXJuZSwgVklDLCBBdXN0cmFsaWE7IERlcGFydG1lbnQgb2YgTnVyc2luZywgVW1lYSBVbml2

ZXJzaXR5LCBVbWVhLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBOZXVyb2xvZ3ksIEZhY3VsdHkg

b2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQnJpdGlzaCBDb2x1bWJpYSwgVmFuY291dmVyLCBC

QywgQ2FuYWRhLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMg

YW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBBZ2luZyBSZXNlYXJj

aCBDZW50ZXIsIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtH

ZW5ldmEgVW5pdmVyc2l0eSBIb3NwaXRhbHMgYW5kIFVuaXZlcnNpdHkgb2YgR2VuZXZhLCBHZW5l

dmEsIFN3aXR6ZXJsYW5kOyBJUkNDUyBDZW50cm8gU2FuIEdpb3Zhbm5pIGRpIERpbyBGYXRlYmVu

ZWZyYXRlbGxpLCBCcmVzY2lhLCBJdGFseS4mI3hEO01jR2lsbCBDZW50ZXIgZm9yIFN0dWRpZXMg

aW4gQWdpbmcsIEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZSBSZXNlYXJjaCBVbml0LCBhbmQgRG91

Z2xhcyBNZW50YWwgSGVhbHRoIFVuaXZlcnNpdHkgSW5zdGl0dXRlLCBNb250cmVhbCwgUUMsIENh

bmFkYS4mI3hEO0FsemhlaW1lciBFdXJvcGUsIEx1eGVtYm91cmcgQ2l0eSwgTHV4ZW1ib3VyZy4m

I3hEO0RlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5

LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2YgTmV1cm9nZXJpYXRy

aWNzLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIEh1ZGRpbmdlLCBTd2VkZW47IERlcGFydG1lbnQg

b2YgR2VyaWF0cmljIE1lZGljaW5lLCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1

ZGRpbmdlLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvY2hlbWlzdHJ5LCBJbmdlIEdy

dW5ka2UtSXFiYWwgUmVzZWFyY2ggRmxvb3IsIE5ldyBZb3JrIFN0YXRlIEluc3RpdHV0ZSBmb3Ig

QmFzaWMgUmVzZWFyY2gsIFN0YXRlbiBJc2xhbmQsIE5ZLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9m

IFBzeWNoaWF0cnksIFVuaXZlcnNpdHkgb2YgQ29sb2duZSwgQ29sb2duZSwgR2VybWFueTsgR2Vy

bWFuIENlbnRlciBmb3IgTmV1cm9kZWdlbmVyYXRpdmUgRGlzZWFzZXMgKERaTkUpLCBCb25uLCBH

ZXJtYW55LiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5k

IFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEaXZpc2lvbiBvZiBOZXVy

b2dlcmlhdHJpY3MsIEthcm9saW5za2EgSW5zdGl0dXRldCwgSHVkZGluZ2UsIFN3ZWRlbjsgRGVw

YXJ0bWVudCBvZiBHZXJpYXRyaWMgTWVkaWNpbmUsIEthcm9saW5za2EgVW5pdmVyc2l0eSBIb3Nw

aXRhbCwgSHVkZGluZ2UsIFN3ZWRlbjsgRGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUg

U2NpZW5jZXMgYW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBBZ2lu

ZyBSZXNlYXJjaCBDZW50ZXIsIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2Vk

ZW4uJiN4RDtQZXJzb25hbCBTb2NpYWwgU2VydmljZXMgUmVzZWFyY2ggVW5pdCwgTG9uZG9uIFNj

aG9vbCBvZiBFY29ub21pY3MgYW5kIFBvbGl0aWNhbCBTY2llbmNlLCBMb25kb24sIFVLLiYjeEQ7

UmFkYm91ZHVtYyBBbHpoZWltZXIgQ2VudHJlIGFuZCBEZXBhcnRtZW50IG9mIEdlcmlhdHJpYyBN

ZWRpY2luZSwgUmFkYm91ZCBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBOaWptZWdlbiwgTmV0

aGVybGFuZHMuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBh

bmQgU29jaWV0eSwgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIFRy

YW5zbGF0aW9uYWwgQWx6aGVpbWVyIEJpb2xvZ3ksIEthcm9saW5za2EgSW5zdGl0dXRldCwgSHVk

ZGluZ2UsIFN3ZWRlbjsgRGVwYXJ0bWVudCBvZiBHZXJpYXRyaWMgTWVkaWNpbmUsIEthcm9saW5z

a2EgVW5pdmVyc2l0eSBIb3NwaXRhbCwgSHVkZGluZ2UsIFN3ZWRlbi4mI3hEO0RlcGFydG1lbnQg

b2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFs

emhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2YgTmV1cm9nZXJpYXRyaWNzLCBLYXJvbGluc2th

IEluc3RpdHV0ZXQsIEh1ZGRpbmdlLCBTd2VkZW47IExhYm9yYXRvcnkgb2YgQ2hlbWljYWwgQmlv

bG9neSAmYW1wOyBTaWduYWwgVHJhbnNkdWN0aW9uLCBUaGUgUm9ja2VmZWxsZXIgVW5pdmVyc2l0

eSwgTmV3IFlvcmssIE5ZLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvbG9neSBhbmQgQWx6

aGVpbWVyIENlbnRlciwgVlUgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRlciwgTmV1cm9zY2llbmNl

IENhbXB1cywgQW1zdGVyZGFtLCBOZXRoZXJsYW5kcy4mI3hEO0RlcGFydG1lbnQgb2YgUHN5Y2hp

YXRyeSBhbmQgdGhlIEJlaGF2aW9yYWwgU2NpZW5jZXMgYW5kIERlcGFydG1lbnQgb2YgTmV1cm9s

b2d5LCBLZWNrIFNjaG9vbCBvZiBNZWRpY2luZSwgTGVvbmFyZCBEYXZpcyBTY2hvb2wgb2YgR2Vy

b250b2xvZ3kgb2YgdGhlIFVuaXZlcnNpdHkgb2YgU291dGhlcm4gQ2FsaWZvcm5pYSwgTG9zIEFu

Z2VsZXMsIENBLCBVU0EuJiN4RDtDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCBhbmQgVHJl

YXRtZW50LCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgQnJpZ2hhbSBhbmQgV29tZW4mYXBvcztz

IEhvc3BpdGFsIGFuZCBNYXNzYWNodXNldHRzIEdlbmVyYWwgSG9zcGl0YWwsIEhhcnZhcmQgTWVk

aWNhbCBTY2hvb2wsIEJvc3RvbiwgTUEsIFVTQS4mI3hEO0RhbmlzaCBEZW1lbnRpYSBSZXNlYXJj

aCBDZW50cmUsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBSaWdzaG9zcGl0YWxldCwgVW5pdmVy

c2l0eSBvZiBDb3BlbmhhZ2VuLCBDb3BlbmhhZ2VuLCBEZW5tYXJrLiYjeEQ7Q2xpbmljYWwgTmV1

cm9jaGVtaXN0cnkgTGFib3JhdG9yeSwgRGVwYXJ0bWVudCBvZiBOZXVyb3NjaWVuY2UgYW5kIFBo

eXNpb2xvZ3ksIFRoZSBTYWhsZ3JlbnNrYSBBY2FkZW15IGF0IHRoZSBVbml2ZXJzaXR5IG9mIEdv

dGhlbmJ1cmcsIE1vbG5kYWwsIFN3ZWRlbjsgVUNMIEluc3RpdHV0ZSBvZiBOZXVyb2xvZ3ksIFF1

ZWVuIFNxdWFyZSwgTG9uZG9uLCBVSy48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5EZWZl

YXRpbmcgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGFuZCBvdGhlciBkZW1lbnRpYXM6IGEgcHJp

b3JpdHkgZm9yIEV1cm9wZWFuIHNjaWVuY2UgYW5kIHNvY2lldHk8L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+TGFuY2V0IE5ldXJvbDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz40NTUt

NTMyPC9wYWdlcz48dm9sdW1lPjE1PC92b2x1bWU+PG51bWJlcj41PC9udW1iZXI+PGtleXdvcmRz

PjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLyp0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkJp

b21lZGljYWwgUmVzZWFyY2gvZWNvbm9taWNzLypvcmdhbml6YXRpb24gJmFtcDsgYWRtaW5pc3Ry

YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+RGVtZW50aWEvKnRoZXJhcHk8L2tleXdvcmQ+PGtleXdv

cmQ+RXVyb3BlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48L2tleXdvcmRzPjxk

YXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXByPC9kYXRlPjwvcHViLWRh

dGVzPjwvZGF0ZXM+PGlzYm4+MTQ3NC00NDY1IChFbGVjdHJvbmljKSYjeEQ7MTQ3NC00NDIyIChM

aW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNjk4NzcwMTwvYWNjZXNzaW9uLW51bT48dXJs

cz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8y

Njk4NzcwMTwvdXJsPjx1cmw+aHR0cHM6Ly9hYy5lbHMtY2RuLmNvbS9TMTQ3NDQ0MjIxNjAwMDYy

NC8xLXMyLjAtUzE0NzQ0NDIyMTYwMDA2MjQtbWFpbi5wZGY/X3RpZD0wNzdmMDgxNS1jYjU2LTQw

YzUtYWRiZi1mOGJmYWE1YmM5YTcmYW1wO2FjZG5hdD0xNTM0NDk1MjYwXzgxZjAyYTNkZmI4ZGJj

YjAxY2NjZWMxMmUyOWY2Y2VlPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmlj

LXJlc291cmNlLW51bT4xMC4xMDE2L1MxNDc0LTQ0MjIoMTYpMDAwNjItNDwvZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 4,44,48,49. These pathways and targets will be useful in the future and could potentially lead to a combined therapeutic strategy.Positron Emission Tomography (PET), Biomarkers and early diagnosis in ADAnother important part is the biomarkers. Amyloid accumulation comes early in the disease, long before clinical diagnosis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gb3JzYmVyZzwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+

PFJlY051bT4yMDcwPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+NTA8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDcwPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ3ODEzMjAiPjIwNzA8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkZvcnNiZXJnLCBBLjwvYXV0aG9yPjxh

dXRob3I+QWxta3Zpc3QsIE8uPC9hdXRob3I+PGF1dGhvcj5FbmdsZXIsIEguPC9hdXRob3I+PGF1

dGhvcj5XYWxsLCBBLjwvYXV0aG9yPjxhdXRob3I+TGFuZ3N0cm9tLCBCLjwvYXV0aG9yPjxhdXRo

b3I+Tm9yZGJlcmcsIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk

ZHJlc3M+S2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwg

Q2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFs

IEh1ZGRpbmdlLCBTdG9ja2hvbG0sIFN3ZWRlbi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRs

ZT5IaWdoIFBJQiByZXRlbnRpb24gaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGlzIGFuIGVh

cmx5IGV2ZW50IHdpdGggY29tcGxleCByZWxhdGlvbnNoaXAgd2l0aCBDU0YgYmlvbWFya2VycyBh

bmQgZnVuY3Rpb25hbCBwYXJhbWV0ZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkN1cnIgQWx6

aGVpbWVyIFJlczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRp

dGxlPkN1cnIgQWx6aGVpbWVyIFJlczwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjU2

LTY2PC9wYWdlcz48dm9sdW1lPjc8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4y

MDEwLzAzLzA5PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3

b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNl

LypjZXJlYnJvc3BpbmFsIGZsdWlkLypkaWFnbm9zdGljIGltYWdpbmcvcGh5c2lvcGF0aG9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPipCZW56b3RoaWF6b2xlczwva2V5d29yZD48a2V5d29yZD5CaW9t

YXJrZXJzLypjZXJlYnJvc3BpbmFsIGZsdWlkPC9rZXl3b3JkPjxrZXl3b3JkPkVhcmx5IERpYWdu

b3Npczwva2V5d29yZD48a2V5d29yZD5Fbnp5bWUtTGlua2VkIEltbXVub3NvcmJlbnQgQXNzYXk8

L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZsdW9yb2Rlb3h5Z2x1

Y29zZSBGMTg8L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y29zZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxr

ZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbWFnZSBJbnRlcnByZXRhdGlvbiwgQ29t

cHV0ZXItQXNzaXN0ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5N

ZW1vcnkgRGlzb3JkZXJzL2RpYWdub3N0aWMgaW1hZ2luZy9ldGlvbG9neS9tZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBvc2l0cm9uLUVt

aXNzaW9uIFRvbW9ncmFwaHk8L2tleXdvcmQ+PGtleXdvcmQ+KlJhZGlvcGhhcm1hY2V1dGljYWxz

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTA8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5GZWI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xODc1LTU4MjggKEVsZWN0

cm9uaWMpJiN4RDsxNTY3LTIwNTAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIwMjA1

NjcxPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMDIwNTY3MTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gb3JzYmVyZzwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+

PFJlY051bT4yMDcwPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+NTA8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDcwPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ3ODEzMjAiPjIwNzA8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkZvcnNiZXJnLCBBLjwvYXV0aG9yPjxh

dXRob3I+QWxta3Zpc3QsIE8uPC9hdXRob3I+PGF1dGhvcj5FbmdsZXIsIEguPC9hdXRob3I+PGF1

dGhvcj5XYWxsLCBBLjwvYXV0aG9yPjxhdXRob3I+TGFuZ3N0cm9tLCBCLjwvYXV0aG9yPjxhdXRo

b3I+Tm9yZGJlcmcsIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk

ZHJlc3M+S2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwg

Q2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFs

IEh1ZGRpbmdlLCBTdG9ja2hvbG0sIFN3ZWRlbi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRs

ZT5IaWdoIFBJQiByZXRlbnRpb24gaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGlzIGFuIGVh

cmx5IGV2ZW50IHdpdGggY29tcGxleCByZWxhdGlvbnNoaXAgd2l0aCBDU0YgYmlvbWFya2VycyBh

bmQgZnVuY3Rpb25hbCBwYXJhbWV0ZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkN1cnIgQWx6

aGVpbWVyIFJlczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRp

dGxlPkN1cnIgQWx6aGVpbWVyIFJlczwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjU2

LTY2PC9wYWdlcz48dm9sdW1lPjc8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4y

MDEwLzAzLzA5PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3

b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNl

LypjZXJlYnJvc3BpbmFsIGZsdWlkLypkaWFnbm9zdGljIGltYWdpbmcvcGh5c2lvcGF0aG9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPipCZW56b3RoaWF6b2xlczwva2V5d29yZD48a2V5d29yZD5CaW9t

YXJrZXJzLypjZXJlYnJvc3BpbmFsIGZsdWlkPC9rZXl3b3JkPjxrZXl3b3JkPkVhcmx5IERpYWdu

b3Npczwva2V5d29yZD48a2V5d29yZD5Fbnp5bWUtTGlua2VkIEltbXVub3NvcmJlbnQgQXNzYXk8

L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZsdW9yb2Rlb3h5Z2x1

Y29zZSBGMTg8L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y29zZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxr

ZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbWFnZSBJbnRlcnByZXRhdGlvbiwgQ29t

cHV0ZXItQXNzaXN0ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5N

ZW1vcnkgRGlzb3JkZXJzL2RpYWdub3N0aWMgaW1hZ2luZy9ldGlvbG9neS9tZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBvc2l0cm9uLUVt

aXNzaW9uIFRvbW9ncmFwaHk8L2tleXdvcmQ+PGtleXdvcmQ+KlJhZGlvcGhhcm1hY2V1dGljYWxz

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTA8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5GZWI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xODc1LTU4MjggKEVsZWN0

cm9uaWMpJiN4RDsxNTY3LTIwNTAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIwMjA1

NjcxPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMDIwNTY3MTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 50. With PET, scanning it is possible to see the amyloid assemblies in the brain PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LbHVuazwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJl

Y051bT4yMDY5PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NTE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDY5PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ3ODEyMjAiPjIwNjk8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPktsdW5rLCBXLiBFLjwvYXV0aG9yPjxhdXRo

b3I+RW5nbGVyLCBILjwvYXV0aG9yPjxhdXRob3I+Tm9yZGJlcmcsIEEuPC9hdXRob3I+PGF1dGhv

cj5XYW5nLCBZLjwvYXV0aG9yPjxhdXRob3I+QmxvbXF2aXN0LCBHLjwvYXV0aG9yPjxhdXRob3I+

SG9sdCwgRC4gUC48L2F1dGhvcj48YXV0aG9yPkJlcmdzdHJvbSwgTS48L2F1dGhvcj48YXV0aG9y

PlNhdml0Y2hldmEsIEkuPC9hdXRob3I+PGF1dGhvcj5IdWFuZywgRy4gRi48L2F1dGhvcj48YXV0

aG9yPkVzdHJhZGEsIFMuPC9hdXRob3I+PGF1dGhvcj5BdXNlbiwgQi48L2F1dGhvcj48YXV0aG9y

PkRlYm5hdGgsIE0uIEwuPC9hdXRob3I+PGF1dGhvcj5CYXJsZXR0YSwgSi48L2F1dGhvcj48YXV0

aG9yPlByaWNlLCBKLiBDLjwvYXV0aG9yPjxhdXRob3I+U2FuZGVsbCwgSi48L2F1dGhvcj48YXV0

aG9yPkxvcHJlc3RpLCBCLiBKLjwvYXV0aG9yPjxhdXRob3I+V2FsbCwgQS48L2F1dGhvcj48YXV0

aG9yPktvaXZpc3RvLCBQLjwvYXV0aG9yPjxhdXRob3I+QW50b25pLCBHLjwvYXV0aG9yPjxhdXRo

b3I+TWF0aGlzLCBDLiBBLjwvYXV0aG9yPjxhdXRob3I+TGFuZ3N0cm9tLCBCLjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgUHN5Y2hp

YXRyeSwgUEVUIEZhY2lsaXR5LCBVbml2ZXJzaXR5IG9mIFBpdHRzYnVyZ2gsIDIwMCBMb3Rocm9w

IFN0cmVldCwgUGl0dHNidXJnaCwgUEEgMTUyMTMtMjU4MiwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPkltYWdpbmcgYnJhaW4gYW15bG9pZCBpbiBBbHpoZWltZXImYXBvcztzIGRp

c2Vhc2Ugd2l0aCBQaXR0c2J1cmdoIENvbXBvdW5kLUI8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+

QW5uIE5ldXJvbDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4zMDYtMTk8L3BhZ2Vz

Pjx2b2x1bWU+NTU8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48ZWRpdGlvbj4yMDA0LzAzLzAz

PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29yZD5BZ2Vk

PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFs

emhlaW1lciBEaXNlYXNlLypkaWFnbm9zdGljIGltYWdpbmcvbWV0YWJvbGlzbS9waHlzaW9wYXRo

b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZC8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD4qQW5pbGluZSBDb21wb3VuZHMvYmxvb2QvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3Jk

PkF1dG9yYWRpb2dyYXBoeS9tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPkJpbmRpbmcgU2l0ZXM8

L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vYW5hdG9teSAmYW1wOyBoaXN0b2xvZ3kvKm1ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4gQ2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkRp

YWdub3NpcywgRGlmZmVyZW50aWFsPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48

a2V5d29yZD5GbHVvcm9kZW94eWdsdWNvc2UgRjE4PC9rZXl3b3JkPjxrZXl3b3JkPkdsdWNvc2Uv

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFs

ZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD4qVGhpYXpv

bGVzL2Jsb29kL2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5UaW1lIEZhY3RvcnM8L2tleXdv

cmQ+PGtleXdvcmQ+VG9tb2dyYXBoeSwgRW1pc3Npb24tQ29tcHV0ZWQvKm1ldGhvZHM8L2tleXdv

cmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1h

cjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAzNjQtNTEzNCAoUHJpbnQpJiN4RDsw

MzY0LTUxMzQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjE0OTkxODA4PC9hY2Nlc3Np

b24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWgu

Z292L3B1Ym1lZC8xNDk5MTgwODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+MTAuMTAwMi9hbmEuMjAwMDk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LbHVuazwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJl

Y051bT4yMDY5PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NTE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDY5PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ3ODEyMjAiPjIwNjk8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPktsdW5rLCBXLiBFLjwvYXV0aG9yPjxhdXRo

b3I+RW5nbGVyLCBILjwvYXV0aG9yPjxhdXRob3I+Tm9yZGJlcmcsIEEuPC9hdXRob3I+PGF1dGhv

cj5XYW5nLCBZLjwvYXV0aG9yPjxhdXRob3I+QmxvbXF2aXN0LCBHLjwvYXV0aG9yPjxhdXRob3I+

SG9sdCwgRC4gUC48L2F1dGhvcj48YXV0aG9yPkJlcmdzdHJvbSwgTS48L2F1dGhvcj48YXV0aG9y

PlNhdml0Y2hldmEsIEkuPC9hdXRob3I+PGF1dGhvcj5IdWFuZywgRy4gRi48L2F1dGhvcj48YXV0

aG9yPkVzdHJhZGEsIFMuPC9hdXRob3I+PGF1dGhvcj5BdXNlbiwgQi48L2F1dGhvcj48YXV0aG9y

PkRlYm5hdGgsIE0uIEwuPC9hdXRob3I+PGF1dGhvcj5CYXJsZXR0YSwgSi48L2F1dGhvcj48YXV0

aG9yPlByaWNlLCBKLiBDLjwvYXV0aG9yPjxhdXRob3I+U2FuZGVsbCwgSi48L2F1dGhvcj48YXV0

aG9yPkxvcHJlc3RpLCBCLiBKLjwvYXV0aG9yPjxhdXRob3I+V2FsbCwgQS48L2F1dGhvcj48YXV0

aG9yPktvaXZpc3RvLCBQLjwvYXV0aG9yPjxhdXRob3I+QW50b25pLCBHLjwvYXV0aG9yPjxhdXRo

b3I+TWF0aGlzLCBDLiBBLjwvYXV0aG9yPjxhdXRob3I+TGFuZ3N0cm9tLCBCLjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgUHN5Y2hp

YXRyeSwgUEVUIEZhY2lsaXR5LCBVbml2ZXJzaXR5IG9mIFBpdHRzYnVyZ2gsIDIwMCBMb3Rocm9w

IFN0cmVldCwgUGl0dHNidXJnaCwgUEEgMTUyMTMtMjU4MiwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPkltYWdpbmcgYnJhaW4gYW15bG9pZCBpbiBBbHpoZWltZXImYXBvcztzIGRp

c2Vhc2Ugd2l0aCBQaXR0c2J1cmdoIENvbXBvdW5kLUI8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+

QW5uIE5ldXJvbDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4zMDYtMTk8L3BhZ2Vz

Pjx2b2x1bWU+NTU8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48ZWRpdGlvbj4yMDA0LzAzLzAz

PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29yZD5BZ2Vk

PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFs

emhlaW1lciBEaXNlYXNlLypkaWFnbm9zdGljIGltYWdpbmcvbWV0YWJvbGlzbS9waHlzaW9wYXRo

b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZC8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD4qQW5pbGluZSBDb21wb3VuZHMvYmxvb2QvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3Jk

PkF1dG9yYWRpb2dyYXBoeS9tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPkJpbmRpbmcgU2l0ZXM8

L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vYW5hdG9teSAmYW1wOyBoaXN0b2xvZ3kvKm1ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4gQ2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkRp

YWdub3NpcywgRGlmZmVyZW50aWFsPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48

a2V5d29yZD5GbHVvcm9kZW94eWdsdWNvc2UgRjE4PC9rZXl3b3JkPjxrZXl3b3JkPkdsdWNvc2Uv

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFs

ZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD4qVGhpYXpv

bGVzL2Jsb29kL2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5UaW1lIEZhY3RvcnM8L2tleXdv

cmQ+PGtleXdvcmQ+VG9tb2dyYXBoeSwgRW1pc3Npb24tQ29tcHV0ZWQvKm1ldGhvZHM8L2tleXdv

cmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1h

cjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAzNjQtNTEzNCAoUHJpbnQpJiN4RDsw

MzY0LTUxMzQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjE0OTkxODA4PC9hY2Nlc3Np

b24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWgu

Z292L3B1Ym1lZC8xNDk5MTgwODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+MTAuMTAwMi9hbmEuMjAwMDk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 51. Today other markers are known, such as inflammatory markers in PET imaging coming up years before the diagnosis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb2RyaWd1ZXotVmllaXRlejwvQXV0aG9yPjxZZWFyPjIw

MTY8L1llYXI+PFJlY051bT4yMDY4PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJz

dXBlcnNjcmlwdCI+NTItNTQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJl

cj4yMDY4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndh

MHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ3ODA4Njgi

PjIwNjg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xl

Ij4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlJvZHJpZ3Vlei1W

aWVpdGV6LCBFLjwvYXV0aG9yPjxhdXRob3I+U2FpbnQtQXViZXJ0LCBMLjwvYXV0aG9yPjxhdXRo

b3I+Q2FydGVyLCBTLiBGLjwvYXV0aG9yPjxhdXRob3I+QWxta3Zpc3QsIE8uPC9hdXRob3I+PGF1

dGhvcj5GYXJpZCwgSy48L2F1dGhvcj48YXV0aG9yPlNjaG9sbCwgTS48L2F1dGhvcj48YXV0aG9y

PkNoaW90aXMsIEsuPC9hdXRob3I+PGF1dGhvcj5UaG9yZGFyZG90dGlyLCBTLjwvYXV0aG9yPjxh

dXRob3I+R3JhZmYsIEMuPC9hdXRob3I+PGF1dGhvcj5XYWxsLCBBLjwvYXV0aG9yPjxhdXRob3I+

TGFuZ3N0cm9tLCBCLjwvYXV0aG9yPjxhdXRob3I+Tm9yZGJlcmcsIEEuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+MSBEZXBhcnRtZW50IE5WUywgQ2VudHJl

IGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIFRyYW5zbGF0aW9uYWwgQWx6aGVp

bWVyIE5ldXJvYmlvbG9neSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCAxNDEgNTcgSHVkZGluZ2Us

IFN0b2NraG9sbSwgU3dlZGVuIEFnbmV0YS5LLk5vcmRiZXJnQGtpLnNlLiYjeEQ7MSBEZXBhcnRt

ZW50IE5WUywgQ2VudHJlIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIFRyYW5z

bGF0aW9uYWwgQWx6aGVpbWVyIE5ldXJvYmlvbG9neSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCAx

NDEgNTcgSHVkZGluZ2UsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7MSBEZXBhcnRtZW50IE5WUywg

Q2VudHJlIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIFRyYW5zbGF0aW9uYWwg

QWx6aGVpbWVyIE5ldXJvYmlvbG9neSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCAxNDEgNTcgSHVk

ZGluZ2UsIFN0b2NraG9sbSwgU3dlZGVuIDIgRGVwYXJ0bWVudCBvZiBQc3ljaG9sb2d5LCBTdG9j

a2hvbG0gVW5pdmVyc2l0eSwgMTA2IDkxIFN0b2NraG9sbSwgU3dlZGVuIDMgRGVwYXJ0bWVudCBv

ZiBHZXJpYXRyaWMgTWVkaWNpbmUsIEthcm9saW5za2EgVW5pdmVyc2l0eSBIb3NwaXRhbCBIdWRk

aW5nZSwgMTQxIDg2LCBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEOzMgRGVwYXJ0bWVudCBvZiBHZXJp

YXRyaWMgTWVkaWNpbmUsIEthcm9saW5za2EgVW5pdmVyc2l0eSBIb3NwaXRhbCBIdWRkaW5nZSwg

MTQxIDg2LCBTdG9ja2hvbG0sIFN3ZWRlbiA0IERlcGFydG1lbnQgTlZTLCBDZW50ZXIgZm9yIEFs

emhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2YgTmV1cm9nZXJpYXRyaWNzLCBLYXJvbGluc2th

IEluc3RpdHV0ZXQsIDE0MSA1NyBIdWRkaW5nZSwgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDs1IERl

cGFydG1lbnQgb2YgU3VyZ2ljYWwgU2NpZW5jZXMsIFNlY3Rpb24gb2YgTnVjbGVhciBNZWRpY2lu

ZSAmYW1wOyBQRVQsIFVwcHNhbGEgVW5pdmVyc2l0eSwgNzUxIDg1IFVwcHNhbGEsIFN3ZWRlbi4m

I3hEOzYgRGVwYXJ0bWVudCBvZiBDaGVtaXN0cnksIFVwcHNhbGEgVW5pdmVyc2l0eSwgNzAxIDA1

IFVwcHNhbGEsIFN3ZWRlbi4mI3hEOzEgRGVwYXJ0bWVudCBOVlMsIENlbnRyZSBmb3IgQWx6aGVp

bWVyIFJlc2VhcmNoLCBEaXZpc2lvbiBvZiBUcmFuc2xhdGlvbmFsIEFsemhlaW1lciBOZXVyb2Jp

b2xvZ3ksIEthcm9saW5za2EgSW5zdGl0dXRldCwgMTQxIDU3IEh1ZGRpbmdlLCBTdG9ja2hvbG0s

IFN3ZWRlbiAzIERlcGFydG1lbnQgb2YgR2VyaWF0cmljIE1lZGljaW5lLCBLYXJvbGluc2thIFVu

aXZlcnNpdHkgSG9zcGl0YWwgSHVkZGluZ2UsIDE0MSA4NiwgU3RvY2tob2xtLCBTd2VkZW4uPC9h

dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+RGl2ZXJnaW5nIGxvbmdpdHVkaW5hbCBjaGFuZ2Vz

IGluIGFzdHJvY3l0b3NpcyBhbmQgYW15bG9pZCBQRVQgaW4gYXV0b3NvbWFsIGRvbWluYW50IEFs

emhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5CcmFpbjwvc2Vj

b25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkJyYWluPC9mdWxs

LXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+OTIyLTM2PC9wYWdlcz48dm9sdW1lPjEzOTwvdm9s

dW1lPjxudW1iZXI+UHQgMzwvbnVtYmVyPjxlZGl0aW9uPjIwMTYvMDEvMjg8L2VkaXRpb24+PGtl

eXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRpYWdub3N0aWMgaW1hZ2luZy9nZW5ldGljczwva2V5

d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvZ2VuZXRpY3M8L2tleXdvcmQ+PGtl

eXdvcmQ+Q3Jvc3MtU2VjdGlvbmFsIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9r

ZXl3b3JkPjxrZXl3b3JkPkZvbGxvdy1VcCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkdsaW9z

aXMvKmRpYWdub3N0aWMgaW1hZ2luZy9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8

L2tleXdvcmQ+PGtleXdvcmQ+TG9uZ2l0dWRpbmFsIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+

TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5QbGFx

dWUsIEFteWxvaWQvKmRpYWdub3N0aWMgaW1hZ2luZy9nZW5ldGljczwva2V5d29yZD48a2V5d29y

ZD5Qb3NpdHJvbi1FbWlzc2lvbiBUb21vZ3JhcGh5Lyp0cmVuZHM8L2tleXdvcmQ+PGtleXdvcmQ+

MTFDLVBpdHRzYnVyZ2ggY29tcG91bmQgQjwva2V5d29yZD48a2V5d29yZD4xMUMtZGV1dGVyaXVt

LUwtZGVwcmVueWw8L2tleXdvcmQ+PGtleXdvcmQ+MThGLWZsdW9yb2Rlb3h5Z2x1Y29zZTwva2V5

d29yZD48a2V5d29yZD5hc3Ryb2N5dG9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+YXV0b3NvbWFsIGRv

bWluYW50IEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRl

cz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWFyPC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PGlzYm4+MTQ2MC0yMTU2IChFbGVjdHJvbmljKSYjeEQ7MDAwNi04OTUwIChMaW5r

aW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNjgxMzk2OTwvYWNjZXNzaW9uLW51bT48dXJscz48

cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjY4

MTM5Njk8L3VybD48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcG1jL2FydGljbGVz

L1BNQzQ3NjYzODAvcGRmL2F3djQwNC5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1

c3RvbTI+UE1DNDc2NjM4MDwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA5

My9icmFpbi9hd3Y0MDQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48

Q2l0ZT48QXV0aG9yPkFpc2VuPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVtPjIwNzE8

L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjIwNzE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5

cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1

YXYiIHRpbWVzdGFtcD0iMTUzNDg1NTE4NSI+MjA3MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYt

dHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxh

dXRob3JzPjxhdXRob3I+QWlzZW4sIFAuIFMuPC9hdXRob3I+PGF1dGhvcj5QZXRlcnNlbiwgUi4g

Qy48L2F1dGhvcj48YXV0aG9yPkRvbm9odWUsIE0uPC9hdXRob3I+PGF1dGhvcj5XZWluZXIsIE0u

IFcuPC9hdXRob3I+PGF1dGhvcj5BbHpoZWltZXImYXBvcztzIERpc2Vhc2UgTmV1cm9pbWFnaW5n

LCBJbml0aWF0aXZlPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJl

c3M+RGVwYXJ0bWVudCBvZiBOZXVyb3NjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIENhbGlmb3JuaWEg

U2FuIERpZWdvLCBTYW4gRGllZ28sIENBLCBVU0EuIEVsZWN0cm9uaWMgYWRkcmVzczogcGFpc2Vu

QHVjc2QuZWR1LiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIE1heW8gQ2xpbmljLCBSb2No

ZXN0ZXIsIE1OLCBVU0EuJiN4RDtEaXZpc2lvbiBvZiBCaW9zdGF0aXN0aWNzIGFuZCBCaW9pbmZv

cm1hdGljcywgRGVwYXJ0bWVudCBvZiBGYW1pbHkgTWVkaWNpbmUgYW5kIFB1YmxpYyBIZWFsdGgs

IFVuaXZlcnNpdHkgb2YgQ2FsaWZvcm5pYSBTYW4gRGllZ28sIFNhbiBEaWVnbywgQ0EsIFVTQS4m

I3hEO0RlcGFydG1lbnRzIG9mIFJhZGlvbG9neSBhbmQgQmlvbWVkaWNhbCBJbWFnaW5nLCBNZWRp

Y2luZSwgUHN5Y2hpYXRyeSBhbmQgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IG9mIENhbGlmb3JuaWEg

U2FuIEZyYW5jaXNjbywgU2FuIEZyYW5zaXNjbywgQ0EsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0

bGVzPjx0aXRsZT5BbHpoZWltZXImYXBvcztzIERpc2Vhc2UgTmV1cm9pbWFnaW5nIEluaXRpYXRp

dmUgMiBDbGluaWNhbCBDb3JlOiBQcm9ncmVzcyBhbmQgcGxhbnM8L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+QWx6aGVpbWVycyBEZW1lbnQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+

NzM0LTk8L3BhZ2VzPjx2b2x1bWU+MTE8L3ZvbHVtZT48bnVtYmVyPjc8L251bWJlcj48ZWRpdGlv

bj4yMDE1LzA3LzIyPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2UgRmFjdG9yczwva2V5

d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9jb21wbGljYXRpb25zLypkaWFnbm9zaXM8

L2tleXdvcmQ+PGtleXdvcmQ+Q2xpbmljYWwgVHJpYWxzIGFzIFRvcGljL2hpc3RvcnkvKm1ldGhv

ZHM8L2tleXdvcmQ+PGtleXdvcmQ+Q29nbml0aW9uIERpc29yZGVycy9kaWFnbm9zaXMvZXRpb2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+Q29tcHV0ZXIgQ29tbXVuaWNhdGlvbiBOZXR3b3Jrczwva2V5

d29yZD48a2V5d29yZD5IaXN0b3J5LCAyMHRoIENlbnR1cnk8L2tleXdvcmQ+PGtleXdvcmQ+SGlz

dG9yeSwgMjFzdCBDZW50dXJ5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5

d29yZD5Mb25naXR1ZGluYWwgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD4qTmV1cm9pbWFnaW5n

L2hpc3RvcnkvbWV0aG9kcy9zdGFuZGFyZHM8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyJmFw

b3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+

Q29nbml0aXZlIGFzc2Vzc21lbnQ8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAx

NTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxp

c2JuPjE1NTItNTI3OSAoRWxlY3Ryb25pYykmI3hEOzE1NTItNTI2MCAoTGlua2luZyk8L2lzYm4+

PGFjY2Vzc2lvbi1udW0+MjYxOTQzMDk8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJs

cz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI2MTk0MzA5PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQ2NDM4NDA8L2N1c3RvbTI+PGVsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5qYWx6LjIwMTUuMDUuMDA1PC9lbGVjdHJvbmlj

LXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5BaXNlbjwvQXV0aG9y

PjxZZWFyPjIwMTA8L1llYXI+PFJlY051bT4yMDcyPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJl

cj4yMDcyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndh

MHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NTUxODUi

PjIwNzI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xl

Ij4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkFpc2VuLCBQLiBT

LjwvYXV0aG9yPjxhdXRob3I+UGV0ZXJzZW4sIFIuIEMuPC9hdXRob3I+PGF1dGhvcj5Eb25vaHVl

LCBNLiBDLjwvYXV0aG9yPjxhdXRob3I+R2Ftc3QsIEEuPC9hdXRob3I+PGF1dGhvcj5SYW1hbiwg

Ui48L2F1dGhvcj48YXV0aG9yPlRob21hcywgUi4gRy48L2F1dGhvcj48YXV0aG9yPldhbHRlciwg

Uy48L2F1dGhvcj48YXV0aG9yPlRyb2phbm93c2tpLCBKLiBRLjwvYXV0aG9yPjxhdXRob3I+U2hh

dywgTC4gTS48L2F1dGhvcj48YXV0aG9yPkJlY2tldHQsIEwuIEEuPC9hdXRob3I+PGF1dGhvcj5K

YWNrLCBDLiBSLiwgSnIuPC9hdXRob3I+PGF1dGhvcj5KYWd1c3QsIFcuPC9hdXRob3I+PGF1dGhv

cj5Ub2dhLCBBLiBXLjwvYXV0aG9yPjxhdXRob3I+U2F5a2luLCBBLiBKLjwvYXV0aG9yPjxhdXRo

b3I+TW9ycmlzLCBKLiBDLjwvYXV0aG9yPjxhdXRob3I+R3JlZW4sIFIuIEMuPC9hdXRob3I+PGF1

dGhvcj5XZWluZXIsIE0uIFcuPC9hdXRob3I+PGF1dGhvcj5BbHpoZWltZXImYXBvcztzIERpc2Vh

c2UgTmV1cm9pbWFnaW5nLCBJbml0aWF0aXZlPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb3NjaWVuY2VzLCBVbml2ZXJzaXR5

IG9mIENhbGlmb3JuaWEgU2FuIERpZWdvLCBDQSwgVVNBLiBwYWlzZW5AdWNzZC5lZHU8L2F1dGgt

YWRkcmVzcz48dGl0bGVzPjx0aXRsZT5DbGluaWNhbCBDb3JlIG9mIHRoZSBBbHpoZWltZXImYXBv

cztzIERpc2Vhc2UgTmV1cm9pbWFnaW5nIEluaXRpYXRpdmU6IHByb2dyZXNzIGFuZCBwbGFuczwv

dGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbHpoZWltZXJzIERlbWVudDwvc2Vjb25kYXJ5LXRpdGxl

PjwvdGl0bGVzPjxwYWdlcz4yMzktNDY8L3BhZ2VzPjx2b2x1bWU+Njwvdm9sdW1lPjxudW1iZXI+

MzwvbnVtYmVyPjxlZGl0aW9uPjIwMTAvMDUvMTE8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdv

cmQ+QWx6aGVpbWVyIERpc2Vhc2UvY2VyZWJyb3NwaW5hbCBmbHVpZC8qZGlhZ25vc2lzL2dlbmV0

aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL2RpYWdub3N0aWMgaW1hZ2luZy9wYXRob2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+Q2xpbmljYWwgVHJpYWxzIGFzIFRvcGljL21ldGhvZHMvc3RhdGlz

dGljcyAmYW1wOyBudW1lcmljYWwgZGF0YTwva2V5d29yZD48a2V5d29yZD5Db2duaXRpb24gRGlz

b3JkZXJzL2RpYWdub3N0aWMgaW1hZ2luZy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+KkRp

YWdub3N0aWMgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5EaXNlYXNlIFByb2dyZXNzaW9uPC9r

ZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IaXBwb2NhbXB1cy9kaWFn

bm9zdGljIGltYWdpbmcvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29y

ZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbnRhbCBTdGF0dXMgU2NoZWR1bGU8

L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9wc3ljaG9sb2dpY2FsIFRlc3RzPC9rZXl3b3JkPjxrZXl3

b3JkPlByb2dyYW0gRGV2ZWxvcG1lbnQ8L2tleXdvcmQ+PGtleXdvcmQ+UmFkaW9udWNsaWRlIElt

YWdpbmc8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMDwveWVhcj48cHViLWRh

dGVzPjxkYXRlPk1heTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTItNTI3OSAo

RWxlY3Ryb25pYykmI3hEOzE1NTItNTI2MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+

MjA0NTE4NzI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8v

d3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIwNDUxODcyPC91cmw+PC9yZWxhdGVkLXVybHM+

PC91cmxzPjxjdXN0b20yPlBNQzI4Njc4NDM8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjEwLjEwMTYvai5qYWx6LjIwMTAuMDMuMDA2PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48

L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb2RyaWd1ZXotVmllaXRlejwvQXV0aG9yPjxZZWFyPjIw

MTY8L1llYXI+PFJlY051bT4yMDY4PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJz

dXBlcnNjcmlwdCI+NTItNTQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJl

cj4yMDY4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndh

MHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ3ODA4Njgi

PjIwNjg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xl

Ij4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlJvZHJpZ3Vlei1W

aWVpdGV6LCBFLjwvYXV0aG9yPjxhdXRob3I+U2FpbnQtQXViZXJ0LCBMLjwvYXV0aG9yPjxhdXRo

b3I+Q2FydGVyLCBTLiBGLjwvYXV0aG9yPjxhdXRob3I+QWxta3Zpc3QsIE8uPC9hdXRob3I+PGF1

dGhvcj5GYXJpZCwgSy48L2F1dGhvcj48YXV0aG9yPlNjaG9sbCwgTS48L2F1dGhvcj48YXV0aG9y

PkNoaW90aXMsIEsuPC9hdXRob3I+PGF1dGhvcj5UaG9yZGFyZG90dGlyLCBTLjwvYXV0aG9yPjxh

dXRob3I+R3JhZmYsIEMuPC9hdXRob3I+PGF1dGhvcj5XYWxsLCBBLjwvYXV0aG9yPjxhdXRob3I+

TGFuZ3N0cm9tLCBCLjwvYXV0aG9yPjxhdXRob3I+Tm9yZGJlcmcsIEEuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+MSBEZXBhcnRtZW50IE5WUywgQ2VudHJl

IGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIFRyYW5zbGF0aW9uYWwgQWx6aGVp

bWVyIE5ldXJvYmlvbG9neSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCAxNDEgNTcgSHVkZGluZ2Us

IFN0b2NraG9sbSwgU3dlZGVuIEFnbmV0YS5LLk5vcmRiZXJnQGtpLnNlLiYjeEQ7MSBEZXBhcnRt

ZW50IE5WUywgQ2VudHJlIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIFRyYW5z

bGF0aW9uYWwgQWx6aGVpbWVyIE5ldXJvYmlvbG9neSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCAx

NDEgNTcgSHVkZGluZ2UsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7MSBEZXBhcnRtZW50IE5WUywg

Q2VudHJlIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIFRyYW5zbGF0aW9uYWwg

QWx6aGVpbWVyIE5ldXJvYmlvbG9neSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCAxNDEgNTcgSHVk

ZGluZ2UsIFN0b2NraG9sbSwgU3dlZGVuIDIgRGVwYXJ0bWVudCBvZiBQc3ljaG9sb2d5LCBTdG9j

a2hvbG0gVW5pdmVyc2l0eSwgMTA2IDkxIFN0b2NraG9sbSwgU3dlZGVuIDMgRGVwYXJ0bWVudCBv

ZiBHZXJpYXRyaWMgTWVkaWNpbmUsIEthcm9saW5za2EgVW5pdmVyc2l0eSBIb3NwaXRhbCBIdWRk

aW5nZSwgMTQxIDg2LCBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEOzMgRGVwYXJ0bWVudCBvZiBHZXJp

YXRyaWMgTWVkaWNpbmUsIEthcm9saW5za2EgVW5pdmVyc2l0eSBIb3NwaXRhbCBIdWRkaW5nZSwg

MTQxIDg2LCBTdG9ja2hvbG0sIFN3ZWRlbiA0IERlcGFydG1lbnQgTlZTLCBDZW50ZXIgZm9yIEFs

emhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2YgTmV1cm9nZXJpYXRyaWNzLCBLYXJvbGluc2th

IEluc3RpdHV0ZXQsIDE0MSA1NyBIdWRkaW5nZSwgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDs1IERl

cGFydG1lbnQgb2YgU3VyZ2ljYWwgU2NpZW5jZXMsIFNlY3Rpb24gb2YgTnVjbGVhciBNZWRpY2lu

ZSAmYW1wOyBQRVQsIFVwcHNhbGEgVW5pdmVyc2l0eSwgNzUxIDg1IFVwcHNhbGEsIFN3ZWRlbi4m

I3hEOzYgRGVwYXJ0bWVudCBvZiBDaGVtaXN0cnksIFVwcHNhbGEgVW5pdmVyc2l0eSwgNzAxIDA1

IFVwcHNhbGEsIFN3ZWRlbi4mI3hEOzEgRGVwYXJ0bWVudCBOVlMsIENlbnRyZSBmb3IgQWx6aGVp

bWVyIFJlc2VhcmNoLCBEaXZpc2lvbiBvZiBUcmFuc2xhdGlvbmFsIEFsemhlaW1lciBOZXVyb2Jp

b2xvZ3ksIEthcm9saW5za2EgSW5zdGl0dXRldCwgMTQxIDU3IEh1ZGRpbmdlLCBTdG9ja2hvbG0s

IFN3ZWRlbiAzIERlcGFydG1lbnQgb2YgR2VyaWF0cmljIE1lZGljaW5lLCBLYXJvbGluc2thIFVu

aXZlcnNpdHkgSG9zcGl0YWwgSHVkZGluZ2UsIDE0MSA4NiwgU3RvY2tob2xtLCBTd2VkZW4uPC9h

dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+RGl2ZXJnaW5nIGxvbmdpdHVkaW5hbCBjaGFuZ2Vz

IGluIGFzdHJvY3l0b3NpcyBhbmQgYW15bG9pZCBQRVQgaW4gYXV0b3NvbWFsIGRvbWluYW50IEFs

emhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5CcmFpbjwvc2Vj

b25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkJyYWluPC9mdWxs

LXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+OTIyLTM2PC9wYWdlcz48dm9sdW1lPjEzOTwvdm9s

dW1lPjxudW1iZXI+UHQgMzwvbnVtYmVyPjxlZGl0aW9uPjIwMTYvMDEvMjg8L2VkaXRpb24+PGtl

eXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRpYWdub3N0aWMgaW1hZ2luZy9nZW5ldGljczwva2V5

d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvZ2VuZXRpY3M8L2tleXdvcmQ+PGtl

eXdvcmQ+Q3Jvc3MtU2VjdGlvbmFsIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9r

ZXl3b3JkPjxrZXl3b3JkPkZvbGxvdy1VcCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkdsaW9z

aXMvKmRpYWdub3N0aWMgaW1hZ2luZy9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8

L2tleXdvcmQ+PGtleXdvcmQ+TG9uZ2l0dWRpbmFsIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+

TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5QbGFx

dWUsIEFteWxvaWQvKmRpYWdub3N0aWMgaW1hZ2luZy9nZW5ldGljczwva2V5d29yZD48a2V5d29y

ZD5Qb3NpdHJvbi1FbWlzc2lvbiBUb21vZ3JhcGh5Lyp0cmVuZHM8L2tleXdvcmQ+PGtleXdvcmQ+

MTFDLVBpdHRzYnVyZ2ggY29tcG91bmQgQjwva2V5d29yZD48a2V5d29yZD4xMUMtZGV1dGVyaXVt

LUwtZGVwcmVueWw8L2tleXdvcmQ+PGtleXdvcmQ+MThGLWZsdW9yb2Rlb3h5Z2x1Y29zZTwva2V5

d29yZD48a2V5d29yZD5hc3Ryb2N5dG9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+YXV0b3NvbWFsIGRv

bWluYW50IEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRl

cz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWFyPC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PGlzYm4+MTQ2MC0yMTU2IChFbGVjdHJvbmljKSYjeEQ7MDAwNi04OTUwIChMaW5r

aW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNjgxMzk2OTwvYWNjZXNzaW9uLW51bT48dXJscz48

cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjY4

MTM5Njk8L3VybD48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcG1jL2FydGljbGVz

L1BNQzQ3NjYzODAvcGRmL2F3djQwNC5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1

c3RvbTI+UE1DNDc2NjM4MDwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA5

My9icmFpbi9hd3Y0MDQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48

Q2l0ZT48QXV0aG9yPkFpc2VuPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVtPjIwNzE8

L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjIwNzE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5

cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1

YXYiIHRpbWVzdGFtcD0iMTUzNDg1NTE4NSI+MjA3MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYt

dHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxh

dXRob3JzPjxhdXRob3I+QWlzZW4sIFAuIFMuPC9hdXRob3I+PGF1dGhvcj5QZXRlcnNlbiwgUi4g

Qy48L2F1dGhvcj48YXV0aG9yPkRvbm9odWUsIE0uPC9hdXRob3I+PGF1dGhvcj5XZWluZXIsIE0u

IFcuPC9hdXRob3I+PGF1dGhvcj5BbHpoZWltZXImYXBvcztzIERpc2Vhc2UgTmV1cm9pbWFnaW5n

LCBJbml0aWF0aXZlPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJl

c3M+RGVwYXJ0bWVudCBvZiBOZXVyb3NjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIENhbGlmb3JuaWEg

U2FuIERpZWdvLCBTYW4gRGllZ28sIENBLCBVU0EuIEVsZWN0cm9uaWMgYWRkcmVzczogcGFpc2Vu

QHVjc2QuZWR1LiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIE1heW8gQ2xpbmljLCBSb2No

ZXN0ZXIsIE1OLCBVU0EuJiN4RDtEaXZpc2lvbiBvZiBCaW9zdGF0aXN0aWNzIGFuZCBCaW9pbmZv

cm1hdGljcywgRGVwYXJ0bWVudCBvZiBGYW1pbHkgTWVkaWNpbmUgYW5kIFB1YmxpYyBIZWFsdGgs

IFVuaXZlcnNpdHkgb2YgQ2FsaWZvcm5pYSBTYW4gRGllZ28sIFNhbiBEaWVnbywgQ0EsIFVTQS4m

I3hEO0RlcGFydG1lbnRzIG9mIFJhZGlvbG9neSBhbmQgQmlvbWVkaWNhbCBJbWFnaW5nLCBNZWRp

Y2luZSwgUHN5Y2hpYXRyeSBhbmQgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IG9mIENhbGlmb3JuaWEg

U2FuIEZyYW5jaXNjbywgU2FuIEZyYW5zaXNjbywgQ0EsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0

bGVzPjx0aXRsZT5BbHpoZWltZXImYXBvcztzIERpc2Vhc2UgTmV1cm9pbWFnaW5nIEluaXRpYXRp

dmUgMiBDbGluaWNhbCBDb3JlOiBQcm9ncmVzcyBhbmQgcGxhbnM8L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+QWx6aGVpbWVycyBEZW1lbnQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+

NzM0LTk8L3BhZ2VzPjx2b2x1bWU+MTE8L3ZvbHVtZT48bnVtYmVyPjc8L251bWJlcj48ZWRpdGlv

bj4yMDE1LzA3LzIyPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2UgRmFjdG9yczwva2V5

d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9jb21wbGljYXRpb25zLypkaWFnbm9zaXM8

L2tleXdvcmQ+PGtleXdvcmQ+Q2xpbmljYWwgVHJpYWxzIGFzIFRvcGljL2hpc3RvcnkvKm1ldGhv

ZHM8L2tleXdvcmQ+PGtleXdvcmQ+Q29nbml0aW9uIERpc29yZGVycy9kaWFnbm9zaXMvZXRpb2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+Q29tcHV0ZXIgQ29tbXVuaWNhdGlvbiBOZXR3b3Jrczwva2V5

d29yZD48a2V5d29yZD5IaXN0b3J5LCAyMHRoIENlbnR1cnk8L2tleXdvcmQ+PGtleXdvcmQ+SGlz

dG9yeSwgMjFzdCBDZW50dXJ5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5

d29yZD5Mb25naXR1ZGluYWwgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD4qTmV1cm9pbWFnaW5n

L2hpc3RvcnkvbWV0aG9kcy9zdGFuZGFyZHM8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyJmFw

b3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+

Q29nbml0aXZlIGFzc2Vzc21lbnQ8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAx

NTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxp

c2JuPjE1NTItNTI3OSAoRWxlY3Ryb25pYykmI3hEOzE1NTItNTI2MCAoTGlua2luZyk8L2lzYm4+

PGFjY2Vzc2lvbi1udW0+MjYxOTQzMDk8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJs

cz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI2MTk0MzA5PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQ2NDM4NDA8L2N1c3RvbTI+PGVsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5qYWx6LjIwMTUuMDUuMDA1PC9lbGVjdHJvbmlj

LXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5BaXNlbjwvQXV0aG9y

PjxZZWFyPjIwMTA8L1llYXI+PFJlY051bT4yMDcyPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJl

cj4yMDcyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndh

MHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NTUxODUi

PjIwNzI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xl

Ij4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkFpc2VuLCBQLiBT

LjwvYXV0aG9yPjxhdXRob3I+UGV0ZXJzZW4sIFIuIEMuPC9hdXRob3I+PGF1dGhvcj5Eb25vaHVl

LCBNLiBDLjwvYXV0aG9yPjxhdXRob3I+R2Ftc3QsIEEuPC9hdXRob3I+PGF1dGhvcj5SYW1hbiwg

Ui48L2F1dGhvcj48YXV0aG9yPlRob21hcywgUi4gRy48L2F1dGhvcj48YXV0aG9yPldhbHRlciwg

Uy48L2F1dGhvcj48YXV0aG9yPlRyb2phbm93c2tpLCBKLiBRLjwvYXV0aG9yPjxhdXRob3I+U2hh

dywgTC4gTS48L2F1dGhvcj48YXV0aG9yPkJlY2tldHQsIEwuIEEuPC9hdXRob3I+PGF1dGhvcj5K

YWNrLCBDLiBSLiwgSnIuPC9hdXRob3I+PGF1dGhvcj5KYWd1c3QsIFcuPC9hdXRob3I+PGF1dGhv

cj5Ub2dhLCBBLiBXLjwvYXV0aG9yPjxhdXRob3I+U2F5a2luLCBBLiBKLjwvYXV0aG9yPjxhdXRo

b3I+TW9ycmlzLCBKLiBDLjwvYXV0aG9yPjxhdXRob3I+R3JlZW4sIFIuIEMuPC9hdXRob3I+PGF1

dGhvcj5XZWluZXIsIE0uIFcuPC9hdXRob3I+PGF1dGhvcj5BbHpoZWltZXImYXBvcztzIERpc2Vh

c2UgTmV1cm9pbWFnaW5nLCBJbml0aWF0aXZlPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb3NjaWVuY2VzLCBVbml2ZXJzaXR5

IG9mIENhbGlmb3JuaWEgU2FuIERpZWdvLCBDQSwgVVNBLiBwYWlzZW5AdWNzZC5lZHU8L2F1dGgt

YWRkcmVzcz48dGl0bGVzPjx0aXRsZT5DbGluaWNhbCBDb3JlIG9mIHRoZSBBbHpoZWltZXImYXBv

cztzIERpc2Vhc2UgTmV1cm9pbWFnaW5nIEluaXRpYXRpdmU6IHByb2dyZXNzIGFuZCBwbGFuczwv

dGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbHpoZWltZXJzIERlbWVudDwvc2Vjb25kYXJ5LXRpdGxl

PjwvdGl0bGVzPjxwYWdlcz4yMzktNDY8L3BhZ2VzPjx2b2x1bWU+Njwvdm9sdW1lPjxudW1iZXI+

MzwvbnVtYmVyPjxlZGl0aW9uPjIwMTAvMDUvMTE8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdv

cmQ+QWx6aGVpbWVyIERpc2Vhc2UvY2VyZWJyb3NwaW5hbCBmbHVpZC8qZGlhZ25vc2lzL2dlbmV0

aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL2RpYWdub3N0aWMgaW1hZ2luZy9wYXRob2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+Q2xpbmljYWwgVHJpYWxzIGFzIFRvcGljL21ldGhvZHMvc3RhdGlz

dGljcyAmYW1wOyBudW1lcmljYWwgZGF0YTwva2V5d29yZD48a2V5d29yZD5Db2duaXRpb24gRGlz

b3JkZXJzL2RpYWdub3N0aWMgaW1hZ2luZy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+KkRp

YWdub3N0aWMgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5EaXNlYXNlIFByb2dyZXNzaW9uPC9r

ZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IaXBwb2NhbXB1cy9kaWFn

bm9zdGljIGltYWdpbmcvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29y

ZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbnRhbCBTdGF0dXMgU2NoZWR1bGU8

L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9wc3ljaG9sb2dpY2FsIFRlc3RzPC9rZXl3b3JkPjxrZXl3

b3JkPlByb2dyYW0gRGV2ZWxvcG1lbnQ8L2tleXdvcmQ+PGtleXdvcmQ+UmFkaW9udWNsaWRlIElt

YWdpbmc8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMDwveWVhcj48cHViLWRh

dGVzPjxkYXRlPk1heTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTItNTI3OSAo

RWxlY3Ryb25pYykmI3hEOzE1NTItNTI2MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+

MjA0NTE4NzI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8v

d3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIwNDUxODcyPC91cmw+PC9yZWxhdGVkLXVybHM+

PC91cmxzPjxjdXN0b20yPlBNQzI4Njc4NDM8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjEwLjEwMTYvai5qYWx6LjIwMTAuMDMuMDA2PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48

L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 52-54. Today with the help of biomarkers, we can put the diagnosis 10-15 years earlier in patients. Recently, a group from the National Institute on Aging and Alzheimer's Association (NIA-AA) have proposed a framework of preclinical AD based on biomarkers capable to determine the state of the pathology PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KYWNrPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj

TnVtPjEyMzk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij41

NTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEyMzk8L3JlYy1udW1i

ZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBo

cGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDQyNTk3NiI+MTIzOTwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SmFjaywgQy4gUi4sIEpyLjwvYXV0aG9yPjxh

dXRob3I+QmVubmV0dCwgRC4gQS48L2F1dGhvcj48YXV0aG9yPkJsZW5ub3csIEsuPC9hdXRob3I+

PGF1dGhvcj5DYXJyaWxsbywgTS4gQy48L2F1dGhvcj48YXV0aG9yPkR1bm4sIEIuPC9hdXRob3I+

PGF1dGhvcj5IYWViZXJsZWluLCBTLiBCLjwvYXV0aG9yPjxhdXRob3I+SG9sdHptYW4sIEQuIE0u

PC9hdXRob3I+PGF1dGhvcj5KYWd1c3QsIFcuPC9hdXRob3I+PGF1dGhvcj5KZXNzZW4sIEYuPC9h

dXRob3I+PGF1dGhvcj5LYXJsYXdpc2gsIEouPC9hdXRob3I+PGF1dGhvcj5MaXUsIEUuPC9hdXRo

b3I+PGF1dGhvcj5Nb2xpbnVldm8sIEouIEwuPC9hdXRob3I+PGF1dGhvcj5Nb250aW5lLCBULjwv

YXV0aG9yPjxhdXRob3I+UGhlbHBzLCBDLjwvYXV0aG9yPjxhdXRob3I+UmFua2luLCBLLiBQLjwv

YXV0aG9yPjxhdXRob3I+Um93ZSwgQy4gQy48L2F1dGhvcj48YXV0aG9yPlNjaGVsdGVucywgUC48

L2F1dGhvcj48YXV0aG9yPlNpZW1lcnMsIEUuPC9hdXRob3I+PGF1dGhvcj5TbnlkZXIsIEguIE0u

PC9hdXRob3I+PGF1dGhvcj5TcGVybGluZywgUi48L2F1dGhvcj48YXV0aG9yPkNvbnRyaWJ1dG9y

cyw8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRt

ZW50IG9mIFJhZGlvbG9neSwgTWF5byBDbGluaWMsIFJvY2hlc3RlciwgTU4sIFVTQS4gRWxlY3Ry

b25pYyBhZGRyZXNzOiBqYWNrLmNsaWZmb3JkQG1heW8uZWR1LiYjeEQ7RGVwYXJ0bWVudCBvZiBO

ZXVyb2xvZ2ljYWwgU2NpZW5jZXMsIFJ1c2ggVW5pdmVyc2l0eSwgQ2hpY2FnbywgSUwsIFVTQS4m

I3hEO0RlcGFydG1lbnQgb2YgUHN5Y2hpYXRyeSBhbmQgTmV1cm9jaGVtaXN0cnksIFVuaXZlcnNp

dHkgb2YgR290aGVuYnVyZywgR290aGVuYnVyZywgU3dlZGVuLiYjeEQ7TWVkaWNhbCAmYW1wOyBT

Y2llbnRpZmljIFJlbGF0aW9ucywgQWx6aGVpbWVyJmFwb3M7cyBBc3NvY2lhdGlvbiwgQ2hpY2Fn

bywgSUwsIFVTQS4mI3hEO09mZmljZSBvZiBEcnVnIEV2YWx1YXRpb24sIEZEQSwgU2lsdmVyIFNw

cmluZywgTUQsIFVTQS4mI3hEO0Jpb2dlbiwgQ2FtYnJpZGdlLCBNQSwgVVNBLiYjeEQ7RGVwYXJ0

bWVudCBvZiBOZXVyb2xvZ3ksIFdhc2hpbmd0b24gVW5pdmVyc2l0eSwgU3QuIExvdWlzLCBNTywg

VVNBLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoIGFuZCBOZXVyb3NjaWVuY2UsIFVu

aXZlcnNpdHkgb2YgQ2FsaWZvcm5pYSBCZXJrZWxleSwgQmVya2VsZXksIENBLCBVU0EuJiN4RDtE

ZXBhcnRtZW50IG9mIFBzeWNoaWF0cnksIFVuaXZlcnNpdHkgb2YgQ29sb2duZSwgTWVkaWNhbCBG

YWN1bHR5LCBDb2xvZ25lLCBHZXJtYW55LiYjeEQ7RGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgVW5p

dmVyc2l0eSBvZiBQZW5uc3lsdmFuaWEsIFBoaWxhZGVscGhpYSwgUEEsIFVTQS4mI3hEO1Byb3Ro

ZW5hIEJpb3NjaWVuY2VzLCBJbmMuLCBTYW4gRnJhbmNpc2NvLCBDQSwgVVNBLiYjeEQ7QmFyY2Vs

b25hQmV0YSBCcmFpbiBSZXNlYXJjaCBDZW50ZXIsIFBhc3F1YWwgTWFyYWdhbGwgRm91bmRhdGlv

biBhbmQgSG9zcGl0YWwgQ2xpbmljLUlESUJBUFMsIEJhcmNlbG9uYSwgU3BhaW4uJiN4RDtEZXBh

cnRtZW50IG9mIFBhdGhvbG9neSwgU3RhbmZvcmQgVW5pdmVyc2l0eSwgU3RhbmRmb3JkLCBDQSwg

VVNBLiYjeEQ7Rm9ybWVybHkgYXQgTmF0aW9uYWwgSW5zdGl0dXRlIG9uIEFnaW5nLCBCZXRoZXNk

YSwgTUQsIFVTQS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IG9mIENh

bGlmb3JuaWEgU2FuIEZyYW5jaXNjbywgU2FuIEZyYW5jaXNjbywgQ0EsIFVTQS4mI3hEO0RlcGFy

dG1lbnQgb2YgTW9sZWN1bGFyIEltYWdpbmcsIEF1c3RpbiBIZWFsdGgsIFVuaXZlcnNpdHkgb2Yg

TWVsYm91cm5lLCBNZWxib3VybmUsIEF1c3RyYWxpYS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9s

b2d5LCBWVSBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBBbXN0ZXJkYW0sIE5ldGhlcmxhbmRz

LiYjeEQ7Rm9ybWVybHkgYXQgRWxpIExpbGx5IGFuZCBDb21wYW55LCBJbmRpYW5hcG9saXMsIElO

LCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgQnJpZ2hhbSBhbmQgV29tZW4mYXBv

cztzIEhvc3BpdGFsLCBCb3N0b24sIE1BLCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+TklBLUFBIFJlc2VhcmNoIEZyYW1ld29yazogVG93YXJkIGEgYmlvbG9naWNhbCBkZWZpbml0

aW9uIG9mIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5B

bHpoZWltZXJzIERlbWVudDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz41MzUtNTYy

PC9wYWdlcz48dm9sdW1lPjE0PC92b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PGtleXdvcmRzPjxr

ZXl3b3JkPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZSBkaWFnbm9zaXM8L2tleXdvcmQ+PGtleXdv

cmQ+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+QW15

bG9pZCBQRVQ8L2tleXdvcmQ+PGtleXdvcmQ+QmlvbWFya2VycyBBbHpoZWltZXImYXBvcztzIGRp

c2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Q1NGIGJpb21hcmtlcnMgQWx6aGVpbWVyJmFwb3M7cyBk

aXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPlByZWNsaW5pY2FsIEFsemhlaW1lciZhcG9zO3MgZGlz

ZWFzZTwva2V5d29yZD48a2V5d29yZD5UYXUgUEVUPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVz

Pjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BcHI8L2RhdGU+PC9wdWItZGF0ZXM+

PC9kYXRlcz48aXNibj4xNTUyLTUyNzkgKEVsZWN0cm9uaWMpJiN4RDsxNTUyLTUyNjAgKExpbmtp

bmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5NjUzNjA2PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxy

ZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yOTY1

MzYwNjwvdXJsPjx1cmw+aHR0cHM6Ly9hYy5lbHMtY2RuLmNvbS9TMTU1MjUyNjAxODMwMDcyNC8x

LXMyLjAtUzE1NTI1MjYwMTgzMDA3MjQtbWFpbi5wZGY/X3RpZD1kZmFjYzM3Zi0yMDE0LTRiOWMt

YTViZS05NDlhMzliMTA2ZTMmYW1wO2FjZG5hdD0xNTM0NDk0OTAwX2NlNjM0NjZkMmJhM2UwZmI0

MjJmMWQwODJiZjAzY2E5PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzU5

NTg2MjU8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5qYWx6LjIw

MTguMDIuMDE4PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmRO

b3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KYWNrPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj

TnVtPjEyMzk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij41

NTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEyMzk8L3JlYy1udW1i

ZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBo

cGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDQyNTk3NiI+MTIzOTwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SmFjaywgQy4gUi4sIEpyLjwvYXV0aG9yPjxh

dXRob3I+QmVubmV0dCwgRC4gQS48L2F1dGhvcj48YXV0aG9yPkJsZW5ub3csIEsuPC9hdXRob3I+

PGF1dGhvcj5DYXJyaWxsbywgTS4gQy48L2F1dGhvcj48YXV0aG9yPkR1bm4sIEIuPC9hdXRob3I+

PGF1dGhvcj5IYWViZXJsZWluLCBTLiBCLjwvYXV0aG9yPjxhdXRob3I+SG9sdHptYW4sIEQuIE0u

PC9hdXRob3I+PGF1dGhvcj5KYWd1c3QsIFcuPC9hdXRob3I+PGF1dGhvcj5KZXNzZW4sIEYuPC9h

dXRob3I+PGF1dGhvcj5LYXJsYXdpc2gsIEouPC9hdXRob3I+PGF1dGhvcj5MaXUsIEUuPC9hdXRo

b3I+PGF1dGhvcj5Nb2xpbnVldm8sIEouIEwuPC9hdXRob3I+PGF1dGhvcj5Nb250aW5lLCBULjwv

YXV0aG9yPjxhdXRob3I+UGhlbHBzLCBDLjwvYXV0aG9yPjxhdXRob3I+UmFua2luLCBLLiBQLjwv

YXV0aG9yPjxhdXRob3I+Um93ZSwgQy4gQy48L2F1dGhvcj48YXV0aG9yPlNjaGVsdGVucywgUC48

L2F1dGhvcj48YXV0aG9yPlNpZW1lcnMsIEUuPC9hdXRob3I+PGF1dGhvcj5TbnlkZXIsIEguIE0u

PC9hdXRob3I+PGF1dGhvcj5TcGVybGluZywgUi48L2F1dGhvcj48YXV0aG9yPkNvbnRyaWJ1dG9y

cyw8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRt

ZW50IG9mIFJhZGlvbG9neSwgTWF5byBDbGluaWMsIFJvY2hlc3RlciwgTU4sIFVTQS4gRWxlY3Ry

b25pYyBhZGRyZXNzOiBqYWNrLmNsaWZmb3JkQG1heW8uZWR1LiYjeEQ7RGVwYXJ0bWVudCBvZiBO

ZXVyb2xvZ2ljYWwgU2NpZW5jZXMsIFJ1c2ggVW5pdmVyc2l0eSwgQ2hpY2FnbywgSUwsIFVTQS4m

I3hEO0RlcGFydG1lbnQgb2YgUHN5Y2hpYXRyeSBhbmQgTmV1cm9jaGVtaXN0cnksIFVuaXZlcnNp

dHkgb2YgR290aGVuYnVyZywgR290aGVuYnVyZywgU3dlZGVuLiYjeEQ7TWVkaWNhbCAmYW1wOyBT

Y2llbnRpZmljIFJlbGF0aW9ucywgQWx6aGVpbWVyJmFwb3M7cyBBc3NvY2lhdGlvbiwgQ2hpY2Fn

bywgSUwsIFVTQS4mI3hEO09mZmljZSBvZiBEcnVnIEV2YWx1YXRpb24sIEZEQSwgU2lsdmVyIFNw

cmluZywgTUQsIFVTQS4mI3hEO0Jpb2dlbiwgQ2FtYnJpZGdlLCBNQSwgVVNBLiYjeEQ7RGVwYXJ0

bWVudCBvZiBOZXVyb2xvZ3ksIFdhc2hpbmd0b24gVW5pdmVyc2l0eSwgU3QuIExvdWlzLCBNTywg

VVNBLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoIGFuZCBOZXVyb3NjaWVuY2UsIFVu

aXZlcnNpdHkgb2YgQ2FsaWZvcm5pYSBCZXJrZWxleSwgQmVya2VsZXksIENBLCBVU0EuJiN4RDtE

ZXBhcnRtZW50IG9mIFBzeWNoaWF0cnksIFVuaXZlcnNpdHkgb2YgQ29sb2duZSwgTWVkaWNhbCBG

YWN1bHR5LCBDb2xvZ25lLCBHZXJtYW55LiYjeEQ7RGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgVW5p

dmVyc2l0eSBvZiBQZW5uc3lsdmFuaWEsIFBoaWxhZGVscGhpYSwgUEEsIFVTQS4mI3hEO1Byb3Ro

ZW5hIEJpb3NjaWVuY2VzLCBJbmMuLCBTYW4gRnJhbmNpc2NvLCBDQSwgVVNBLiYjeEQ7QmFyY2Vs

b25hQmV0YSBCcmFpbiBSZXNlYXJjaCBDZW50ZXIsIFBhc3F1YWwgTWFyYWdhbGwgRm91bmRhdGlv

biBhbmQgSG9zcGl0YWwgQ2xpbmljLUlESUJBUFMsIEJhcmNlbG9uYSwgU3BhaW4uJiN4RDtEZXBh

cnRtZW50IG9mIFBhdGhvbG9neSwgU3RhbmZvcmQgVW5pdmVyc2l0eSwgU3RhbmRmb3JkLCBDQSwg

VVNBLiYjeEQ7Rm9ybWVybHkgYXQgTmF0aW9uYWwgSW5zdGl0dXRlIG9uIEFnaW5nLCBCZXRoZXNk

YSwgTUQsIFVTQS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IG9mIENh

bGlmb3JuaWEgU2FuIEZyYW5jaXNjbywgU2FuIEZyYW5jaXNjbywgQ0EsIFVTQS4mI3hEO0RlcGFy

dG1lbnQgb2YgTW9sZWN1bGFyIEltYWdpbmcsIEF1c3RpbiBIZWFsdGgsIFVuaXZlcnNpdHkgb2Yg

TWVsYm91cm5lLCBNZWxib3VybmUsIEF1c3RyYWxpYS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9s

b2d5LCBWVSBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBBbXN0ZXJkYW0sIE5ldGhlcmxhbmRz

LiYjeEQ7Rm9ybWVybHkgYXQgRWxpIExpbGx5IGFuZCBDb21wYW55LCBJbmRpYW5hcG9saXMsIElO

LCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgQnJpZ2hhbSBhbmQgV29tZW4mYXBv

cztzIEhvc3BpdGFsLCBCb3N0b24sIE1BLCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+TklBLUFBIFJlc2VhcmNoIEZyYW1ld29yazogVG93YXJkIGEgYmlvbG9naWNhbCBkZWZpbml0

aW9uIG9mIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5B

bHpoZWltZXJzIERlbWVudDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz41MzUtNTYy

PC9wYWdlcz48dm9sdW1lPjE0PC92b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PGtleXdvcmRzPjxr

ZXl3b3JkPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZSBkaWFnbm9zaXM8L2tleXdvcmQ+PGtleXdv

cmQ+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+QW15

bG9pZCBQRVQ8L2tleXdvcmQ+PGtleXdvcmQ+QmlvbWFya2VycyBBbHpoZWltZXImYXBvcztzIGRp

c2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Q1NGIGJpb21hcmtlcnMgQWx6aGVpbWVyJmFwb3M7cyBk

aXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPlByZWNsaW5pY2FsIEFsemhlaW1lciZhcG9zO3MgZGlz

ZWFzZTwva2V5d29yZD48a2V5d29yZD5UYXUgUEVUPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVz

Pjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BcHI8L2RhdGU+PC9wdWItZGF0ZXM+

PC9kYXRlcz48aXNibj4xNTUyLTUyNzkgKEVsZWN0cm9uaWMpJiN4RDsxNTUyLTUyNjAgKExpbmtp

bmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5NjUzNjA2PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxy

ZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yOTY1

MzYwNjwvdXJsPjx1cmw+aHR0cHM6Ly9hYy5lbHMtY2RuLmNvbS9TMTU1MjUyNjAxODMwMDcyNC8x

LXMyLjAtUzE1NTI1MjYwMTgzMDA3MjQtbWFpbi5wZGY/X3RpZD1kZmFjYzM3Zi0yMDE0LTRiOWMt

YTViZS05NDlhMzliMTA2ZTMmYW1wO2FjZG5hdD0xNTM0NDk0OTAwX2NlNjM0NjZkMmJhM2UwZmI0

MjJmMWQwODJiZjAzY2E5PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzU5

NTg2MjU8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5qYWx6LjIw

MTguMDIuMDE4PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmRO

b3RlPgB=

ADDIN EN.CITE.DATA 55.Many research efforts aim to find specific patterns between Aβ accumulation in the human brain and AD progression. Patients with MCI have shown that converting to AD implies PIB retention in the frontal cortex two to three years before the symptoms appear PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gb3JzYmVyZzwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+

PFJlY051bT4yMDgwPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+NTY8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDgwPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NTU2ODEiPjIwODA8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkZvcnNiZXJnLCBBLjwvYXV0aG9yPjxh

dXRob3I+RW5nbGVyLCBILjwvYXV0aG9yPjxhdXRob3I+QWxta3Zpc3QsIE8uPC9hdXRob3I+PGF1

dGhvcj5CbG9tcXVpc3QsIEcuPC9hdXRob3I+PGF1dGhvcj5IYWdtYW4sIEcuPC9hdXRob3I+PGF1

dGhvcj5XYWxsLCBBLjwvYXV0aG9yPjxhdXRob3I+UmluZ2hlaW0sIEEuPC9hdXRob3I+PGF1dGhv

cj5MYW5nc3Ryb20sIEIuPC9hdXRob3I+PGF1dGhvcj5Ob3JkYmVyZywgQS48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5LYXJvbGluc2thIEluc3RpdHV0ZSwg

RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIFN0

b2NraG9sbSwgU3dlZGVuLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlBFVCBpbWFnaW5n

IG9mIGFteWxvaWQgZGVwb3NpdGlvbiBpbiBwYXRpZW50cyB3aXRoIG1pbGQgY29nbml0aXZlIGlt

cGFpcm1lbnQ8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmV1cm9iaW9sIEFnaW5nPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmV1cm9iaW9sIEFnaW5n

PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTQ1Ni02NTwvcGFnZXM+PHZvbHVtZT4y

OTwvdm9sdW1lPjxudW1iZXI+MTA8L251bWJlcj48ZWRpdGlvbj4yMDA3LzA1LzE1PC9lZGl0aW9u

PjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBv

dmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFnaW5nL21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2RpYWdub3N0aWMgaW1hZ2luZy9wYXRob2xvZ3kv

cGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9t

ZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkJlbnpvdGhpYXpvbGVzPC9rZXl3b3JkPjxrZXl3

b3JkPkNlcmVicmFsIENvcnRleC8qZGlhZ25vc3RpYyBpbWFnaW5nLypwYXRob2xvZ3kvcGh5c2lv

cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbiBEaXNvcmRlcnMvKmRpYWdub3N0

aWMgaW1hZ2luZy8qcGF0aG9sb2d5L3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5E

aXNlYXNlIFByb2dyZXNzaW9uPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5

d29yZD5GbHVvcm9kZW94eWdsdWNvc2UgRjE4PC9rZXl3b3JkPjxrZXl3b3JkPkdsdWNvc2UvbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwv

a2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5OZXVyb3BzeWNo

b2xvZ2ljYWwgVGVzdHM8L2tleXdvcmQ+PGtleXdvcmQ+UGxhcXVlLCBBbXlsb2lkLypkaWFnbm9z

dGljIGltYWdpbmcvbWV0YWJvbGlzbS8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBvc2l0

cm9uLUVtaXNzaW9uIFRvbW9ncmFwaHk8L2tleXdvcmQ+PGtleXdvcmQ+UHJlZGljdGl2ZSBWYWx1

ZSBvZiBUZXN0czwva2V5d29yZD48a2V5d29yZD5Qcm9nbm9zaXM8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAwODwveWVhcj48cHViLWRhdGVzPjxkYXRlPk9jdDwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTgtMTQ5NyAoRWxlY3Ryb25pYykmI3hEOzAxOTctNDU4

MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTc0OTkzOTI8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVi

bWVkLzE3NDk5MzkyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC4xMDE2L2oubmV1cm9iaW9sYWdpbmcuMjAwNy4wMy4wMjk8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gb3JzYmVyZzwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+

PFJlY051bT4yMDgwPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+NTY8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDgwPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NTU2ODEiPjIwODA8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkZvcnNiZXJnLCBBLjwvYXV0aG9yPjxh

dXRob3I+RW5nbGVyLCBILjwvYXV0aG9yPjxhdXRob3I+QWxta3Zpc3QsIE8uPC9hdXRob3I+PGF1

dGhvcj5CbG9tcXVpc3QsIEcuPC9hdXRob3I+PGF1dGhvcj5IYWdtYW4sIEcuPC9hdXRob3I+PGF1

dGhvcj5XYWxsLCBBLjwvYXV0aG9yPjxhdXRob3I+UmluZ2hlaW0sIEEuPC9hdXRob3I+PGF1dGhv

cj5MYW5nc3Ryb20sIEIuPC9hdXRob3I+PGF1dGhvcj5Ob3JkYmVyZywgQS48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5LYXJvbGluc2thIEluc3RpdHV0ZSwg

RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIFN0

b2NraG9sbSwgU3dlZGVuLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlBFVCBpbWFnaW5n

IG9mIGFteWxvaWQgZGVwb3NpdGlvbiBpbiBwYXRpZW50cyB3aXRoIG1pbGQgY29nbml0aXZlIGlt

cGFpcm1lbnQ8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmV1cm9iaW9sIEFnaW5nPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmV1cm9iaW9sIEFnaW5n

PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTQ1Ni02NTwvcGFnZXM+PHZvbHVtZT4y

OTwvdm9sdW1lPjxudW1iZXI+MTA8L251bWJlcj48ZWRpdGlvbj4yMDA3LzA1LzE1PC9lZGl0aW9u

PjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBv

dmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFnaW5nL21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2RpYWdub3N0aWMgaW1hZ2luZy9wYXRob2xvZ3kv

cGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9t

ZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkJlbnpvdGhpYXpvbGVzPC9rZXl3b3JkPjxrZXl3

b3JkPkNlcmVicmFsIENvcnRleC8qZGlhZ25vc3RpYyBpbWFnaW5nLypwYXRob2xvZ3kvcGh5c2lv

cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbiBEaXNvcmRlcnMvKmRpYWdub3N0

aWMgaW1hZ2luZy8qcGF0aG9sb2d5L3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5E

aXNlYXNlIFByb2dyZXNzaW9uPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5

d29yZD5GbHVvcm9kZW94eWdsdWNvc2UgRjE4PC9rZXl3b3JkPjxrZXl3b3JkPkdsdWNvc2UvbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwv

a2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5OZXVyb3BzeWNo

b2xvZ2ljYWwgVGVzdHM8L2tleXdvcmQ+PGtleXdvcmQ+UGxhcXVlLCBBbXlsb2lkLypkaWFnbm9z

dGljIGltYWdpbmcvbWV0YWJvbGlzbS8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBvc2l0

cm9uLUVtaXNzaW9uIFRvbW9ncmFwaHk8L2tleXdvcmQ+PGtleXdvcmQ+UHJlZGljdGl2ZSBWYWx1

ZSBvZiBUZXN0czwva2V5d29yZD48a2V5d29yZD5Qcm9nbm9zaXM8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAwODwveWVhcj48cHViLWRhdGVzPjxkYXRlPk9jdDwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTgtMTQ5NyAoRWxlY3Ryb25pYykmI3hEOzAxOTctNDU4

MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTc0OTkzOTI8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVi

bWVkLzE3NDk5MzkyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC4xMDE2L2oubmV1cm9iaW9sYWdpbmcuMjAwNy4wMy4wMjk8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 56. Additionally, stable PIB retention after 2 years in human brains can be used to pinpoint the stage before the onset of cognitive decline in AD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gb3JzYmVyZzwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+

PFJlY051bT4yMDcwPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+NTA8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDcwPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ3ODEzMjAiPjIwNzA8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkZvcnNiZXJnLCBBLjwvYXV0aG9yPjxh

dXRob3I+QWxta3Zpc3QsIE8uPC9hdXRob3I+PGF1dGhvcj5FbmdsZXIsIEguPC9hdXRob3I+PGF1

dGhvcj5XYWxsLCBBLjwvYXV0aG9yPjxhdXRob3I+TGFuZ3N0cm9tLCBCLjwvYXV0aG9yPjxhdXRo

b3I+Tm9yZGJlcmcsIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk

ZHJlc3M+S2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwg

Q2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFs

IEh1ZGRpbmdlLCBTdG9ja2hvbG0sIFN3ZWRlbi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRs

ZT5IaWdoIFBJQiByZXRlbnRpb24gaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGlzIGFuIGVh

cmx5IGV2ZW50IHdpdGggY29tcGxleCByZWxhdGlvbnNoaXAgd2l0aCBDU0YgYmlvbWFya2VycyBh

bmQgZnVuY3Rpb25hbCBwYXJhbWV0ZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkN1cnIgQWx6

aGVpbWVyIFJlczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRp

dGxlPkN1cnIgQWx6aGVpbWVyIFJlczwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjU2

LTY2PC9wYWdlcz48dm9sdW1lPjc8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4y

MDEwLzAzLzA5PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3

b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNl

LypjZXJlYnJvc3BpbmFsIGZsdWlkLypkaWFnbm9zdGljIGltYWdpbmcvcGh5c2lvcGF0aG9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPipCZW56b3RoaWF6b2xlczwva2V5d29yZD48a2V5d29yZD5CaW9t

YXJrZXJzLypjZXJlYnJvc3BpbmFsIGZsdWlkPC9rZXl3b3JkPjxrZXl3b3JkPkVhcmx5IERpYWdu

b3Npczwva2V5d29yZD48a2V5d29yZD5Fbnp5bWUtTGlua2VkIEltbXVub3NvcmJlbnQgQXNzYXk8

L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZsdW9yb2Rlb3h5Z2x1

Y29zZSBGMTg8L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y29zZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxr

ZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbWFnZSBJbnRlcnByZXRhdGlvbiwgQ29t

cHV0ZXItQXNzaXN0ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5N

ZW1vcnkgRGlzb3JkZXJzL2RpYWdub3N0aWMgaW1hZ2luZy9ldGlvbG9neS9tZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBvc2l0cm9uLUVt

aXNzaW9uIFRvbW9ncmFwaHk8L2tleXdvcmQ+PGtleXdvcmQ+KlJhZGlvcGhhcm1hY2V1dGljYWxz

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTA8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5GZWI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xODc1LTU4MjggKEVsZWN0

cm9uaWMpJiN4RDsxNTY3LTIwNTAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIwMjA1

NjcxPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMDIwNTY3MTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gb3JzYmVyZzwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+

PFJlY051bT4yMDcwPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+NTA8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDcwPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ3ODEzMjAiPjIwNzA8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkZvcnNiZXJnLCBBLjwvYXV0aG9yPjxh

dXRob3I+QWxta3Zpc3QsIE8uPC9hdXRob3I+PGF1dGhvcj5FbmdsZXIsIEguPC9hdXRob3I+PGF1

dGhvcj5XYWxsLCBBLjwvYXV0aG9yPjxhdXRob3I+TGFuZ3N0cm9tLCBCLjwvYXV0aG9yPjxhdXRo

b3I+Tm9yZGJlcmcsIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk

ZHJlc3M+S2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwg

Q2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFs

IEh1ZGRpbmdlLCBTdG9ja2hvbG0sIFN3ZWRlbi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRs

ZT5IaWdoIFBJQiByZXRlbnRpb24gaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGlzIGFuIGVh

cmx5IGV2ZW50IHdpdGggY29tcGxleCByZWxhdGlvbnNoaXAgd2l0aCBDU0YgYmlvbWFya2VycyBh

bmQgZnVuY3Rpb25hbCBwYXJhbWV0ZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkN1cnIgQWx6

aGVpbWVyIFJlczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRp

dGxlPkN1cnIgQWx6aGVpbWVyIFJlczwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjU2

LTY2PC9wYWdlcz48dm9sdW1lPjc8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4y

MDEwLzAzLzA5PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3

b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNl

LypjZXJlYnJvc3BpbmFsIGZsdWlkLypkaWFnbm9zdGljIGltYWdpbmcvcGh5c2lvcGF0aG9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPipCZW56b3RoaWF6b2xlczwva2V5d29yZD48a2V5d29yZD5CaW9t

YXJrZXJzLypjZXJlYnJvc3BpbmFsIGZsdWlkPC9rZXl3b3JkPjxrZXl3b3JkPkVhcmx5IERpYWdu

b3Npczwva2V5d29yZD48a2V5d29yZD5Fbnp5bWUtTGlua2VkIEltbXVub3NvcmJlbnQgQXNzYXk8

L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZsdW9yb2Rlb3h5Z2x1

Y29zZSBGMTg8L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y29zZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxr

ZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbWFnZSBJbnRlcnByZXRhdGlvbiwgQ29t

cHV0ZXItQXNzaXN0ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5N

ZW1vcnkgRGlzb3JkZXJzL2RpYWdub3N0aWMgaW1hZ2luZy9ldGlvbG9neS9tZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBvc2l0cm9uLUVt

aXNzaW9uIFRvbW9ncmFwaHk8L2tleXdvcmQ+PGtleXdvcmQ+KlJhZGlvcGhhcm1hY2V1dGljYWxz

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTA8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5GZWI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xODc1LTU4MjggKEVsZWN0

cm9uaWMpJiN4RDsxNTY3LTIwNTAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIwMjA1

NjcxPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMDIwNTY3MTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 50. Yet, resolution limits on PET scanning do not allow identifying small changes in Aβ accumulation in the preclinical stage that might be important for preventive or intervention strategies. Because of this, more studies are required to complement imaging data to accurately diagnose early stages of AD. Clinical trials and Immunotherapy in ADThere are clinical trials ongoing with molecules affecting the Aβ metabolism by either decreasing their production, inhibiting their aggregation or increasing the clearance PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYW5naWFsYXNjaGU8L0F1dGhvcj48WWVhcj4yMDEwPC9Z

ZWFyPjxSZWNOdW0+MzIxNzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJz

Y3JpcHQiPjEzLDE0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzIx

NzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUy

cHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1MzgzMDMwIj4zMjE3

PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8

L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5NYW5naWFsYXNjaGUsIEYu

PC9hdXRob3I+PGF1dGhvcj5Tb2xvbW9uLCBBLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48

L2F1dGhvcj48YXV0aG9yPk1lY29jY2ksIFAuPC9hdXRob3I+PGF1dGhvcj5LaXZpcGVsdG8sIE0u

PC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+QWdpbmcgUmVz

ZWFyY2ggQ2VudGVyLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVuLjwv

YXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogY2xp

bmljYWwgdHJpYWxzIGFuZCBkcnVnIGRldmVsb3BtZW50PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PkxhbmNldCBOZXVyb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NzAyLTE2PC9w

YWdlcz48dm9sdW1lPjk8L3ZvbHVtZT48bnVtYmVyPjc8L251bWJlcj48a2V5d29yZHM+PGtleXdv

cmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcgdGhlcmFweS9ldGlvbG9neS9wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+QW50aXBzeWNob3RpYyBBZ2VudHMvKnRoZXJhcGV1dGljIHVzZTwva2V5

d29yZD48a2V5d29yZD5DbGluaWNhbCBUcmlhbHMgYXMgVG9waWM8L2tleXdvcmQ+PGtleXdvcmQ+

KkRydWcgRGVzaWduPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48L2tleXdvcmRz

PjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVsPC9kYXRlPjwvcHVi

LWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ3NC00NDY1IChFbGVjdHJvbmljKSYjeEQ7MTQ3NC00NDIy

IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMDYxMDM0NjwvYWNjZXNzaW9uLW51bT48

dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMjA2MTAzNDY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjEwMTYvUzE0NzQtNDQyMigxMCk3MDExOS04PC9lbGVjdHJvbmljLXJlc291cmNl

LW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5TY2huZWlkZXI8L0F1dGhvcj48WWVh

cj4yMDE0PC9ZZWFyPjxSZWNOdW0+MzIxNjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MzIx

NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUy

cHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1MzgzMDMwIj4zMjE2

PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8

L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TY2huZWlkZXIsIEwuIFMu

PC9hdXRob3I+PGF1dGhvcj5NYW5naWFsYXNjaGUsIEYuPC9hdXRob3I+PGF1dGhvcj5BbmRyZWFz

ZW4sIE4uPC9hdXRob3I+PGF1dGhvcj5GZWxkbWFuLCBILjwvYXV0aG9yPjxhdXRob3I+R2lhY29i

aW5pLCBFLjwvYXV0aG9yPjxhdXRob3I+Sm9uZXMsIFIuPC9hdXRob3I+PGF1dGhvcj5NYW50dWEs

IFYuPC9hdXRob3I+PGF1dGhvcj5NZWNvY2NpLCBQLjwvYXV0aG9yPjxhdXRob3I+UGFuaSwgTC48

L2F1dGhvcj48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5LaXZpcGVsdG8sIE0u

PC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVu

dHMgb2YgUHN5Y2hpYXRyeSBhbmQgdGhlIEJlaGF2aW9yYWwgU2NpZW5jZXMsIGFuZCBOZXVyb2xv

Z3ksIEtlY2sgU2Nob29sIG9mIE1lZGljaW5lLCBMZW9uYXJkIERhdmlzIFNjaG9vbCBvZiBHZXJv

bnRvbG9neSBvZiB0aGUgVW5pdmVyc2l0eSBvZiBTb3V0aGVybiBDYWxpZm9ybmlhLCBMb3MgQW5n

ZWxlcywgQ0EsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5DbGluaWNhbCB0cmlh

bHMgYW5kIGxhdGUtc3RhZ2UgZHJ1ZyBkZXZlbG9wbWVudCBmb3IgQWx6aGVpbWVyJmFwb3M7cyBk

aXNlYXNlOiBhbiBhcHByYWlzYWwgZnJvbSAxOTg0IHRvIDIwMTQ8L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+SiBJbnRlcm4gTWVkPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+SiBJbnRlcm4gTWVkPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+

MjUxLTgzPC9wYWdlcz48dm9sdW1lPjI3NTwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxrZXl3

b3Jkcz48a2V5d29yZD4qQWx6aGVpbWVyIERpc2Vhc2UvY29tcGxpY2F0aW9ucy9kcnVnIHRoZXJh

cHkvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5CaW9tYXJrZXJzLyphbmFseXNpczwva2V5

d29yZD48a2V5d29yZD5DaG9saW5lc3RlcmFzZSBJbmhpYml0b3JzLyp0aGVyYXBldXRpYyB1c2U8

L2tleXdvcmQ+PGtleXdvcmQ+RG9wYW1pbmUgQWdlbnRzL3RoZXJhcGV1dGljIHVzZTwva2V5d29y

ZD48a2V5d29yZD5EcnVnIE1vbml0b3JpbmcvbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5IdW1h

bnM8L2tleXdvcmQ+PGtleXdvcmQ+TWVkaWNhdGlvbiBUaGVyYXB5IE1hbmFnZW1lbnQ8L2tleXdv

cmQ+PGtleXdvcmQ+TWVtYW50aW5lLyp0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+

TWVtb3J5IERpc29yZGVycy8qZHJ1ZyB0aGVyYXB5L2V0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

Pk5vb3Ryb3BpYyBBZ2VudHMvKnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5QcmFj

dGljZSBHdWlkZWxpbmVzIGFzIFRvcGljPC9rZXl3b3JkPjxrZXl3b3JkPlJhbmRvbWl6ZWQgQ29u

dHJvbGxlZCBUcmlhbHMgYXMgVG9waWM8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyPC9rZXl3

b3JkPjxrZXl3b3JkPmNsaW5pY2FsIHRyaWFsPC9rZXl3b3JkPjxrZXl3b3JkPmRlbWVudGlhPC9r

ZXl3b3JkPjxrZXl3b3JkPmRydWcgZGV2ZWxvcG1lbnQ8L2tleXdvcmQ+PGtleXdvcmQ+dHJlYXRt

ZW50PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT5NYXI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMzY1LTI3OTYgKEVs

ZWN0cm9uaWMpJiN4RDswOTU0LTY4MjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI0

NjA1ODA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3

dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNDYwNTgwODwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48Y3VzdG9tMj5QTUMzOTU2NzUyPC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4xMTExL2pvaW0uMTIxOTE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYW5naWFsYXNjaGU8L0F1dGhvcj48WWVhcj4yMDEwPC9Z

ZWFyPjxSZWNOdW0+MzIxNzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJz

Y3JpcHQiPjEzLDE0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzIx

NzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUy

cHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1MzgzMDMwIj4zMjE3

PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8

L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5NYW5naWFsYXNjaGUsIEYu

PC9hdXRob3I+PGF1dGhvcj5Tb2xvbW9uLCBBLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48

L2F1dGhvcj48YXV0aG9yPk1lY29jY2ksIFAuPC9hdXRob3I+PGF1dGhvcj5LaXZpcGVsdG8sIE0u

PC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+QWdpbmcgUmVz

ZWFyY2ggQ2VudGVyLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVuLjwv

YXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogY2xp

bmljYWwgdHJpYWxzIGFuZCBkcnVnIGRldmVsb3BtZW50PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PkxhbmNldCBOZXVyb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NzAyLTE2PC9w

YWdlcz48dm9sdW1lPjk8L3ZvbHVtZT48bnVtYmVyPjc8L251bWJlcj48a2V5d29yZHM+PGtleXdv

cmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcgdGhlcmFweS9ldGlvbG9neS9wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+QW50aXBzeWNob3RpYyBBZ2VudHMvKnRoZXJhcGV1dGljIHVzZTwva2V5

d29yZD48a2V5d29yZD5DbGluaWNhbCBUcmlhbHMgYXMgVG9waWM8L2tleXdvcmQ+PGtleXdvcmQ+

KkRydWcgRGVzaWduPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48L2tleXdvcmRz

PjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVsPC9kYXRlPjwvcHVi

LWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ3NC00NDY1IChFbGVjdHJvbmljKSYjeEQ7MTQ3NC00NDIy

IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMDYxMDM0NjwvYWNjZXNzaW9uLW51bT48

dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMjA2MTAzNDY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjEwMTYvUzE0NzQtNDQyMigxMCk3MDExOS04PC9lbGVjdHJvbmljLXJlc291cmNl

LW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5TY2huZWlkZXI8L0F1dGhvcj48WWVh

cj4yMDE0PC9ZZWFyPjxSZWNOdW0+MzIxNjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MzIx

NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUy

cHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1MzgzMDMwIj4zMjE2

PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8

L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TY2huZWlkZXIsIEwuIFMu

PC9hdXRob3I+PGF1dGhvcj5NYW5naWFsYXNjaGUsIEYuPC9hdXRob3I+PGF1dGhvcj5BbmRyZWFz

ZW4sIE4uPC9hdXRob3I+PGF1dGhvcj5GZWxkbWFuLCBILjwvYXV0aG9yPjxhdXRob3I+R2lhY29i

aW5pLCBFLjwvYXV0aG9yPjxhdXRob3I+Sm9uZXMsIFIuPC9hdXRob3I+PGF1dGhvcj5NYW50dWEs

IFYuPC9hdXRob3I+PGF1dGhvcj5NZWNvY2NpLCBQLjwvYXV0aG9yPjxhdXRob3I+UGFuaSwgTC48

L2F1dGhvcj48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5LaXZpcGVsdG8sIE0u

PC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVu

dHMgb2YgUHN5Y2hpYXRyeSBhbmQgdGhlIEJlaGF2aW9yYWwgU2NpZW5jZXMsIGFuZCBOZXVyb2xv

Z3ksIEtlY2sgU2Nob29sIG9mIE1lZGljaW5lLCBMZW9uYXJkIERhdmlzIFNjaG9vbCBvZiBHZXJv

bnRvbG9neSBvZiB0aGUgVW5pdmVyc2l0eSBvZiBTb3V0aGVybiBDYWxpZm9ybmlhLCBMb3MgQW5n

ZWxlcywgQ0EsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5DbGluaWNhbCB0cmlh

bHMgYW5kIGxhdGUtc3RhZ2UgZHJ1ZyBkZXZlbG9wbWVudCBmb3IgQWx6aGVpbWVyJmFwb3M7cyBk

aXNlYXNlOiBhbiBhcHByYWlzYWwgZnJvbSAxOTg0IHRvIDIwMTQ8L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+SiBJbnRlcm4gTWVkPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+SiBJbnRlcm4gTWVkPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+

MjUxLTgzPC9wYWdlcz48dm9sdW1lPjI3NTwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxrZXl3

b3Jkcz48a2V5d29yZD4qQWx6aGVpbWVyIERpc2Vhc2UvY29tcGxpY2F0aW9ucy9kcnVnIHRoZXJh

cHkvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5CaW9tYXJrZXJzLyphbmFseXNpczwva2V5

d29yZD48a2V5d29yZD5DaG9saW5lc3RlcmFzZSBJbmhpYml0b3JzLyp0aGVyYXBldXRpYyB1c2U8

L2tleXdvcmQ+PGtleXdvcmQ+RG9wYW1pbmUgQWdlbnRzL3RoZXJhcGV1dGljIHVzZTwva2V5d29y

ZD48a2V5d29yZD5EcnVnIE1vbml0b3JpbmcvbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5IdW1h

bnM8L2tleXdvcmQ+PGtleXdvcmQ+TWVkaWNhdGlvbiBUaGVyYXB5IE1hbmFnZW1lbnQ8L2tleXdv

cmQ+PGtleXdvcmQ+TWVtYW50aW5lLyp0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+

TWVtb3J5IERpc29yZGVycy8qZHJ1ZyB0aGVyYXB5L2V0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

Pk5vb3Ryb3BpYyBBZ2VudHMvKnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5QcmFj

dGljZSBHdWlkZWxpbmVzIGFzIFRvcGljPC9rZXl3b3JkPjxrZXl3b3JkPlJhbmRvbWl6ZWQgQ29u

dHJvbGxlZCBUcmlhbHMgYXMgVG9waWM8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyPC9rZXl3

b3JkPjxrZXl3b3JkPmNsaW5pY2FsIHRyaWFsPC9rZXl3b3JkPjxrZXl3b3JkPmRlbWVudGlhPC9r

ZXl3b3JkPjxrZXl3b3JkPmRydWcgZGV2ZWxvcG1lbnQ8L2tleXdvcmQ+PGtleXdvcmQ+dHJlYXRt

ZW50PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT5NYXI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMzY1LTI3OTYgKEVs

ZWN0cm9uaWMpJiN4RDswOTU0LTY4MjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI0

NjA1ODA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3

dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNDYwNTgwODwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48Y3VzdG9tMj5QTUMzOTU2NzUyPC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4xMTExL2pvaW0uMTIxOTE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 13,14. Ongoing studies in the field of amyloid-related approaches are clearing out the Aβ monomers, forming dimers, pentamers, oligomers, fibrils, diffuse plaques and senile plaques using antibody therapies. Some antibodies such as aducanumab, even reduce the senile plaques ADDIN EN.CITE <EndNote><Cite><Author>Budd Haeberlein</Author><Year>2017</Year><RecNum>2026</RecNum><DisplayText><style face="superscript">57</style></DisplayText><record><rec-number>2026</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1534510285">2026</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Budd Haeberlein, S.</author><author>O&apos;Gorman, J.</author><author>Chiao, P.</author><author>Bussiere, T.</author><author>von Rosenstiel, P.</author><author>Tian, Y.</author><author>Zhu, Y.</author><author>von Hehn, C.</author><author>Gheuens, S.</author><author>Skordos, L.</author><author>Chen, T.</author><author>Sandrock, A.</author></authors></contributors><auth-address>Samantha Budd Haeberlein, Cambridge, 225 Binney Street, Cambridge, MA 02142, USA, Email: samantha.buddhaeberlein@, Telephone: (617) 679-2000.</auth-address><titles><title>Clinical Development of Aducanumab, an Anti-Abeta Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer&apos;s Disease</title><secondary-title>J Prev Alzheimers Dis</secondary-title></titles><periodical><full-title>J Prev Alzheimers Dis</full-title></periodical><pages>255-263</pages><volume>4</volume><number>4</number><edition>2017/11/29</edition><keywords><keyword>*Alzheimer&apos;s disease</keyword><keyword>*aducanumab</keyword><keyword>*amyloid-beta</keyword><keyword>Biogen</keyword><keyword>TB: employee and stock ownership, patent holder, Biogen.</keyword></keywords><dates><year>2017</year></dates><isbn>2426-0266 (Electronic)&#xD;2274-5807 (Linking)</isbn><accession-num>29181491</accession-num><urls><related-urls><url>. Since 2013, many trials have been withdrawn due to lack of effects, most notably the anti-amyloid antibody solanezumab PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib25pZzwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl

Y051bT4yMDg0PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NTg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDg0PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NjIyMDUiPjIwODQ8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhvbmlnLCBMLiBTLjwvYXV0aG9yPjxhdXRo

b3I+VmVsbGFzLCBCLjwvYXV0aG9yPjxhdXRob3I+V29vZHdhcmQsIE0uPC9hdXRob3I+PGF1dGhv

cj5Cb2FkYSwgTS48L2F1dGhvcj48YXV0aG9yPkJ1bGxvY2ssIFIuPC9hdXRob3I+PGF1dGhvcj5C

b3JyaWUsIE0uPC9hdXRob3I+PGF1dGhvcj5IYWdlciwgSy48L2F1dGhvcj48YXV0aG9yPkFuZHJl

YXNlbiwgTi48L2F1dGhvcj48YXV0aG9yPlNjYXJwaW5pLCBFLjwvYXV0aG9yPjxhdXRob3I+TGl1

LVNlaWZlcnQsIEguPC9hdXRob3I+PGF1dGhvcj5DYXNlLCBNLjwvYXV0aG9yPjxhdXRob3I+RGVh

biwgUi4gQS48L2F1dGhvcj48YXV0aG9yPkhha2UsIEEuPC9hdXRob3I+PGF1dGhvcj5TdW5kZWxs

LCBLLjwvYXV0aG9yPjxhdXRob3I+UG9vbGUgSG9mZm1hbm4sIFYuPC9hdXRob3I+PGF1dGhvcj5D

YXJsc29uLCBDLjwvYXV0aG9yPjxhdXRob3I+S2hhbm5hLCBSLjwvYXV0aG9yPjxhdXRob3I+TWlu

dHVuLCBNLjwvYXV0aG9yPjxhdXRob3I+RGVNYXR0b3MsIFIuPC9hdXRob3I+PGF1dGhvcj5TZWx6

bGVyLCBLLiBKLjwvYXV0aG9yPjxhdXRob3I+U2llbWVycywgRS48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Gcm9tIHRoZSBEZXBhcnRtZW50IG9mIE5ldXJv

bG9neSBhbmQgVGF1YiBJbnN0aXR1dGUgZm9yIFJlc2VhcmNoIG9uIEFsemhlaW1lciZhcG9zO3Mg

RGlzZWFzZSBhbmQgdGhlIEFnaW5nIEJyYWluLCBDb2x1bWJpYSBVbml2ZXJzaXR5IE1lZGljYWwg

Q2VudGVyLCBOZXcgWW9yayAoTC5TLkguKTsgR2Vyb250b3BvbGUsIENlbnRyZSBIb3NwaXRhbGll

ciBVbml2ZXJzaXRhaXJlIFRvdWxvdXNlLCBVbml0ZSBNaXh0ZSBkZSBSZWNoZXJjaGUgSU5TRVJN

IFVuaXRlIDEwMjcgVW5pdmVyc2l0ZSBUb3Vsb3VzZSBJSUktUGF1bCBTYWJhdGllciwgVG91bG91

c2UsIEZyYW5jZSAoQi5WLik7IEF1c3RpbiBIZWFsdGggQ29udGludWluZyBDYXJlIENsaW5pY2Fs

IFNlcnZpY2UgVW5pdCwgSGVpZGVsYmVyZywgYW5kIHRoZSBVbml2ZXJzaXR5IG9mIE1lbGJvdXJu

ZSwgTWVsYm91cm5lLCBWSUMgLSBib3RoIGluIEF1c3RyYWxpYSAoTS5XLik7IEZ1bmRhY2lvIEFD

RSwgQWx6aGVpbWVyIFJlc2VhcmNoIENlbnRlciBhbmQgTWVtb3J5IENsaW5pYywgSW5zdGl0dXQg

Q2F0YWxhIGRlIE5ldXJvY2llbmNpZXMgQXBsaWNhZGVzLCBCYXJjZWxvbmEgKE0uIEJvYWRhKTsg

S2luZ3NoaWxsIFJlc2VhcmNoIENlbnRyZSwgVmljdG9yaWEgSG9zcGl0YWwsIFN3aW5kb24sIFVu

aXRlZCBLaW5nZG9tIChSLkIuKTsgdGhlIERpdmlzaW9uIG9mIEdlcmlhdHJpYyBNZWRpY2luZSwg

U2NodWxpY2ggU2Nob29sIG9mIE1lZGljaW5lIGFuZCBEZW50aXN0cnksIFdlc3Rlcm4gVW5pdmVy

c2l0eSwgTG9uZG9uLCBPTiwgQ2FuYWRhIChNLiBCb3JyaWUpOyBDbGluaWMgZm9yIE1lZGljaW5l

IG9mIHRoZSBFbGRlcmx5LCBEaWFrb3ZlcmUgSGVucmlldHRlbnN0aWZ0LCBIYW5ub3ZlciwgR2Vy

bWFueSAoSy5ILik7IEthcm9saW5za2EgSW5zdGl0dXRldCBBbHpoZWltZXImYXBvcztzIERpc2Vh

c2UgUmVzZWFyY2ggQ2VudGVyIGFuZCBDbGluaWNhbCBUcmlhbCBVbml0LCBHZXJpYXRyaWMgQ2xp

bmljLCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCBTd2VkZW4gKE4u

QS4pOyB0aGUgRGVwYXJ0bWVudCBvZiBQYXRob3BoeXNpb2xvZ3kgYW5kIFRyYW5zcGxhbnRhdGlv

biwgTmV1cm9sb2d5IFVuaXQsIERpbm8gRmVycmFyaSBDZW50ZXIsIFVuaXZlcnNpdHkgb2YgTWls

YW4sIEZvbmRhemlvbmUgQ2EmYXBvczsgR3JhbmRhLCBJc3RpdHV0byBkaSBSaWNvdmVybyBlIEN1

cmEgYSBDYXJhdHRlcmUgU2NpZW50aWZpY28gT3NwZWRhbGUgUG9saWNsaW5pY28sIE1pbGFuIChF

LiBTY2FycGluaSk7IEVsaSBMaWxseSAoSC5MLi1TLiwgTS5DLiwgQS5ILiwgSy5TLiwgVi5QLkgu

LCBDLkMuLCBSLksuLCBNLk0uLCBSLkQuLCBLLkouUy4sIEUuIFNpZW1lcnMpIGFuZCB0aGUgRGVw

YXJ0bWVudCBvZiBQYXRob2xvZ3kgYW5kIExhYm9yYXRvcnkgTWVkaWNpbmUsIEluZGlhbmEgVW5p

dmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUgKFIuQS5ELikgLSBib3RoIGluIEluZGlhbmFwb2xp

czsgYW5kIEF2aWQgUmFkaW9waGFybWFjZXV0aWNhbHMsIFBoaWxhZGVscGhpYSAoTS5NLikuPC9h

dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VHJpYWwgb2YgU29sYW5lenVtYWIgZm9yIE1pbGQg

RGVtZW50aWEgRHVlIHRvIEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZTwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5OIEVuZ2wgSiBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MzIx

LTMzMDwvcGFnZXM+PHZvbHVtZT4zNzg8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZWRpdGlv

bj4yMDE4LzAxLzI1PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BY3Rpdml0aWVzIG9mIERh

aWx5IExpdmluZzwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQs

IDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2RpYWdub3Np

cy8qZHJ1ZyB0aGVyYXB5L3BzeWNob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRh

LVBlcHRpZGVzL2NlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJvZGll

cywgTW9ub2Nsb25hbCwgSHVtYW5pemVkL2FkdmVyc2UgZWZmZWN0cy8qdGhlcmFwZXV0aWMgdXNl

PC9rZXl3b3JkPjxrZXl3b3JkPkJpb21hcmtlcnMvY2VyZWJyb3NwaW5hbCBmbHVpZDwva2V5d29y

ZD48a2V5d29yZD5Eb3VibGUtQmxpbmQgTWV0aG9kPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwv

a2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+KkltbXVub3RoZXJhcHk8

L2tleXdvcmQ+PGtleXdvcmQ+SW5mdXNpb25zLCBJbnRyYXZlbm91czwva2V5d29yZD48a2V5d29y

ZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbnRhbCBTdGF0dXMgYW5kIERlbWVudGlhIFRlc3Rz

PC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBlcHRpZGUg

RnJhZ21lbnRzL2NlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+UGxhcXVlLCBB

bXlsb2lkL2RydWcgdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Qb3NpdHJvbi1FbWlzc2lvbiBU

b21vZ3JhcGh5PC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBGYWlsdXJlPC9rZXl3b3JkPjwv

a2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KYW4gMjU8

L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTMzLTQ0MDYgKEVsZWN0cm9uaWMpJiN4

RDswMDI4LTQ3OTMgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5MzY1Mjk0PC9hY2Nl

c3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5u

aWguZ292L3B1Ym1lZC8yOTM2NTI5NDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTA1Ni9ORUpNb2ExNzA1OTcxPC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib25pZzwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl

Y051bT4yMDg0PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NTg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDg0PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NjIyMDUiPjIwODQ8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhvbmlnLCBMLiBTLjwvYXV0aG9yPjxhdXRo

b3I+VmVsbGFzLCBCLjwvYXV0aG9yPjxhdXRob3I+V29vZHdhcmQsIE0uPC9hdXRob3I+PGF1dGhv

cj5Cb2FkYSwgTS48L2F1dGhvcj48YXV0aG9yPkJ1bGxvY2ssIFIuPC9hdXRob3I+PGF1dGhvcj5C

b3JyaWUsIE0uPC9hdXRob3I+PGF1dGhvcj5IYWdlciwgSy48L2F1dGhvcj48YXV0aG9yPkFuZHJl

YXNlbiwgTi48L2F1dGhvcj48YXV0aG9yPlNjYXJwaW5pLCBFLjwvYXV0aG9yPjxhdXRob3I+TGl1

LVNlaWZlcnQsIEguPC9hdXRob3I+PGF1dGhvcj5DYXNlLCBNLjwvYXV0aG9yPjxhdXRob3I+RGVh

biwgUi4gQS48L2F1dGhvcj48YXV0aG9yPkhha2UsIEEuPC9hdXRob3I+PGF1dGhvcj5TdW5kZWxs

LCBLLjwvYXV0aG9yPjxhdXRob3I+UG9vbGUgSG9mZm1hbm4sIFYuPC9hdXRob3I+PGF1dGhvcj5D

YXJsc29uLCBDLjwvYXV0aG9yPjxhdXRob3I+S2hhbm5hLCBSLjwvYXV0aG9yPjxhdXRob3I+TWlu

dHVuLCBNLjwvYXV0aG9yPjxhdXRob3I+RGVNYXR0b3MsIFIuPC9hdXRob3I+PGF1dGhvcj5TZWx6

bGVyLCBLLiBKLjwvYXV0aG9yPjxhdXRob3I+U2llbWVycywgRS48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Gcm9tIHRoZSBEZXBhcnRtZW50IG9mIE5ldXJv

bG9neSBhbmQgVGF1YiBJbnN0aXR1dGUgZm9yIFJlc2VhcmNoIG9uIEFsemhlaW1lciZhcG9zO3Mg

RGlzZWFzZSBhbmQgdGhlIEFnaW5nIEJyYWluLCBDb2x1bWJpYSBVbml2ZXJzaXR5IE1lZGljYWwg

Q2VudGVyLCBOZXcgWW9yayAoTC5TLkguKTsgR2Vyb250b3BvbGUsIENlbnRyZSBIb3NwaXRhbGll

ciBVbml2ZXJzaXRhaXJlIFRvdWxvdXNlLCBVbml0ZSBNaXh0ZSBkZSBSZWNoZXJjaGUgSU5TRVJN

IFVuaXRlIDEwMjcgVW5pdmVyc2l0ZSBUb3Vsb3VzZSBJSUktUGF1bCBTYWJhdGllciwgVG91bG91

c2UsIEZyYW5jZSAoQi5WLik7IEF1c3RpbiBIZWFsdGggQ29udGludWluZyBDYXJlIENsaW5pY2Fs

IFNlcnZpY2UgVW5pdCwgSGVpZGVsYmVyZywgYW5kIHRoZSBVbml2ZXJzaXR5IG9mIE1lbGJvdXJu

ZSwgTWVsYm91cm5lLCBWSUMgLSBib3RoIGluIEF1c3RyYWxpYSAoTS5XLik7IEZ1bmRhY2lvIEFD

RSwgQWx6aGVpbWVyIFJlc2VhcmNoIENlbnRlciBhbmQgTWVtb3J5IENsaW5pYywgSW5zdGl0dXQg

Q2F0YWxhIGRlIE5ldXJvY2llbmNpZXMgQXBsaWNhZGVzLCBCYXJjZWxvbmEgKE0uIEJvYWRhKTsg

S2luZ3NoaWxsIFJlc2VhcmNoIENlbnRyZSwgVmljdG9yaWEgSG9zcGl0YWwsIFN3aW5kb24sIFVu

aXRlZCBLaW5nZG9tIChSLkIuKTsgdGhlIERpdmlzaW9uIG9mIEdlcmlhdHJpYyBNZWRpY2luZSwg

U2NodWxpY2ggU2Nob29sIG9mIE1lZGljaW5lIGFuZCBEZW50aXN0cnksIFdlc3Rlcm4gVW5pdmVy

c2l0eSwgTG9uZG9uLCBPTiwgQ2FuYWRhIChNLiBCb3JyaWUpOyBDbGluaWMgZm9yIE1lZGljaW5l

IG9mIHRoZSBFbGRlcmx5LCBEaWFrb3ZlcmUgSGVucmlldHRlbnN0aWZ0LCBIYW5ub3ZlciwgR2Vy

bWFueSAoSy5ILik7IEthcm9saW5za2EgSW5zdGl0dXRldCBBbHpoZWltZXImYXBvcztzIERpc2Vh

c2UgUmVzZWFyY2ggQ2VudGVyIGFuZCBDbGluaWNhbCBUcmlhbCBVbml0LCBHZXJpYXRyaWMgQ2xp

bmljLCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCBTd2VkZW4gKE4u

QS4pOyB0aGUgRGVwYXJ0bWVudCBvZiBQYXRob3BoeXNpb2xvZ3kgYW5kIFRyYW5zcGxhbnRhdGlv

biwgTmV1cm9sb2d5IFVuaXQsIERpbm8gRmVycmFyaSBDZW50ZXIsIFVuaXZlcnNpdHkgb2YgTWls

YW4sIEZvbmRhemlvbmUgQ2EmYXBvczsgR3JhbmRhLCBJc3RpdHV0byBkaSBSaWNvdmVybyBlIEN1

cmEgYSBDYXJhdHRlcmUgU2NpZW50aWZpY28gT3NwZWRhbGUgUG9saWNsaW5pY28sIE1pbGFuIChF

LiBTY2FycGluaSk7IEVsaSBMaWxseSAoSC5MLi1TLiwgTS5DLiwgQS5ILiwgSy5TLiwgVi5QLkgu

LCBDLkMuLCBSLksuLCBNLk0uLCBSLkQuLCBLLkouUy4sIEUuIFNpZW1lcnMpIGFuZCB0aGUgRGVw

YXJ0bWVudCBvZiBQYXRob2xvZ3kgYW5kIExhYm9yYXRvcnkgTWVkaWNpbmUsIEluZGlhbmEgVW5p

dmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUgKFIuQS5ELikgLSBib3RoIGluIEluZGlhbmFwb2xp

czsgYW5kIEF2aWQgUmFkaW9waGFybWFjZXV0aWNhbHMsIFBoaWxhZGVscGhpYSAoTS5NLikuPC9h

dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VHJpYWwgb2YgU29sYW5lenVtYWIgZm9yIE1pbGQg

RGVtZW50aWEgRHVlIHRvIEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZTwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5OIEVuZ2wgSiBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MzIx

LTMzMDwvcGFnZXM+PHZvbHVtZT4zNzg8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZWRpdGlv

bj4yMDE4LzAxLzI1PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BY3Rpdml0aWVzIG9mIERh

aWx5IExpdmluZzwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQs

IDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2RpYWdub3Np

cy8qZHJ1ZyB0aGVyYXB5L3BzeWNob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRh

LVBlcHRpZGVzL2NlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJvZGll

cywgTW9ub2Nsb25hbCwgSHVtYW5pemVkL2FkdmVyc2UgZWZmZWN0cy8qdGhlcmFwZXV0aWMgdXNl

PC9rZXl3b3JkPjxrZXl3b3JkPkJpb21hcmtlcnMvY2VyZWJyb3NwaW5hbCBmbHVpZDwva2V5d29y

ZD48a2V5d29yZD5Eb3VibGUtQmxpbmQgTWV0aG9kPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwv

a2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+KkltbXVub3RoZXJhcHk8

L2tleXdvcmQ+PGtleXdvcmQ+SW5mdXNpb25zLCBJbnRyYXZlbm91czwva2V5d29yZD48a2V5d29y

ZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbnRhbCBTdGF0dXMgYW5kIERlbWVudGlhIFRlc3Rz

PC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBlcHRpZGUg

RnJhZ21lbnRzL2NlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+UGxhcXVlLCBB

bXlsb2lkL2RydWcgdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Qb3NpdHJvbi1FbWlzc2lvbiBU

b21vZ3JhcGh5PC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBGYWlsdXJlPC9rZXl3b3JkPjwv

a2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KYW4gMjU8

L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTMzLTQ0MDYgKEVsZWN0cm9uaWMpJiN4

RDswMDI4LTQ3OTMgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5MzY1Mjk0PC9hY2Nl

c3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5u

aWguZ292L3B1Ym1lZC8yOTM2NTI5NDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTA1Ni9ORUpNb2ExNzA1OTcxPC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 58 and the BACE1 inhibitor verubecestat PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FZ2FuPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj

TnVtPjIwODU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij41

OTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjIwODU8L3JlYy1udW1i

ZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBo

cGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDg2MjQ3OSI+MjA4NTwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RWdhbiwgTS4gRi48L2F1dGhvcj48YXV0aG9y

Pktvc3QsIEouPC9hdXRob3I+PGF1dGhvcj5UYXJpb3QsIFAuIE4uPC9hdXRob3I+PGF1dGhvcj5B

aXNlbiwgUC4gUy48L2F1dGhvcj48YXV0aG9yPkN1bW1pbmdzLCBKLiBMLjwvYXV0aG9yPjxhdXRo

b3I+VmVsbGFzLCBCLjwvYXV0aG9yPjxhdXRob3I+U3VyLCBDLjwvYXV0aG9yPjxhdXRob3I+TXVr

YWksIFkuPC9hdXRob3I+PGF1dGhvcj5Wb3NzLCBULjwvYXV0aG9yPjxhdXRob3I+RnVydGVrLCBD

LjwvYXV0aG9yPjxhdXRob3I+TWFob25leSwgRS48L2F1dGhvcj48YXV0aG9yPkhhcnBlciBNb3ps

ZXksIEwuPC9hdXRob3I+PGF1dGhvcj5WYW5kZW5iZXJnaGUsIFIuPC9hdXRob3I+PGF1dGhvcj5N

bywgWS48L2F1dGhvcj48YXV0aG9yPk1pY2hlbHNvbiwgRC48L2F1dGhvcj48L2F1dGhvcnM+PC9j

b250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Gcm9tIE1lcmNrIFJlc2VhcmNoIExhYm9yYXRvcmll

cywgTWVyY2ssIEtlbmlsd29ydGgsIE5KIChNLkYuRS4sIEouSy4sIEMuUy4sIFkuIE11a2FpLCBU

LlYuLCBDLkYuLCBFLk0uLCBMLkguTS4sIFkuIE1vLCBELk0uKTsgQmFubmVyIEFsemhlaW1lciZh

cG9zO3MgSW5zdGl0dXRlLCBQaG9lbml4LCBBWiAoUC5OLlQuKTsgVW5pdmVyc2l0eSBvZiBTb3V0

aGVybiBDYWxpZm9ybmlhLCBTYW4gRGllZ28gKFAuUy5BLik7IENsZXZlbGFuZCBDbGluaWMgTG91

IFJ1dm8gQ2VudGVyIGZvciBCcmFpbiBIZWFsdGgsIExhcyBWZWdhcyAoSi5MLkMuKTsgR2Vyb250

b3BvbGUsIElOU0VSTSBVbml0ZSAxMDI3LCBBbHpoZWltZXImYXBvcztzIERpc2Vhc2UgUmVzZWFy

Y2ggYW5kIENsaW5pY2FsIENlbnRlciwgVG91bG91c2UgVW5pdmVyc2l0eSBIb3NwaXRhbCwgVG91

bG91c2UsIEZyYW5jZSAoQi5WLik7IGFuZCBMZXV2ZW4gSW5zdGl0dXRlIG9mIE5ldXJvc2NpZW5j

ZSBhbmQgRGlzZWFzZSwgQWx6aGVpbWVyIFJlc2VhcmNoIENlbnRlciwgYW5kIHRoZSBMYWJvcmF0

b3J5IGZvciBDb2duaXRpdmUgTmV1cm9sb2d5LCBEZXBhcnRtZW50IG9mIE5ldXJvc2NpZW5jZXMs

IEthdGhvbGlla2UgVW5pdmVyc2l0ZWl0IExldXZlbiwgYW5kIE5ldXJvbG9neSwgVW5pdmVyc2l0

eSBIb3NwaXRhbHMgLSBib3RoIGluIExldXZlbiwgQmVsZ2l1bSAoUi5WLikuPC9hdXRoLWFkZHJl

c3M+PHRpdGxlcz48dGl0bGU+UmFuZG9taXplZCBUcmlhbCBvZiBWZXJ1YmVjZXN0YXQgZm9yIE1p

bGQtdG8tTW9kZXJhdGUgQWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPk4gRW5nbCBKIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xNjkx

LTE3MDM8L3BhZ2VzPjx2b2x1bWU+Mzc4PC92b2x1bWU+PG51bWJlcj4xODwvbnVtYmVyPjxlZGl0

aW9uPjIwMTgvMDUvMDM8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFjdGl2aXRpZXMgb2Yg

RGFpbHkgTGl2aW5nPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdl

ZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweS9wc3ljaG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgUHJlY3Vyc29yIFBy

b3RlaW4gU2VjcmV0YXNlcy8qYW50YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9yczwva2V5d29yZD48

a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvYW5hbHlzaXMvY2VyZWJyb3NwaW5hbCBmbHVp

ZDwva2V5d29yZD48a2V5d29yZD5Bc3BhcnRpYyBBY2lkIEVuZG9wZXB0aWRhc2VzLyphbnRhZ29u

aXN0cyAmYW1wOyBpbmhpYml0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPkJpb21hcmtlcnMvY2VyZWJy

b3NwaW5hbCBmbHVpZDwva2V5d29yZD48a2V5d29yZD5CcmFpbiBDaGVtaXN0cnkvZHJ1ZyBlZmZl

Y3RzPC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtl

eXdvcmQ+Q3ljbGljIFMtT3hpZGVzL2FkdmVyc2UgZWZmZWN0cy8qdGhlcmFwZXV0aWMgdXNlPC9r

ZXl3b3JkPjxrZXl3b3JkPkRvc2UtUmVzcG9uc2UgUmVsYXRpb25zaGlwLCBEcnVnPC9rZXl3b3Jk

PjxrZXl3b3JkPkRvdWJsZS1CbGluZCBNZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9r

ZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxr

ZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvcHN5Y2hvbG9naWNhbCBU

ZXN0czwva2V5d29yZD48a2V5d29yZD5UaGlhZGlhemluZXMvYWR2ZXJzZSBlZmZlY3RzLyp0aGVy

YXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+VHJlYXRtZW50IEZhaWx1cmU8L2tleXdvcmQ+

PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxODwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1heSAz

PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUzMy00NDA2IChFbGVjdHJvbmljKSYj

eEQ7MDAyOC00NzkzIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yOTcxOTE3OTwvYWNj

ZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMjk3MTkxNzk8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwNTYvTkVKTW9hMTcwNjQ0MTwvZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FZ2FuPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj

TnVtPjIwODU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij41

OTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjIwODU8L3JlYy1udW1i

ZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBo

cGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDg2MjQ3OSI+MjA4NTwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RWdhbiwgTS4gRi48L2F1dGhvcj48YXV0aG9y

Pktvc3QsIEouPC9hdXRob3I+PGF1dGhvcj5UYXJpb3QsIFAuIE4uPC9hdXRob3I+PGF1dGhvcj5B

aXNlbiwgUC4gUy48L2F1dGhvcj48YXV0aG9yPkN1bW1pbmdzLCBKLiBMLjwvYXV0aG9yPjxhdXRo

b3I+VmVsbGFzLCBCLjwvYXV0aG9yPjxhdXRob3I+U3VyLCBDLjwvYXV0aG9yPjxhdXRob3I+TXVr

YWksIFkuPC9hdXRob3I+PGF1dGhvcj5Wb3NzLCBULjwvYXV0aG9yPjxhdXRob3I+RnVydGVrLCBD

LjwvYXV0aG9yPjxhdXRob3I+TWFob25leSwgRS48L2F1dGhvcj48YXV0aG9yPkhhcnBlciBNb3ps

ZXksIEwuPC9hdXRob3I+PGF1dGhvcj5WYW5kZW5iZXJnaGUsIFIuPC9hdXRob3I+PGF1dGhvcj5N

bywgWS48L2F1dGhvcj48YXV0aG9yPk1pY2hlbHNvbiwgRC48L2F1dGhvcj48L2F1dGhvcnM+PC9j

b250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Gcm9tIE1lcmNrIFJlc2VhcmNoIExhYm9yYXRvcmll

cywgTWVyY2ssIEtlbmlsd29ydGgsIE5KIChNLkYuRS4sIEouSy4sIEMuUy4sIFkuIE11a2FpLCBU

LlYuLCBDLkYuLCBFLk0uLCBMLkguTS4sIFkuIE1vLCBELk0uKTsgQmFubmVyIEFsemhlaW1lciZh

cG9zO3MgSW5zdGl0dXRlLCBQaG9lbml4LCBBWiAoUC5OLlQuKTsgVW5pdmVyc2l0eSBvZiBTb3V0

aGVybiBDYWxpZm9ybmlhLCBTYW4gRGllZ28gKFAuUy5BLik7IENsZXZlbGFuZCBDbGluaWMgTG91

IFJ1dm8gQ2VudGVyIGZvciBCcmFpbiBIZWFsdGgsIExhcyBWZWdhcyAoSi5MLkMuKTsgR2Vyb250

b3BvbGUsIElOU0VSTSBVbml0ZSAxMDI3LCBBbHpoZWltZXImYXBvcztzIERpc2Vhc2UgUmVzZWFy

Y2ggYW5kIENsaW5pY2FsIENlbnRlciwgVG91bG91c2UgVW5pdmVyc2l0eSBIb3NwaXRhbCwgVG91

bG91c2UsIEZyYW5jZSAoQi5WLik7IGFuZCBMZXV2ZW4gSW5zdGl0dXRlIG9mIE5ldXJvc2NpZW5j

ZSBhbmQgRGlzZWFzZSwgQWx6aGVpbWVyIFJlc2VhcmNoIENlbnRlciwgYW5kIHRoZSBMYWJvcmF0

b3J5IGZvciBDb2duaXRpdmUgTmV1cm9sb2d5LCBEZXBhcnRtZW50IG9mIE5ldXJvc2NpZW5jZXMs

IEthdGhvbGlla2UgVW5pdmVyc2l0ZWl0IExldXZlbiwgYW5kIE5ldXJvbG9neSwgVW5pdmVyc2l0

eSBIb3NwaXRhbHMgLSBib3RoIGluIExldXZlbiwgQmVsZ2l1bSAoUi5WLikuPC9hdXRoLWFkZHJl

c3M+PHRpdGxlcz48dGl0bGU+UmFuZG9taXplZCBUcmlhbCBvZiBWZXJ1YmVjZXN0YXQgZm9yIE1p

bGQtdG8tTW9kZXJhdGUgQWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPk4gRW5nbCBKIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xNjkx

LTE3MDM8L3BhZ2VzPjx2b2x1bWU+Mzc4PC92b2x1bWU+PG51bWJlcj4xODwvbnVtYmVyPjxlZGl0

aW9uPjIwMTgvMDUvMDM8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFjdGl2aXRpZXMgb2Yg

RGFpbHkgTGl2aW5nPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdl

ZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweS9wc3ljaG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgUHJlY3Vyc29yIFBy

b3RlaW4gU2VjcmV0YXNlcy8qYW50YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9yczwva2V5d29yZD48

a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvYW5hbHlzaXMvY2VyZWJyb3NwaW5hbCBmbHVp

ZDwva2V5d29yZD48a2V5d29yZD5Bc3BhcnRpYyBBY2lkIEVuZG9wZXB0aWRhc2VzLyphbnRhZ29u

aXN0cyAmYW1wOyBpbmhpYml0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPkJpb21hcmtlcnMvY2VyZWJy

b3NwaW5hbCBmbHVpZDwva2V5d29yZD48a2V5d29yZD5CcmFpbiBDaGVtaXN0cnkvZHJ1ZyBlZmZl

Y3RzPC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtl

eXdvcmQ+Q3ljbGljIFMtT3hpZGVzL2FkdmVyc2UgZWZmZWN0cy8qdGhlcmFwZXV0aWMgdXNlPC9r

ZXl3b3JkPjxrZXl3b3JkPkRvc2UtUmVzcG9uc2UgUmVsYXRpb25zaGlwLCBEcnVnPC9rZXl3b3Jk

PjxrZXl3b3JkPkRvdWJsZS1CbGluZCBNZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9r

ZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxr

ZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvcHN5Y2hvbG9naWNhbCBU

ZXN0czwva2V5d29yZD48a2V5d29yZD5UaGlhZGlhemluZXMvYWR2ZXJzZSBlZmZlY3RzLyp0aGVy

YXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+VHJlYXRtZW50IEZhaWx1cmU8L2tleXdvcmQ+

PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxODwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1heSAz

PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUzMy00NDA2IChFbGVjdHJvbmljKSYj

eEQ7MDAyOC00NzkzIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yOTcxOTE3OTwvYWNj

ZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMjk3MTkxNzk8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwNTYvTkVKTW9hMTcwNjQ0MTwvZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 59. The negative outcome in these trials has led to an extensive revision of the amyloid cascade hypothesis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdWxpc2FubzwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+

PFJlY051bT4yMDkzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MTYsMTksNjAsNjE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4y

MDkzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4

NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NjMzNTIiPjIw

OTM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x

NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkd1bGlzYW5vLCBXLjwv

YXV0aG9yPjxhdXRob3I+TWF1Z2VyaSwgRC48L2F1dGhvcj48YXV0aG9yPkJhbHRyb25zLCBNLiBB

LjwvYXV0aG9yPjxhdXRob3I+RmEsIE0uPC9hdXRob3I+PGF1dGhvcj5BbWF0bywgQS48L2F1dGhv

cj48YXV0aG9yPlBhbG1lcmksIEEuPC9hdXRob3I+PGF1dGhvcj5EJmFwb3M7QWRhbWlvLCBMLjwv

YXV0aG9yPjxhdXRob3I+R3Jhc3NpLCBDLjwvYXV0aG9yPjxhdXRob3I+RGV2YW5hbmQsIEQuIFAu

PC9hdXRob3I+PGF1dGhvcj5Ib25pZywgTC4gUy48L2F1dGhvcj48YXV0aG9yPlB1enpvLCBELjwv

YXV0aG9yPjxhdXRob3I+QXJhbmNpbywgTy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIEJpb21lZGljYWwgYW5kIEJpb3RlY2hub2xv

Z2ljYWwgU2NpZW5jZXMsIFNlY3Rpb24gb2YgUGh5c2lvbG9neSwgVW5pdmVyc2l0eSBvZiBDYXRh

bmlhLCBDYXRhbmlhLCBJdGFseS4mI3hEO1RhdWIgSW5zdGl0dXRlIGZvciBSZXNlYXJjaCBvbiBB

bHpoZWltZXImYXBvcztzIERpc2Vhc2UgYW5kIHRoZSBBZ2luZyBCcmFpbiwgQ29sdW1iaWEgVW5p

dmVyc2l0eSwgTmV3IFlvcmssIE5ZLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIEJpb2NoZW1pc3Ry

eSBhbmQgTW9sZWN1bGFyIEJpb2xvZ3kgYW5kIEluc3RpdHV0ZSBvZiBCaW90ZWNobm9sb2d5IGFu

ZCBCaW9tZWRpY2luZSwgVW5pdmVyc2l0YXQgQXV0b25vbWEgZGUgQmFyY2Vsb25hLCBCZWxsYXRl

cnJhLCBTcGFpbi4mI3hEO0RlcGFydG1lbnQgb2YgQW5hZXN0aGVzaW9sb2d5LCBVbml2ZXJzaXRh

IENhdHRvbGljYSBkZWwgU2Fjcm8gQ3VvcmUsIFJvbWUsIEl0YWx5LiYjeEQ7RGVwYXJ0bWVudCBv

ZiBQaGFybWFjb2xvZ3ksIFBoeXNpb2xvZ3kgYW5kIE5ldXJvc2NpZW5jZSwgUnV0Z2VycyBVbml2

ZXJzaXR5LCBOZXdhcmssIE5KLCBVU0EuJiN4RDtJbnN0aXR1dGUgb2YgSHVtYW4gUGh5c2lvbG9n

eSwgVW5pdmVyc2l0YSBDYXR0b2xpY2EgZGVsIFNhY3JvIEN1b3JlLCBSb21lLCBJdGFseS4mI3hE

O0RlcGFydG1lbnQgb2YgUHN5Y2hpYXRyeSwgQ29sdW1iaWEgVW5pdmVyc2l0eSBDb2xsZWdlIG9m

IFBoeXNpY2lhbnMgYW5kIFN1cmdlb25zLCBOZXcgWW9yaywgTlksIFVTQS4mI3hEO0RlcGFydG1l

bnQgb2YgTmV1cm9sb2d5LCBDb2x1bWJpYSBVbml2ZXJzaXR5IENvbGxlZ2Ugb2YgUGh5c2ljaWFu

cyBhbmQgU3VyZ2VvbnMsIE5ldyBZb3JrLCBOWSwgVVNBLiYjeEQ7RGVwYXJ0bWVudCBvZiBQYXRo

b2xvZ3kgYW5kIENlbGwgQmlvbG9neSwgQ29sdW1iaWEgVW5pdmVyc2l0eSwgTmV3IFlvcmssIE5Z

LCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Um9sZSBvZiBBbXlsb2lkLWJldGEg

YW5kIFRhdSBQcm90ZWlucyBpbiBBbHpoZWltZXImYXBvcztzIERpc2Vhc2U6IENvbmZ1dGluZyB0

aGUgQW15bG9pZCBDYXNjYWRlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogQWx6aGVpbWVycyBE

aXM8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIEFs

emhlaW1lcnMgRGlzPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+UzYxMS1TNjMxPC9w

YWdlcz48dm9sdW1lPjY0PC92b2x1bWU+PG51bWJlcj5zMTwvbnVtYmVyPjxlZGl0aW9uPjIwMTgv

MDYvMDY8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFteWxvaWQtYmV0YSBwZXB0aWRlPC9r

ZXl3b3JkPjxrZXl3b3JkPmFteWxvaWQtYmV0YSBwcm90ZWluIHByZWN1cnNvcjwva2V5d29yZD48

a2V5d29yZD5vbGlnb21lcnM8L2tleXdvcmQ+PGtleXdvcmQ+c3luYXB0aWMgZHlzZnVuY3Rpb248

L2tleXdvcmQ+PGtleXdvcmQ+dGF1PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTg8L3llYXI+PC9kYXRlcz48aXNibj4xODc1LTg5MDggKEVsZWN0cm9uaWMpJiN4RDsxMzg3LTI4

NzcgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5ODY1MDU1PC9hY2Nlc3Npb24tbnVt

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8yOTg2NTA1NTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+MTAuMzIzMy9KQUQtMTc5OTM1PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3Jl

Y29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5Hb2xkPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48

UmVjTnVtPjIwODc8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjIwODc8L3JlYy1udW1iZXI+

PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3

eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDg2MzI2MiI+MjA4Nzwva2V5PjwvZm9yZWln

bi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29u

dHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+R29sZCwgTS48L2F1dGhvcj48L2F1dGhvcnM+PC9j

b250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5HbG9iYWwgUHJvZHVjdCBEZXZlbG9wbWVudCwgTmV1

cm9zY2llbmNlLCBQUEQsIE1vcnJpc3ZpbGxlLCBOQywgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRs

ZXM+PHRpdGxlPlBoYXNlIElJIGNsaW5pY2FsIHRyaWFscyBvZiBhbnRpLWFteWxvaWQgYmV0YSBh

bnRpYm9kaWVzOiBXaGVuIGlzIGVub3VnaCwgZW5vdWdoPzwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5BbHpoZWltZXJzIERlbWVudCAoTiBZKTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJp

b2RpY2FsPjxmdWxsLXRpdGxlPkFsemhlaW1lcnMgRGVtZW50IChOIFkpPC9mdWxsLXRpdGxlPjwv

cGVyaW9kaWNhbD48cGFnZXM+NDAyLTQwOTwvcGFnZXM+PHZvbHVtZT4zPC92b2x1bWU+PG51bWJl

cj4zPC9udW1iZXI+PGVkaXRpb24+MjAxNy8xMC8yNzwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdv

cmQ+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0

YTwva2V5d29yZD48a2V5d29yZD5DbGluaWNhbCB0cmlhbHM8L2tleXdvcmQ+PGtleXdvcmQ+SW52

ZXN0bWVudDwva2V5d29yZD48a2V5d29yZD5Nb25vY2xvbmFsIGFudGlib2RpZXM8L2tleXdvcmQ+

PGtleXdvcmQ+UGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBoYXNlIElJPC9rZXl3b3Jk

PjxrZXl3b3JkPlBoYXNlIElJSTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE3

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlz

Ym4+MjM1Mi04NzM3IChQcmludCkmI3hEOzIzNTItODczNyAoTGlua2luZyk8L2lzYm4+PGFjY2Vz

c2lvbi1udW0+MjkwNjczNDY8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJs

Pmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI5MDY3MzQ2PC91cmw+PC9yZWxh

dGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzU2NTE0MjQ8L2N1c3RvbTI+PGVsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjEwLjEwMTYvai50cmNpLjIwMTcuMDQuMDA1PC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5IYXJkeTwvQXV0aG9yPjxZZWFy

PjIwMTc8L1llYXI+PFJlY051bT4yMTI1PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4yMTI1

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NjM3MTEiPjIxMjU8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhhcmR5LCBKLjwvYXV0aG9y

PjxhdXRob3I+RGUgU3Ryb29wZXIsIEIuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

Pjx0aXRsZXM+PHRpdGxlPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogd2hlcmUgbmV4dCBmb3Ig

YW50aS1hbXlsb2lkIHRoZXJhcGllcz88L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QnJhaW48L3Nl

Y29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5CcmFpbjwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjg1My04NTU8L3BhZ2VzPjx2b2x1bWU+MTQwPC92

b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PGVkaXRpb24+MjAxNy8wNC8wNTwvZWRpdGlvbj48ZGF0

ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkFwciAxPC9kYXRlPjwvcHViLWRh

dGVzPjwvZGF0ZXM+PGlzYm4+MTQ2MC0yMTU2IChFbGVjdHJvbmljKSYjeEQ7MDAwNi04OTUwIChM

aW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yODM3NTQ2MTwvYWNjZXNzaW9uLW51bT48dXJs

cz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQv

MjgzNzU0NjE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjEwLjEwOTMvYnJhaW4vYXd4MDU5PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29y

ZD48L0NpdGU+PENpdGU+PEF1dGhvcj5LYXJyYW48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

ZWNOdW0+MjEzMTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MjEzMTwvcmVjLW51bWJlcj48

Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4

OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0ODYzNzk5Ij4yMTMxPC9rZXk+PC9mb3JlaWdu

LWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250

cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LYXJyYW4sIEUuPC9hdXRob3I+PGF1dGhvcj5EZSBT

dHJvb3BlciwgQi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVz

cz5BbHpoZWltZXImYXBvcztzIFJlc2VhcmNoIFVLIFJlc2VhcmNoLCBDYW1icmlkZ2UsIENhbWJy

aWRnZXNoaXJlLCBVSy4gZXJpYy5rYXJyYW5AYWJidmllLmNvbS4mI3hEO1ZJQiBDZW50ZXIgZm9y

IHRoZSBCaW9sb2d5IG9mIERpc2Vhc2UsIFZJQi1MZXV2ZW4sIExldXZlbiwgQmVsZ2l1bS4gZXJp

Yy5rYXJyYW5AYWJidmllLmNvbS4mI3hEO0luc3RpdHV0ZSBvZiBOZXVyb2xvZ3ksIFVuaXZlcnNp

dHkgQ29sbGVnZSBMb25kb24sIExvbmRvbiwgVUsuIGVyaWMua2FycmFuQGFiYnZpZS5jb20uJiN4

RDtWSUIgQ2VudGVyIGZvciB0aGUgQmlvbG9neSBvZiBEaXNlYXNlLCBWSUItTGV1dmVuLCBMZXV2

ZW4sIEJlbGdpdW0uJiN4RDtDZW50ZXIgZm9yIEh1bWFuIEdlbmV0aWNzLCBVbml2ZXJzaXRhaXJl

IHppZWtlbmh1aXplbiBhbmQgTElORCwgS1UgTGV1dmVuLCBMZXV2ZW4sIEJlbGdpdW0uJiN4RDtJ

bnN0aXR1dGUgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IENvbGxlZ2UgTG9uZG9uLCBMb25kb24s

IFVLLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSBhbXlsb2lkIGNhc2NhZGUgaHlw

b3RoZXNpczogYXJlIHdlIHBvaXNlZCBmb3Igc3VjY2VzcyBvciBmYWlsdXJlPzwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5KIE5ldXJvY2hlbTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJp

b2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9jaGVtPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48

cGFnZXM+MjM3LTI1MjwvcGFnZXM+PHZvbHVtZT4xMzkgU3VwcGwgMjwvdm9sdW1lPjxlZGl0aW9u

PjIwMTYvMTEvMDE8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNl

L2dlbmV0aWNzLyptZXRhYm9saXNtL3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QW1pbm8gQWNp

ZCBTZXF1ZW5jZTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkL2dlbmV0aWNzL21ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL2FudGFnb25pc3RzICZhbXA7

IGluaGliaXRvcnMvZ2VuZXRpY3MvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9p

ZG9nZW5pYyBQcm90ZWlucy9hbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzL2dlbmV0aWNzL21l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZG9zaXMvZ2VuZXRpY3MvKm1ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BbnRpYm9kaWVz

LCBNb25vY2xvbmFsL3BoYXJtYWNvbG9neS90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdv

cmQ+QnJhaW4vZHJ1ZyBlZmZlY3RzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFu

czwva2V5d29yZD48a2V5d29yZD5TaWduYWwgVHJhbnNkdWN0aW9uL2RydWcgZWZmZWN0cy8qcGh5

c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tleXdv

cmQ+PGtleXdvcmQ+QW15bG9pZCBjYXNjYWRlIGNsaW5pY2FsIGRldmVsb3BtZW50PC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5PY3Q8

L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDcxLTQxNTkgKEVsZWN0cm9uaWMpJiN4

RDswMDIyLTMwNDIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3MjU1OTU4PC9hY2Nl

c3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5u

aWguZ292L3B1Ym1lZC8yNzI1NTk1ODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTExMS9qbmMuMTM2MzI8L2VsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdWxpc2FubzwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+

PFJlY051bT4yMDkzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MTYsMTksNjAsNjE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4y

MDkzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4

NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NjMzNTIiPjIw

OTM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x

NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkd1bGlzYW5vLCBXLjwv

YXV0aG9yPjxhdXRob3I+TWF1Z2VyaSwgRC48L2F1dGhvcj48YXV0aG9yPkJhbHRyb25zLCBNLiBB

LjwvYXV0aG9yPjxhdXRob3I+RmEsIE0uPC9hdXRob3I+PGF1dGhvcj5BbWF0bywgQS48L2F1dGhv

cj48YXV0aG9yPlBhbG1lcmksIEEuPC9hdXRob3I+PGF1dGhvcj5EJmFwb3M7QWRhbWlvLCBMLjwv

YXV0aG9yPjxhdXRob3I+R3Jhc3NpLCBDLjwvYXV0aG9yPjxhdXRob3I+RGV2YW5hbmQsIEQuIFAu

PC9hdXRob3I+PGF1dGhvcj5Ib25pZywgTC4gUy48L2F1dGhvcj48YXV0aG9yPlB1enpvLCBELjwv

YXV0aG9yPjxhdXRob3I+QXJhbmNpbywgTy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIEJpb21lZGljYWwgYW5kIEJpb3RlY2hub2xv

Z2ljYWwgU2NpZW5jZXMsIFNlY3Rpb24gb2YgUGh5c2lvbG9neSwgVW5pdmVyc2l0eSBvZiBDYXRh

bmlhLCBDYXRhbmlhLCBJdGFseS4mI3hEO1RhdWIgSW5zdGl0dXRlIGZvciBSZXNlYXJjaCBvbiBB

bHpoZWltZXImYXBvcztzIERpc2Vhc2UgYW5kIHRoZSBBZ2luZyBCcmFpbiwgQ29sdW1iaWEgVW5p

dmVyc2l0eSwgTmV3IFlvcmssIE5ZLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIEJpb2NoZW1pc3Ry

eSBhbmQgTW9sZWN1bGFyIEJpb2xvZ3kgYW5kIEluc3RpdHV0ZSBvZiBCaW90ZWNobm9sb2d5IGFu

ZCBCaW9tZWRpY2luZSwgVW5pdmVyc2l0YXQgQXV0b25vbWEgZGUgQmFyY2Vsb25hLCBCZWxsYXRl

cnJhLCBTcGFpbi4mI3hEO0RlcGFydG1lbnQgb2YgQW5hZXN0aGVzaW9sb2d5LCBVbml2ZXJzaXRh

IENhdHRvbGljYSBkZWwgU2Fjcm8gQ3VvcmUsIFJvbWUsIEl0YWx5LiYjeEQ7RGVwYXJ0bWVudCBv

ZiBQaGFybWFjb2xvZ3ksIFBoeXNpb2xvZ3kgYW5kIE5ldXJvc2NpZW5jZSwgUnV0Z2VycyBVbml2

ZXJzaXR5LCBOZXdhcmssIE5KLCBVU0EuJiN4RDtJbnN0aXR1dGUgb2YgSHVtYW4gUGh5c2lvbG9n

eSwgVW5pdmVyc2l0YSBDYXR0b2xpY2EgZGVsIFNhY3JvIEN1b3JlLCBSb21lLCBJdGFseS4mI3hE

O0RlcGFydG1lbnQgb2YgUHN5Y2hpYXRyeSwgQ29sdW1iaWEgVW5pdmVyc2l0eSBDb2xsZWdlIG9m

IFBoeXNpY2lhbnMgYW5kIFN1cmdlb25zLCBOZXcgWW9yaywgTlksIFVTQS4mI3hEO0RlcGFydG1l

bnQgb2YgTmV1cm9sb2d5LCBDb2x1bWJpYSBVbml2ZXJzaXR5IENvbGxlZ2Ugb2YgUGh5c2ljaWFu

cyBhbmQgU3VyZ2VvbnMsIE5ldyBZb3JrLCBOWSwgVVNBLiYjeEQ7RGVwYXJ0bWVudCBvZiBQYXRo

b2xvZ3kgYW5kIENlbGwgQmlvbG9neSwgQ29sdW1iaWEgVW5pdmVyc2l0eSwgTmV3IFlvcmssIE5Z

LCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Um9sZSBvZiBBbXlsb2lkLWJldGEg

YW5kIFRhdSBQcm90ZWlucyBpbiBBbHpoZWltZXImYXBvcztzIERpc2Vhc2U6IENvbmZ1dGluZyB0

aGUgQW15bG9pZCBDYXNjYWRlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogQWx6aGVpbWVycyBE

aXM8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIEFs

emhlaW1lcnMgRGlzPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+UzYxMS1TNjMxPC9w

YWdlcz48dm9sdW1lPjY0PC92b2x1bWU+PG51bWJlcj5zMTwvbnVtYmVyPjxlZGl0aW9uPjIwMTgv

MDYvMDY8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFteWxvaWQtYmV0YSBwZXB0aWRlPC9r

ZXl3b3JkPjxrZXl3b3JkPmFteWxvaWQtYmV0YSBwcm90ZWluIHByZWN1cnNvcjwva2V5d29yZD48

a2V5d29yZD5vbGlnb21lcnM8L2tleXdvcmQ+PGtleXdvcmQ+c3luYXB0aWMgZHlzZnVuY3Rpb248

L2tleXdvcmQ+PGtleXdvcmQ+dGF1PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTg8L3llYXI+PC9kYXRlcz48aXNibj4xODc1LTg5MDggKEVsZWN0cm9uaWMpJiN4RDsxMzg3LTI4

NzcgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5ODY1MDU1PC9hY2Nlc3Npb24tbnVt

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8yOTg2NTA1NTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+MTAuMzIzMy9KQUQtMTc5OTM1PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3Jl

Y29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5Hb2xkPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48

UmVjTnVtPjIwODc8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjIwODc8L3JlYy1udW1iZXI+

PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3

eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDg2MzI2MiI+MjA4Nzwva2V5PjwvZm9yZWln

bi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29u

dHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+R29sZCwgTS48L2F1dGhvcj48L2F1dGhvcnM+PC9j

b250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5HbG9iYWwgUHJvZHVjdCBEZXZlbG9wbWVudCwgTmV1

cm9zY2llbmNlLCBQUEQsIE1vcnJpc3ZpbGxlLCBOQywgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRs

ZXM+PHRpdGxlPlBoYXNlIElJIGNsaW5pY2FsIHRyaWFscyBvZiBhbnRpLWFteWxvaWQgYmV0YSBh

bnRpYm9kaWVzOiBXaGVuIGlzIGVub3VnaCwgZW5vdWdoPzwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5BbHpoZWltZXJzIERlbWVudCAoTiBZKTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJp

b2RpY2FsPjxmdWxsLXRpdGxlPkFsemhlaW1lcnMgRGVtZW50IChOIFkpPC9mdWxsLXRpdGxlPjwv

cGVyaW9kaWNhbD48cGFnZXM+NDAyLTQwOTwvcGFnZXM+PHZvbHVtZT4zPC92b2x1bWU+PG51bWJl

cj4zPC9udW1iZXI+PGVkaXRpb24+MjAxNy8xMC8yNzwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdv

cmQ+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0

YTwva2V5d29yZD48a2V5d29yZD5DbGluaWNhbCB0cmlhbHM8L2tleXdvcmQ+PGtleXdvcmQ+SW52

ZXN0bWVudDwva2V5d29yZD48a2V5d29yZD5Nb25vY2xvbmFsIGFudGlib2RpZXM8L2tleXdvcmQ+

PGtleXdvcmQ+UGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBoYXNlIElJPC9rZXl3b3Jk

PjxrZXl3b3JkPlBoYXNlIElJSTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE3

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlz

Ym4+MjM1Mi04NzM3IChQcmludCkmI3hEOzIzNTItODczNyAoTGlua2luZyk8L2lzYm4+PGFjY2Vz

c2lvbi1udW0+MjkwNjczNDY8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJs

Pmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI5MDY3MzQ2PC91cmw+PC9yZWxh

dGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzU2NTE0MjQ8L2N1c3RvbTI+PGVsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjEwLjEwMTYvai50cmNpLjIwMTcuMDQuMDA1PC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5IYXJkeTwvQXV0aG9yPjxZZWFy

PjIwMTc8L1llYXI+PFJlY051bT4yMTI1PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4yMTI1

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NjM3MTEiPjIxMjU8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhhcmR5LCBKLjwvYXV0aG9y

PjxhdXRob3I+RGUgU3Ryb29wZXIsIEIuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

Pjx0aXRsZXM+PHRpdGxlPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogd2hlcmUgbmV4dCBmb3Ig

YW50aS1hbXlsb2lkIHRoZXJhcGllcz88L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QnJhaW48L3Nl

Y29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5CcmFpbjwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjg1My04NTU8L3BhZ2VzPjx2b2x1bWU+MTQwPC92

b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PGVkaXRpb24+MjAxNy8wNC8wNTwvZWRpdGlvbj48ZGF0

ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkFwciAxPC9kYXRlPjwvcHViLWRh

dGVzPjwvZGF0ZXM+PGlzYm4+MTQ2MC0yMTU2IChFbGVjdHJvbmljKSYjeEQ7MDAwNi04OTUwIChM

aW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yODM3NTQ2MTwvYWNjZXNzaW9uLW51bT48dXJs

cz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQv

MjgzNzU0NjE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjEwLjEwOTMvYnJhaW4vYXd4MDU5PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29y

ZD48L0NpdGU+PENpdGU+PEF1dGhvcj5LYXJyYW48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

ZWNOdW0+MjEzMTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MjEzMTwvcmVjLW51bWJlcj48

Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4

OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0ODYzNzk5Ij4yMTMxPC9rZXk+PC9mb3JlaWdu

LWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250

cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LYXJyYW4sIEUuPC9hdXRob3I+PGF1dGhvcj5EZSBT

dHJvb3BlciwgQi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVz

cz5BbHpoZWltZXImYXBvcztzIFJlc2VhcmNoIFVLIFJlc2VhcmNoLCBDYW1icmlkZ2UsIENhbWJy

aWRnZXNoaXJlLCBVSy4gZXJpYy5rYXJyYW5AYWJidmllLmNvbS4mI3hEO1ZJQiBDZW50ZXIgZm9y

IHRoZSBCaW9sb2d5IG9mIERpc2Vhc2UsIFZJQi1MZXV2ZW4sIExldXZlbiwgQmVsZ2l1bS4gZXJp

Yy5rYXJyYW5AYWJidmllLmNvbS4mI3hEO0luc3RpdHV0ZSBvZiBOZXVyb2xvZ3ksIFVuaXZlcnNp

dHkgQ29sbGVnZSBMb25kb24sIExvbmRvbiwgVUsuIGVyaWMua2FycmFuQGFiYnZpZS5jb20uJiN4

RDtWSUIgQ2VudGVyIGZvciB0aGUgQmlvbG9neSBvZiBEaXNlYXNlLCBWSUItTGV1dmVuLCBMZXV2

ZW4sIEJlbGdpdW0uJiN4RDtDZW50ZXIgZm9yIEh1bWFuIEdlbmV0aWNzLCBVbml2ZXJzaXRhaXJl

IHppZWtlbmh1aXplbiBhbmQgTElORCwgS1UgTGV1dmVuLCBMZXV2ZW4sIEJlbGdpdW0uJiN4RDtJ

bnN0aXR1dGUgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IENvbGxlZ2UgTG9uZG9uLCBMb25kb24s

IFVLLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSBhbXlsb2lkIGNhc2NhZGUgaHlw

b3RoZXNpczogYXJlIHdlIHBvaXNlZCBmb3Igc3VjY2VzcyBvciBmYWlsdXJlPzwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5KIE5ldXJvY2hlbTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJp

b2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9jaGVtPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48

cGFnZXM+MjM3LTI1MjwvcGFnZXM+PHZvbHVtZT4xMzkgU3VwcGwgMjwvdm9sdW1lPjxlZGl0aW9u

PjIwMTYvMTEvMDE8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNl

L2dlbmV0aWNzLyptZXRhYm9saXNtL3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QW1pbm8gQWNp

ZCBTZXF1ZW5jZTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkL2dlbmV0aWNzL21ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL2FudGFnb25pc3RzICZhbXA7

IGluaGliaXRvcnMvZ2VuZXRpY3MvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9p

ZG9nZW5pYyBQcm90ZWlucy9hbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzL2dlbmV0aWNzL21l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZG9zaXMvZ2VuZXRpY3MvKm1ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BbnRpYm9kaWVz

LCBNb25vY2xvbmFsL3BoYXJtYWNvbG9neS90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdv

cmQ+QnJhaW4vZHJ1ZyBlZmZlY3RzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFu

czwva2V5d29yZD48a2V5d29yZD5TaWduYWwgVHJhbnNkdWN0aW9uL2RydWcgZWZmZWN0cy8qcGh5

c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tleXdv

cmQ+PGtleXdvcmQ+QW15bG9pZCBjYXNjYWRlIGNsaW5pY2FsIGRldmVsb3BtZW50PC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5PY3Q8

L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDcxLTQxNTkgKEVsZWN0cm9uaWMpJiN4

RDswMDIyLTMwNDIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3MjU1OTU4PC9hY2Nl

c3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5u

aWguZ292L3B1Ym1lZC8yNzI1NTk1ODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTExMS9qbmMuMTM2MzI8L2VsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 16,19,60,61. These clinical trials have provided data supporting previous hypotheses proposing dementia as a product of the cellular phase of AD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZSBTdHJvb3BlcjwvQXV0aG9yPjxZZWFyPjIwMTY8L1ll

YXI+PFJlY051bT4yMTc0PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNj

cmlwdCI+MjE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMTc0PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NjQxMjEiPjIxNzQ8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkRlIFN0cm9vcGVyLCBCLjwvYXV0

aG9yPjxhdXRob3I+S2FycmFuLCBFLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48

YXV0aC1hZGRyZXNzPlZJQiBDZW50ZXIgZm9yIHRoZSBCaW9sb2d5IG9mIERpc2Vhc2UsIFZJQi1M

ZXV2ZW4sIDMwMDAgTGV1dmVuLCBCZWxnaXVtOyBDZW50ZXIgZm9yIEh1bWFuIEdlbmV0aWNzLCBV

bml2ZXJzaXRhaXJlIFppZWtlbmh1aXplbiBhbmQgTElORCwgS1UgTGV1dmVuLCAzMDAwIExldXZl

biwgQmVsZ2l1bTsgSW5zdGl0dXRlIG9mIE5ldXJvbG9neSwgVW5pdmVyc2l0eSBDb2xsZWdlIExv

bmRvbiwgUXVlZW4gU3F1YXJlLCBXQzFOIDNCRyBMb25kb24sIFVLLiBFbGVjdHJvbmljIGFkZHJl

c3M6IGJhcnQuZGVzdHJvb3BlckBjbWUudmliLWt1bGV1dmVuLmJlLiYjeEQ7Q2VudGVyIGZvciBI

dW1hbiBHZW5ldGljcywgVW5pdmVyc2l0YWlyZSBaaWVrZW5odWl6ZW4gYW5kIExJTkQsIEtVIExl

dXZlbiwgMzAwMCBMZXV2ZW4sIEJlbGdpdW07IEluc3RpdHV0ZSBvZiBOZXVyb2xvZ3ksIFVuaXZl

cnNpdHkgQ29sbGVnZSBMb25kb24sIFF1ZWVuIFNxdWFyZSwgV0MxTiAzQkcgTG9uZG9uLCBVSzsg

QWx6aGVpbWVyIFJlc2VhcmNoIFVLLCBDYW1icmlkZ2UsIENCMjEgNkFELCBVSy48L2F1dGgtYWRk

cmVzcz48dGl0bGVzPjx0aXRsZT5UaGUgQ2VsbHVsYXIgUGhhc2Ugb2YgQWx6aGVpbWVyJmFwb3M7

cyBEaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNlbGw8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5DZWxsPC9mdWxsLXRpdGxlPjwvcGVyaW9k

aWNhbD48cGFnZXM+NjAzLTE1PC9wYWdlcz48dm9sdW1lPjE2NDwvdm9sdW1lPjxudW1iZXI+NDwv

bnVtYmVyPjxlZGl0aW9uPjIwMTYvMDIvMTM8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFs

emhlaW1lciBEaXNlYXNlL21ldGFib2xpc20vKnBhdGhvbG9neS9waHlzaW9wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL21ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5Bc3Ryb2N5dGVzL21ldGFib2xpc20v

cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL3BhdGhvbG9neTwva2V5d29yZD48a2V5

d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNy

b2dsaWEvbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cmFsIFBhdGh3

YXlzPC9rZXl3b3JkPjxrZXl3b3JkPk9saWdvZGVuZHJvZ2xpYS9wYXRob2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+U2luZ2xlLUNlbGwgQW5hbHlzaXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkZlYiAxMTwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxpc2JuPjEwOTctNDE3MiAoRWxlY3Ryb25pYykmI3hEOzAwOTItODY3NCAoTGlu

a2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjY4NzE2Mjc8L2FjY2Vzc2lvbi1udW0+PHVybHM+

PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI2

ODcxNjI3PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4xMDE2L2ouY2VsbC4yMDE1LjEyLjA1NjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9y

ZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZSBTdHJvb3BlcjwvQXV0aG9yPjxZZWFyPjIwMTY8L1ll

YXI+PFJlY051bT4yMTc0PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNj

cmlwdCI+MjE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMTc0PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NjQxMjEiPjIxNzQ8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkRlIFN0cm9vcGVyLCBCLjwvYXV0

aG9yPjxhdXRob3I+S2FycmFuLCBFLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48

YXV0aC1hZGRyZXNzPlZJQiBDZW50ZXIgZm9yIHRoZSBCaW9sb2d5IG9mIERpc2Vhc2UsIFZJQi1M

ZXV2ZW4sIDMwMDAgTGV1dmVuLCBCZWxnaXVtOyBDZW50ZXIgZm9yIEh1bWFuIEdlbmV0aWNzLCBV

bml2ZXJzaXRhaXJlIFppZWtlbmh1aXplbiBhbmQgTElORCwgS1UgTGV1dmVuLCAzMDAwIExldXZl

biwgQmVsZ2l1bTsgSW5zdGl0dXRlIG9mIE5ldXJvbG9neSwgVW5pdmVyc2l0eSBDb2xsZWdlIExv

bmRvbiwgUXVlZW4gU3F1YXJlLCBXQzFOIDNCRyBMb25kb24sIFVLLiBFbGVjdHJvbmljIGFkZHJl

c3M6IGJhcnQuZGVzdHJvb3BlckBjbWUudmliLWt1bGV1dmVuLmJlLiYjeEQ7Q2VudGVyIGZvciBI

dW1hbiBHZW5ldGljcywgVW5pdmVyc2l0YWlyZSBaaWVrZW5odWl6ZW4gYW5kIExJTkQsIEtVIExl

dXZlbiwgMzAwMCBMZXV2ZW4sIEJlbGdpdW07IEluc3RpdHV0ZSBvZiBOZXVyb2xvZ3ksIFVuaXZl

cnNpdHkgQ29sbGVnZSBMb25kb24sIFF1ZWVuIFNxdWFyZSwgV0MxTiAzQkcgTG9uZG9uLCBVSzsg

QWx6aGVpbWVyIFJlc2VhcmNoIFVLLCBDYW1icmlkZ2UsIENCMjEgNkFELCBVSy48L2F1dGgtYWRk

cmVzcz48dGl0bGVzPjx0aXRsZT5UaGUgQ2VsbHVsYXIgUGhhc2Ugb2YgQWx6aGVpbWVyJmFwb3M7

cyBEaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNlbGw8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5DZWxsPC9mdWxsLXRpdGxlPjwvcGVyaW9k

aWNhbD48cGFnZXM+NjAzLTE1PC9wYWdlcz48dm9sdW1lPjE2NDwvdm9sdW1lPjxudW1iZXI+NDwv

bnVtYmVyPjxlZGl0aW9uPjIwMTYvMDIvMTM8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFs

emhlaW1lciBEaXNlYXNlL21ldGFib2xpc20vKnBhdGhvbG9neS9waHlzaW9wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL21ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5Bc3Ryb2N5dGVzL21ldGFib2xpc20v

cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL3BhdGhvbG9neTwva2V5d29yZD48a2V5

d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNy

b2dsaWEvbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cmFsIFBhdGh3

YXlzPC9rZXl3b3JkPjxrZXl3b3JkPk9saWdvZGVuZHJvZ2xpYS9wYXRob2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+U2luZ2xlLUNlbGwgQW5hbHlzaXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkZlYiAxMTwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxpc2JuPjEwOTctNDE3MiAoRWxlY3Ryb25pYykmI3hEOzAwOTItODY3NCAoTGlu

a2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjY4NzE2Mjc8L2FjY2Vzc2lvbi1udW0+PHVybHM+

PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI2

ODcxNjI3PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4xMDE2L2ouY2VsbC4yMDE1LjEyLjA1NjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9y

ZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 21, which comprise pathological processes involving targets in microglia, astrocytes, oligodendrocytes, and vasculature before clinical manifestations. Still, several aspects of the amyloid cascade hypothesis remain to be tested, such as the therapeutic relevance of clearing insoluble amyloid versus preventing its production and accumulation ADDIN EN.CITE <EndNote><Cite><Author>Hardy</Author><Year>2017</Year><RecNum>2125</RecNum><DisplayText><style face="superscript">19</style></DisplayText><record><rec-number>2125</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1534863711">2125</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hardy, J.</author><author>De Strooper, B.</author></authors></contributors><titles><title>Alzheimer&apos;s disease: where next for anti-amyloid therapies?</title><secondary-title>Brain</secondary-title></titles><periodical><full-title>Brain</full-title></periodical><pages>853-855</pages><volume>140</volume><number>4</number><edition>2017/04/05</edition><dates><year>2017</year><pub-dates><date>Apr 1</date></pub-dates></dates><isbn>1460-2156 (Electronic)&#xD;0006-8950 (Linking)</isbn><accession-num>28375461</accession-num><urls><related-urls><url>. There is great interest in the immunotherapy approach as a therapeutic option for AD, which comprises the active immunotherapy, also called vaccination ADDIN EN.CITE <EndNote><Cite><Author>Wisniewski</Author><Year>2012</Year><RecNum>2258</RecNum><DisplayText><style face="superscript">62</style></DisplayText><record><rec-number>2258</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1534927801">2258</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wisniewski, T.</author></authors></contributors><auth-address>New York University School of Medicine, Department of Neurology, Psychiatry, and Pathology, Alexandria East River Science Park, New York, NY 10016, USA. thomas.wisniewski@</auth-address><titles><title>Active immunotherapy for Alzheimer&apos;s disease</title><secondary-title>Lancet Neurol</secondary-title></titles><pages>571-2</pages><volume>11</volume><number>7</number><edition>2012/06/09</edition><keywords><keyword>Alzheimer Disease/*drug therapy/*immunology</keyword><keyword>Amyloid beta-Peptides/*immunology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>*Immunotherapy</keyword><keyword>Male</keyword></keywords><dates><year>2012</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1474-4465 (Electronic)&#xD;1474-4422 (Linking)</isbn><accession-num>22677257</accession-num><urls><related-urls><url>(12)70136-9</electronic-resource-num></record></Cite></EndNote>62, and the passive immunotherapy ADDIN EN.CITE <EndNote><Cite><Author>Dodel</Author><Year>2003</Year><RecNum>2325</RecNum><DisplayText><style face="superscript">63</style></DisplayText><record><rec-number>2325</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1534927810">2325</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dodel, R. C.</author><author>Hampel, H.</author><author>Du, Y.</author></authors></contributors><auth-address>Department of Neurology, Friedrich-Wilhelms-University Bonn, Germany. richard.dodel@ukb.uni-bonn.de &lt;richard.dodel@ukb.uni-bonn.de&gt;</auth-address><titles><title>Immunotherapy for Alzheimer&apos;s disease</title><secondary-title>Lancet Neurol</secondary-title></titles><pages>215-20</pages><volume>2</volume><number>4</number><edition>2003/07/10</edition><keywords><keyword>Alzheimer Disease/immunology/*therapy</keyword><keyword>Amyloid beta-Peptides/immunology</keyword><keyword>Animals</keyword><keyword>Disease Models, Animal</keyword><keyword>Humans</keyword><keyword>*Immunotherapy</keyword><keyword>Mice</keyword></keywords><dates><year>2003</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1474-4422 (Print)&#xD;1474-4422 (Linking)</isbn><accession-num>12849209</accession-num><urls><related-urls><url>. For active immunotherapy, the immune system is stimulated to produce antibodies against Aβ ADDIN EN.CITE <EndNote><Cite><Author>Sigurdsson</Author><Year>2001</Year><RecNum>2386</RecNum><DisplayText><style face="superscript">64</style></DisplayText><record><rec-number>2386</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1534928142">2386</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sigurdsson, E. M.</author><author>Scholtzova, H.</author><author>Mehta, P. D.</author><author>Frangione, B.</author><author>Wisniewski, T.</author></authors></contributors><auth-address>Department of Neurology, New York University School of Medicine, 550 First Ave., New York, NY 10016, USA. einar.sigurdsson@med.nyu.edu</auth-address><titles><title>Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer&apos;s disease-associated pathology in transgenic mice</title><secondary-title>Am J Pathol</secondary-title></titles><pages>439-47</pages><volume>159</volume><number>2</number><edition>2001/08/04</edition><keywords><keyword>Alzheimer Disease/*pathology/*prevention &amp; control</keyword><keyword>Amyloid beta-Peptides/chemistry/*genetics/*immunology</keyword><keyword>Animals</keyword><keyword>Brain/*pathology</keyword><keyword>Cell Survival</keyword><keyword>Cerebral Cortex/pathology</keyword><keyword>Enzyme-Linked Immunosorbent Assay</keyword><keyword>Hippocampus/pathology</keyword><keyword>Humans</keyword><keyword>Immunization</keyword><keyword>Interleukin-1/analysis/genetics</keyword><keyword>Mice</keyword><keyword>Mice, Transgenic</keyword><keyword>Microglia/pathology</keyword><keyword>Peptide Fragments/chemistry/*immunology</keyword><keyword>Protein Structure, Secondary</keyword></keywords><dates><year>2001</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0002-9440 (Print)&#xD;0002-9440 (Linking)</isbn><accession-num>11485902</accession-num><urls><related-urls><url>. For passive immunotherapy, pre-formed antibodies are humanized and injected into the individuals with advanced AD ADDIN EN.CITE <EndNote><Cite><Author>Morgan</Author><Year>2011</Year><RecNum>2271</RecNum><DisplayText><style face="superscript">65</style></DisplayText><record><rec-number>2271</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1534927804">2271</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Morgan, D.</author></authors></contributors><auth-address>Alzheimer&apos;s Institute, University of South Florida, Tampa, FL 33613, USA. scientist.dave@</auth-address><titles><title>Immunotherapy for Alzheimer&apos;s disease</title><secondary-title>J Intern Med</secondary-title></titles><periodical><full-title>J Intern Med</full-title><abbr-1>Journal of internal medicine</abbr-1></periodical><pages>54-63</pages><volume>269</volume><number>1</number><edition>2010/12/17</edition><keywords><keyword>Alzheimer Disease/immunology/pathology/*therapy</keyword><keyword>Alzheimer Vaccines/therapeutic use</keyword><keyword>Amyloid beta-Peptides/metabolism</keyword><keyword>Animals</keyword><keyword>Brain/pathology</keyword><keyword>Disease Models, Animal</keyword><keyword>Humans</keyword><keyword>Immunization, Passive/methods</keyword><keyword>Immunotherapy/*methods/trends</keyword><keyword>Mice</keyword><keyword>Mice, Transgenic</keyword></keywords><dates><year>2011</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1365-2796 (Electronic)&#xD;0954-6820 (Linking)</isbn><accession-num>21158978</accession-num><urls><related-urls><url>. Passive immunization protocols require a repeated infusion of the stimulus for the remaining lifespan of the patients. The produced antibodies pass in minute fractions into the brain and bind to fibrils, oligomers and plaques preventing aggregation and/or improving clearance. A promising immunotherapy for AD therapeutics is AADvac1, a vaccine against pathological Tau, have recently published the results of phase I of the FUNDAMANT study (NCT02031198) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ob3ZhazwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

Y051bT4yMDgzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTcsNjY8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDgzPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NjE1NzUiPjIwODM8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk5vdmFrLCBQLjwvYXV0aG9yPjxhdXRo

b3I+U2NobWlkdCwgUi48L2F1dGhvcj48YXV0aG9yPktvbnRzZWtvdmEsIEUuPC9hdXRob3I+PGF1

dGhvcj5aaWxrYSwgTi48L2F1dGhvcj48YXV0aG9yPktvdmFjZWNoLCBCLjwvYXV0aG9yPjxhdXRo

b3I+U2tyYWJhbmEsIFIuPC9hdXRob3I+PGF1dGhvcj5WaW5jZS1LYXptZXJvdmEsIFouPC9hdXRo

b3I+PGF1dGhvcj5LYXRpbmEsIFMuPC9hdXRob3I+PGF1dGhvcj5GaWFsb3ZhLCBMLjwvYXV0aG9y

PjxhdXRob3I+UHJjaW5hLCBNLjwvYXV0aG9yPjxhdXRob3I+UGFycmFrLCBWLjwvYXV0aG9yPjxh

dXRob3I+RGFsLUJpYW5jbywgUC48L2F1dGhvcj48YXV0aG9yPkJydW5uZXIsIE0uPC9hdXRob3I+

PGF1dGhvcj5TdGFmZmVuLCBXLjwvYXV0aG9yPjxhdXRob3I+UmFpbmVyLCBNLjwvYXV0aG9yPjxh

dXRob3I+T25kcnVzLCBNLjwvYXV0aG9yPjxhdXRob3I+Um9wZWxlLCBTLjwvYXV0aG9yPjxhdXRo

b3I+U21pc2VrLCBNLjwvYXV0aG9yPjxhdXRob3I+U2l2YWssIFIuPC9hdXRob3I+PGF1dGhvcj5X

aW5ibGFkLCBCLjwvYXV0aG9yPjxhdXRob3I+Tm92YWssIE0uPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+QVhPTiBOZXVyb3NjaWVuY2UgU0UsIEJyYXRpc2xh

dmEsIFNsb3Zha2lhLiBFbGVjdHJvbmljIGFkZHJlc3M6IHBldHIubm92YWtAYXhvbi1uZXVyb3Nj

aWVuY2UuZXUuJiN4RDtDbGluaWNhbCBEaXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIERlcGFy

dG1lbnQgb2YgTmV1cm9sb2d5LCBNZWRpY2FsIFVuaXZlcnNpdHkgR3JheiwgR3JheiwgQXVzdHJp

YS4mI3hEO0FYT04gTmV1cm9zY2llbmNlIFNFLCBCcmF0aXNsYXZhLCBTbG92YWtpYS4mI3hEO1Vu

aXZlcnNpdHkgQ2xpbmljIG9mIE5ldXJvbG9neSwgTWVkaWNhbCBVbml2ZXJzaXR5IG9mIFZpZW5u

YSwgVmllbm5hLCBBdXN0cmlhLiYjeEQ7VW5pdmVyc2l0eSBDbGluaWMgb2YgQ2xpbmljYWwgUGhh

cm1hY29sb2d5LCBNZWRpY2FsIFVuaXZlcnNpdHkgb2YgVmllbm5hLCBWaWVubmEsIEF1c3RyaWEu

JiN4RDtVbml2ZXJzaXR5IENsaW5pYyBvZiBOZXVyb2xvZ3ksIENocmlzdGlhbi1Eb3BwbGVyLUNs

aW5pYywgU2FsemJ1cmcsIEF1c3RyaWEuJiN4RDtTb2NpYWwgYW5kIE1lZGljYWwgQ2VudHJlIEVh

c3QsIERhbnViZSBIb3NwaXRhbCwgS2FybCBMYW5kc3RlaW5lciBJbnN0aXR1dGUgZm9yIE1lbW9y

eSBhbmQgQWx6aGVpbWVyIFJlc2VhcmNoLCBWaWVubmEsIEF1c3RyaWEuJiN4RDtEaXZpc2lvbiBv

ZiBHZW5lcmFsIE5ldXJvbG9neSwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIE1lZGljYWwgVW5p

dmVyc2l0eSBHcmF6LCBHcmF6LCBBdXN0cmlhLiYjeEQ7S2Fyb2xpbnNrYSBJbnN0aXR1dGUgQWx6

aGVpbWVyIERpc2Vhc2UgUmVzZWFyY2ggQ2VudHJlIGFuZCBDbGluaWNhbCBUcmlhbCBVbml0LCBH

ZXJpYXRyaWMgQ2xpbmljLCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdl

LCBTd2VkZW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+U2FmZXR5IGFuZCBpbW11bm9n

ZW5pY2l0eSBvZiB0aGUgdGF1IHZhY2NpbmUgQUFEdmFjMSBpbiBwYXRpZW50cyB3aXRoIEFsemhl

aW1lciZhcG9zO3MgZGlzZWFzZTogYSByYW5kb21pc2VkLCBkb3VibGUtYmxpbmQsIHBsYWNlYm8t

Y29udHJvbGxlZCwgcGhhc2UgMSB0cmlhbDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5MYW5jZXQg

TmV1cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEyMy0xMzQ8L3BhZ2VzPjx2

b2x1bWU+MTY8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48ZWRpdGlvbj4yMDE2LzEyLzE0PC9l

ZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgw

IGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLyp0aGVyYXB5PC9r

ZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBWYWNjaW5lcy9hZHZlcnNlIGVmZmVjdHMvKnBoYXJt

YWNvbG9neTwva2V5d29yZD48a2V5d29yZD5Eb3VibGUtQmxpbmQgTWV0aG9kPC9rZXl3b3JkPjxr

ZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+

SW1tdW5vdGhlcmFweS9hZHZlcnNlIGVmZmVjdHMvKm1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+

TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD4qT3V0

Y29tZSBBc3Nlc3NtZW50IChIZWFsdGggQ2FyZSk8L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3Rl

aW5zLyppbW11bm9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3ll

YXI+PHB1Yi1kYXRlcz48ZGF0ZT5GZWI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

NDc0LTQ0NjUgKEVsZWN0cm9uaWMpJiN4RDsxNDc0LTQ0MjIgKExpbmtpbmcpPC9pc2JuPjxhY2Nl

c3Npb24tbnVtPjI3OTU1OTk1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy

bD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNzk1NTk5NTwvdXJsPjwvcmVs

YXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMTQ3NC00

NDIyKDE2KTMwMzMxLTM8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48

Q2l0ZT48QXV0aG9yPk5vdmFrPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVjTnVtPjQ2Mzg8

L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjQ2Mzg8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5

cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1

YXYiIHRpbWVzdGFtcD0iMTU0Mzg0NzU4MSI+NDYzODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYt

dHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxh

dXRob3JzPjxhdXRob3I+Tm92YWssIFAuPC9hdXRob3I+PGF1dGhvcj5TY2htaWR0LCBSLjwvYXV0

aG9yPjxhdXRob3I+S29udHNla292YSwgRS48L2F1dGhvcj48YXV0aG9yPktvdmFjZWNoLCBCLjwv

YXV0aG9yPjxhdXRob3I+U21vbGVrLCBULjwvYXV0aG9yPjxhdXRob3I+S2F0aW5hLCBTLjwvYXV0

aG9yPjxhdXRob3I+RmlhbG92YSwgTC48L2F1dGhvcj48YXV0aG9yPlByY2luYSwgTS48L2F1dGhv

cj48YXV0aG9yPlBhcnJhaywgVi48L2F1dGhvcj48YXV0aG9yPkRhbC1CaWFuY28sIFAuPC9hdXRo

b3I+PGF1dGhvcj5CcnVubmVyLCBNLjwvYXV0aG9yPjxhdXRob3I+U3RhZmZlbiwgVy48L2F1dGhv

cj48YXV0aG9yPlJhaW5lciwgTS48L2F1dGhvcj48YXV0aG9yPk9uZHJ1cywgTS48L2F1dGhvcj48

YXV0aG9yPlJvcGVsZSwgUy48L2F1dGhvcj48YXV0aG9yPlNtaXNlaywgTS48L2F1dGhvcj48YXV0

aG9yPlNpdmFrLCBSLjwvYXV0aG9yPjxhdXRob3I+Wmlsa2EsIE4uPC9hdXRob3I+PGF1dGhvcj5X

aW5ibGFkLCBCLjwvYXV0aG9yPjxhdXRob3I+Tm92YWssIE0uPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+QXhvbiBOZXVyb3NjaWVuY2UgQ1JNIFNlcnZpY2Vz

IFNFLCBEdm9yYWtvdm8gbmFicmV6aWUgMTEsIDgxMSAwMiwgQnJhdGlzbGF2YSwgU2xvdmFraWEu

IHBldHIubm92YWtAYXhvbi1uZXVyb3NjaWVuY2UuZXUuJiN4RDtDbGluaWNhbCBEaXZpc2lvbiBv

ZiBOZXVyb2dlcmlhdHJpY3MgYW5kIERpdmlzaW9uIG9mIEdlbmVyYWwgTmV1cm9sb2d5LCBEZXBh

cnRtZW50IG9mIE5ldXJvbG9neSwgTWVkaWNhbCBVbml2ZXJzaXR5IEdyYXosIEF1ZW5icnVnZ2Vy

cGxhdHogMiwgODAzNiwgR3JheiwgQXVzdHJpYS4mI3hEO0F4b24gTmV1cm9zY2llbmNlIFImYW1w

O0QgU2VydmljZXMgU0UsIER2b3Jha292byBuYWJyZXppZSAxMCwgODExIDAyLCBCcmF0aXNsYXZh

LCBTbG92YWtpYS4mI3hEO0F4b24gTmV1cm9zY2llbmNlIENSTSBTZXJ2aWNlcyBTRSwgRHZvcmFr

b3ZvIG5hYnJlemllIDExLCA4MTEgMDIsIEJyYXRpc2xhdmEsIFNsb3Zha2lhLiYjeEQ7VW5pdmVy

c2l0eSBDbGluaWMgb2YgTmV1cm9sb2d5LCBNZWRpY2FsIFVuaXZlcnNpdHkgb2YgVmllbm5hLCBX

YWhyaW5nZXIgR3VydGVsIDE4LTIwLCAxMDkwLCBWaWVubmEsIEF1c3RyaWEuJiN4RDtVbml2ZXJz

aXR5IENsaW5pYyBvZiBDbGluaWNhbCBQaGFybWFjb2xvZ3ksIE1lZGljYWwgVW5pdmVyc2l0eSBv

ZiBWaWVubmEsIFdhaHJpbmdlciBHdXJ0ZWwgMTgtMjAsIDEwOTAsIFZpZW5uYSwgQXVzdHJpYS4m

I3hEO1VuaXZlcnNpdHkgQ2xpbmljIG9mIE5ldXJvbG9neSwgQ2hyaXN0aWFuLURvcHBsZXItQ2xp

bmljLCBJZ25hei1IYXJyZXItU3RyYXNzZSA3OSwgNTAyMCwgU2FsemJ1cmcsIEF1c3RyaWEuJiN4

RDtTb2NpYWwgYW5kIE1lZGljYWwgQ2VudHJlIEVhc3QsIERhbnViZSBIb3NwaXRhbCwgS2FybCBM

YW5kc3RlaW5lciBJbnN0aXR1dGUgZm9yIE1lbW9yeSBhbmQgQWx6aGVpbWVyIFJlc2VhcmNoLCBM

YW5nb2JhcmRlbnN0cmFzc2UgMTIyLCAxMjIwLCBWaWVubmEsIEF1c3RyaWEuJiN4RDtEaXZpc2lv

biBvZiBOZXVyb2dlcmlhdHJpY3MsIERlcGFydG1lbnQgTlZTIENsaW5pY2FsIFRyaWFsIFVuaXQs

IEthcm9saW5za2EgSW5zdGl0dXRlIEFsemhlaW1lciBEaXNlYXNlIFJlc2VhcmNoIENlbnRyZSwg

R2VyaWF0cmljIENsaW5pYywgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIYWxzb3Zh

Z2VuIDcsIFMtMTQxNTcsIEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtBeG9uIE5ldXJvc2NpZW5jZSBT

RSwgNCwgQXJjaC4gTWFrYXJpb3UgJmFtcDsgS2Fsb2dyZW9uLCBOaWNvbGFpZGVzIFNlYSBWaWV3

IENpdHksIDV0aCBmbG9vciwgb2ZmaWNlIDUwNiwgNjAxNiwgTGFybmFjYSwgQ3lwcnVzLjwvYXV0

aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkZVTkRBTUFOVDogYW4gaW50ZXJ2ZW50aW9uYWwgNzIt

d2VlayBwaGFzZSAxIGZvbGxvdy11cCBzdHVkeSBvZiBBQUR2YWMxLCBhbiBhY3RpdmUgaW1tdW5v

dGhlcmFweSBhZ2FpbnN0IHRhdSBwcm90ZWluIHBhdGhvbG9neSBpbiBBbHpoZWltZXImYXBvcztz

IGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWx6aGVpbWVycyBSZXMgVGhlcjwvc2Vj

b25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFsemhlaW1lcnMg

UmVzIFRoZXI8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMDg8L3BhZ2VzPjx2b2x1

bWU+MTA8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4yMDE4LzEwLzI2PC9lZGl0

aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BY3RpdmUgaW1tdW5vdGhlcmFweTwva2V5d29yZD48a2V5

d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Q2xpbmljYWwg

dHJpYWw8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5O

ZXVyb2ZpYnJpbGxhcnkgcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlRhdTwva2V5d29yZD48

a2V5d29yZD5WYWNjaW5lPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3ll

YXI+PHB1Yi1kYXRlcz48ZGF0ZT5PY3QgMjQ8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNi

bj4xNzU4LTkxOTMgKEVsZWN0cm9uaWMpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjMwMzU1MzIyPC9h

Y2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5s

bS5uaWguZ292L3B1Ym1lZC8zMDM1NTMyMjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3Vz

dG9tMj5QTUM2MjAxNTg2PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTg2

L3MxMzE5NS0wMTgtMDQzNi0xPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ob3ZhazwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

Y051bT4yMDgzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTcsNjY8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDgzPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NjE1NzUiPjIwODM8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk5vdmFrLCBQLjwvYXV0aG9yPjxhdXRo

b3I+U2NobWlkdCwgUi48L2F1dGhvcj48YXV0aG9yPktvbnRzZWtvdmEsIEUuPC9hdXRob3I+PGF1

dGhvcj5aaWxrYSwgTi48L2F1dGhvcj48YXV0aG9yPktvdmFjZWNoLCBCLjwvYXV0aG9yPjxhdXRo

b3I+U2tyYWJhbmEsIFIuPC9hdXRob3I+PGF1dGhvcj5WaW5jZS1LYXptZXJvdmEsIFouPC9hdXRo

b3I+PGF1dGhvcj5LYXRpbmEsIFMuPC9hdXRob3I+PGF1dGhvcj5GaWFsb3ZhLCBMLjwvYXV0aG9y

PjxhdXRob3I+UHJjaW5hLCBNLjwvYXV0aG9yPjxhdXRob3I+UGFycmFrLCBWLjwvYXV0aG9yPjxh

dXRob3I+RGFsLUJpYW5jbywgUC48L2F1dGhvcj48YXV0aG9yPkJydW5uZXIsIE0uPC9hdXRob3I+

PGF1dGhvcj5TdGFmZmVuLCBXLjwvYXV0aG9yPjxhdXRob3I+UmFpbmVyLCBNLjwvYXV0aG9yPjxh

dXRob3I+T25kcnVzLCBNLjwvYXV0aG9yPjxhdXRob3I+Um9wZWxlLCBTLjwvYXV0aG9yPjxhdXRo

b3I+U21pc2VrLCBNLjwvYXV0aG9yPjxhdXRob3I+U2l2YWssIFIuPC9hdXRob3I+PGF1dGhvcj5X

aW5ibGFkLCBCLjwvYXV0aG9yPjxhdXRob3I+Tm92YWssIE0uPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+QVhPTiBOZXVyb3NjaWVuY2UgU0UsIEJyYXRpc2xh

dmEsIFNsb3Zha2lhLiBFbGVjdHJvbmljIGFkZHJlc3M6IHBldHIubm92YWtAYXhvbi1uZXVyb3Nj

aWVuY2UuZXUuJiN4RDtDbGluaWNhbCBEaXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIERlcGFy

dG1lbnQgb2YgTmV1cm9sb2d5LCBNZWRpY2FsIFVuaXZlcnNpdHkgR3JheiwgR3JheiwgQXVzdHJp

YS4mI3hEO0FYT04gTmV1cm9zY2llbmNlIFNFLCBCcmF0aXNsYXZhLCBTbG92YWtpYS4mI3hEO1Vu

aXZlcnNpdHkgQ2xpbmljIG9mIE5ldXJvbG9neSwgTWVkaWNhbCBVbml2ZXJzaXR5IG9mIFZpZW5u

YSwgVmllbm5hLCBBdXN0cmlhLiYjeEQ7VW5pdmVyc2l0eSBDbGluaWMgb2YgQ2xpbmljYWwgUGhh

cm1hY29sb2d5LCBNZWRpY2FsIFVuaXZlcnNpdHkgb2YgVmllbm5hLCBWaWVubmEsIEF1c3RyaWEu

JiN4RDtVbml2ZXJzaXR5IENsaW5pYyBvZiBOZXVyb2xvZ3ksIENocmlzdGlhbi1Eb3BwbGVyLUNs

aW5pYywgU2FsemJ1cmcsIEF1c3RyaWEuJiN4RDtTb2NpYWwgYW5kIE1lZGljYWwgQ2VudHJlIEVh

c3QsIERhbnViZSBIb3NwaXRhbCwgS2FybCBMYW5kc3RlaW5lciBJbnN0aXR1dGUgZm9yIE1lbW9y

eSBhbmQgQWx6aGVpbWVyIFJlc2VhcmNoLCBWaWVubmEsIEF1c3RyaWEuJiN4RDtEaXZpc2lvbiBv

ZiBHZW5lcmFsIE5ldXJvbG9neSwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIE1lZGljYWwgVW5p

dmVyc2l0eSBHcmF6LCBHcmF6LCBBdXN0cmlhLiYjeEQ7S2Fyb2xpbnNrYSBJbnN0aXR1dGUgQWx6

aGVpbWVyIERpc2Vhc2UgUmVzZWFyY2ggQ2VudHJlIGFuZCBDbGluaWNhbCBUcmlhbCBVbml0LCBH

ZXJpYXRyaWMgQ2xpbmljLCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdl

LCBTd2VkZW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+U2FmZXR5IGFuZCBpbW11bm9n

ZW5pY2l0eSBvZiB0aGUgdGF1IHZhY2NpbmUgQUFEdmFjMSBpbiBwYXRpZW50cyB3aXRoIEFsemhl

aW1lciZhcG9zO3MgZGlzZWFzZTogYSByYW5kb21pc2VkLCBkb3VibGUtYmxpbmQsIHBsYWNlYm8t

Y29udHJvbGxlZCwgcGhhc2UgMSB0cmlhbDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5MYW5jZXQg

TmV1cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEyMy0xMzQ8L3BhZ2VzPjx2

b2x1bWU+MTY8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48ZWRpdGlvbj4yMDE2LzEyLzE0PC9l

ZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgw

IGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLyp0aGVyYXB5PC9r

ZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBWYWNjaW5lcy9hZHZlcnNlIGVmZmVjdHMvKnBoYXJt

YWNvbG9neTwva2V5d29yZD48a2V5d29yZD5Eb3VibGUtQmxpbmQgTWV0aG9kPC9rZXl3b3JkPjxr

ZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+

SW1tdW5vdGhlcmFweS9hZHZlcnNlIGVmZmVjdHMvKm1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+

TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD4qT3V0

Y29tZSBBc3Nlc3NtZW50IChIZWFsdGggQ2FyZSk8L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3Rl

aW5zLyppbW11bm9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3ll

YXI+PHB1Yi1kYXRlcz48ZGF0ZT5GZWI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

NDc0LTQ0NjUgKEVsZWN0cm9uaWMpJiN4RDsxNDc0LTQ0MjIgKExpbmtpbmcpPC9pc2JuPjxhY2Nl

c3Npb24tbnVtPjI3OTU1OTk1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy

bD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNzk1NTk5NTwvdXJsPjwvcmVs

YXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMTQ3NC00

NDIyKDE2KTMwMzMxLTM8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48

Q2l0ZT48QXV0aG9yPk5vdmFrPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVjTnVtPjQ2Mzg8

L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjQ2Mzg8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5

cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1

YXYiIHRpbWVzdGFtcD0iMTU0Mzg0NzU4MSI+NDYzODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYt

dHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxh

dXRob3JzPjxhdXRob3I+Tm92YWssIFAuPC9hdXRob3I+PGF1dGhvcj5TY2htaWR0LCBSLjwvYXV0

aG9yPjxhdXRob3I+S29udHNla292YSwgRS48L2F1dGhvcj48YXV0aG9yPktvdmFjZWNoLCBCLjwv

YXV0aG9yPjxhdXRob3I+U21vbGVrLCBULjwvYXV0aG9yPjxhdXRob3I+S2F0aW5hLCBTLjwvYXV0

aG9yPjxhdXRob3I+RmlhbG92YSwgTC48L2F1dGhvcj48YXV0aG9yPlByY2luYSwgTS48L2F1dGhv

cj48YXV0aG9yPlBhcnJhaywgVi48L2F1dGhvcj48YXV0aG9yPkRhbC1CaWFuY28sIFAuPC9hdXRo

b3I+PGF1dGhvcj5CcnVubmVyLCBNLjwvYXV0aG9yPjxhdXRob3I+U3RhZmZlbiwgVy48L2F1dGhv

cj48YXV0aG9yPlJhaW5lciwgTS48L2F1dGhvcj48YXV0aG9yPk9uZHJ1cywgTS48L2F1dGhvcj48

YXV0aG9yPlJvcGVsZSwgUy48L2F1dGhvcj48YXV0aG9yPlNtaXNlaywgTS48L2F1dGhvcj48YXV0

aG9yPlNpdmFrLCBSLjwvYXV0aG9yPjxhdXRob3I+Wmlsa2EsIE4uPC9hdXRob3I+PGF1dGhvcj5X

aW5ibGFkLCBCLjwvYXV0aG9yPjxhdXRob3I+Tm92YWssIE0uPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+QXhvbiBOZXVyb3NjaWVuY2UgQ1JNIFNlcnZpY2Vz

IFNFLCBEdm9yYWtvdm8gbmFicmV6aWUgMTEsIDgxMSAwMiwgQnJhdGlzbGF2YSwgU2xvdmFraWEu

IHBldHIubm92YWtAYXhvbi1uZXVyb3NjaWVuY2UuZXUuJiN4RDtDbGluaWNhbCBEaXZpc2lvbiBv

ZiBOZXVyb2dlcmlhdHJpY3MgYW5kIERpdmlzaW9uIG9mIEdlbmVyYWwgTmV1cm9sb2d5LCBEZXBh

cnRtZW50IG9mIE5ldXJvbG9neSwgTWVkaWNhbCBVbml2ZXJzaXR5IEdyYXosIEF1ZW5icnVnZ2Vy

cGxhdHogMiwgODAzNiwgR3JheiwgQXVzdHJpYS4mI3hEO0F4b24gTmV1cm9zY2llbmNlIFImYW1w

O0QgU2VydmljZXMgU0UsIER2b3Jha292byBuYWJyZXppZSAxMCwgODExIDAyLCBCcmF0aXNsYXZh

LCBTbG92YWtpYS4mI3hEO0F4b24gTmV1cm9zY2llbmNlIENSTSBTZXJ2aWNlcyBTRSwgRHZvcmFr

b3ZvIG5hYnJlemllIDExLCA4MTEgMDIsIEJyYXRpc2xhdmEsIFNsb3Zha2lhLiYjeEQ7VW5pdmVy

c2l0eSBDbGluaWMgb2YgTmV1cm9sb2d5LCBNZWRpY2FsIFVuaXZlcnNpdHkgb2YgVmllbm5hLCBX

YWhyaW5nZXIgR3VydGVsIDE4LTIwLCAxMDkwLCBWaWVubmEsIEF1c3RyaWEuJiN4RDtVbml2ZXJz

aXR5IENsaW5pYyBvZiBDbGluaWNhbCBQaGFybWFjb2xvZ3ksIE1lZGljYWwgVW5pdmVyc2l0eSBv

ZiBWaWVubmEsIFdhaHJpbmdlciBHdXJ0ZWwgMTgtMjAsIDEwOTAsIFZpZW5uYSwgQXVzdHJpYS4m

I3hEO1VuaXZlcnNpdHkgQ2xpbmljIG9mIE5ldXJvbG9neSwgQ2hyaXN0aWFuLURvcHBsZXItQ2xp

bmljLCBJZ25hei1IYXJyZXItU3RyYXNzZSA3OSwgNTAyMCwgU2FsemJ1cmcsIEF1c3RyaWEuJiN4

RDtTb2NpYWwgYW5kIE1lZGljYWwgQ2VudHJlIEVhc3QsIERhbnViZSBIb3NwaXRhbCwgS2FybCBM

YW5kc3RlaW5lciBJbnN0aXR1dGUgZm9yIE1lbW9yeSBhbmQgQWx6aGVpbWVyIFJlc2VhcmNoLCBM

YW5nb2JhcmRlbnN0cmFzc2UgMTIyLCAxMjIwLCBWaWVubmEsIEF1c3RyaWEuJiN4RDtEaXZpc2lv

biBvZiBOZXVyb2dlcmlhdHJpY3MsIERlcGFydG1lbnQgTlZTIENsaW5pY2FsIFRyaWFsIFVuaXQs

IEthcm9saW5za2EgSW5zdGl0dXRlIEFsemhlaW1lciBEaXNlYXNlIFJlc2VhcmNoIENlbnRyZSwg

R2VyaWF0cmljIENsaW5pYywgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIYWxzb3Zh

Z2VuIDcsIFMtMTQxNTcsIEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtBeG9uIE5ldXJvc2NpZW5jZSBT

RSwgNCwgQXJjaC4gTWFrYXJpb3UgJmFtcDsgS2Fsb2dyZW9uLCBOaWNvbGFpZGVzIFNlYSBWaWV3

IENpdHksIDV0aCBmbG9vciwgb2ZmaWNlIDUwNiwgNjAxNiwgTGFybmFjYSwgQ3lwcnVzLjwvYXV0

aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkZVTkRBTUFOVDogYW4gaW50ZXJ2ZW50aW9uYWwgNzIt

d2VlayBwaGFzZSAxIGZvbGxvdy11cCBzdHVkeSBvZiBBQUR2YWMxLCBhbiBhY3RpdmUgaW1tdW5v

dGhlcmFweSBhZ2FpbnN0IHRhdSBwcm90ZWluIHBhdGhvbG9neSBpbiBBbHpoZWltZXImYXBvcztz

IGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWx6aGVpbWVycyBSZXMgVGhlcjwvc2Vj

b25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFsemhlaW1lcnMg

UmVzIFRoZXI8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMDg8L3BhZ2VzPjx2b2x1

bWU+MTA8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4yMDE4LzEwLzI2PC9lZGl0

aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BY3RpdmUgaW1tdW5vdGhlcmFweTwva2V5d29yZD48a2V5

d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Q2xpbmljYWwg

dHJpYWw8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5O

ZXVyb2ZpYnJpbGxhcnkgcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlRhdTwva2V5d29yZD48

a2V5d29yZD5WYWNjaW5lPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3ll

YXI+PHB1Yi1kYXRlcz48ZGF0ZT5PY3QgMjQ8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNi

bj4xNzU4LTkxOTMgKEVsZWN0cm9uaWMpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjMwMzU1MzIyPC9h

Y2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5s

bS5uaWguZ292L3B1Ym1lZC8zMDM1NTMyMjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3Vz

dG9tMj5QTUM2MjAxNTg2PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTg2

L3MxMzE5NS0wMTgtMDQzNi0xPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 17,66. The latest report showed slower atrophy in the hippocampus in patients with high titres of antibody response and less cognitive decline.AdvantagesDisadvantagesCostPASSIVE IMMUNOTHERAPIESAducanumab ADDIN EN.CITE <EndNote><Cite><Author>Budd Haeberlein</Author><Year>2017</Year><RecNum>2026</RecNum><DisplayText><style face="superscript">57</style></DisplayText><record><rec-number>2026</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1534510285">2026</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Budd Haeberlein, S.</author><author>O&apos;Gorman, J.</author><author>Chiao, P.</author><author>Bussiere, T.</author><author>von Rosenstiel, P.</author><author>Tian, Y.</author><author>Zhu, Y.</author><author>von Hehn, C.</author><author>Gheuens, S.</author><author>Skordos, L.</author><author>Chen, T.</author><author>Sandrock, A.</author></authors></contributors><auth-address>Samantha Budd Haeberlein, Cambridge, 225 Binney Street, Cambridge, MA 02142, USA, Email: samantha.buddhaeberlein@, Telephone: (617) 679-2000.</auth-address><titles><title>Clinical Development of Aducanumab, an Anti-Abeta Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer&apos;s Disease</title><secondary-title>J Prev Alzheimers Dis</secondary-title></titles><periodical><full-title>J Prev Alzheimers Dis</full-title></periodical><pages>255-263</pages><volume>4</volume><number>4</number><edition>2017/11/29</edition><keywords><keyword>*Alzheimer&apos;s disease</keyword><keyword>*aducanumab</keyword><keyword>*amyloid-beta</keyword><keyword>Biogen</keyword><keyword>TB: employee and stock ownership, patent holder, Biogen.</keyword></keywords><dates><year>2017</year></dates><isbn>2426-0266 (Electronic)&#xD;2274-5807 (Linking)</isbn><accession-num>29181491</accession-num><urls><related-urls><url>

Y051bT4yMDg0PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NTg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDg0PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NjIyMDUiPjIwODQ8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhvbmlnLCBMLiBTLjwvYXV0aG9yPjxhdXRo

b3I+VmVsbGFzLCBCLjwvYXV0aG9yPjxhdXRob3I+V29vZHdhcmQsIE0uPC9hdXRob3I+PGF1dGhv

cj5Cb2FkYSwgTS48L2F1dGhvcj48YXV0aG9yPkJ1bGxvY2ssIFIuPC9hdXRob3I+PGF1dGhvcj5C

b3JyaWUsIE0uPC9hdXRob3I+PGF1dGhvcj5IYWdlciwgSy48L2F1dGhvcj48YXV0aG9yPkFuZHJl

YXNlbiwgTi48L2F1dGhvcj48YXV0aG9yPlNjYXJwaW5pLCBFLjwvYXV0aG9yPjxhdXRob3I+TGl1

LVNlaWZlcnQsIEguPC9hdXRob3I+PGF1dGhvcj5DYXNlLCBNLjwvYXV0aG9yPjxhdXRob3I+RGVh

biwgUi4gQS48L2F1dGhvcj48YXV0aG9yPkhha2UsIEEuPC9hdXRob3I+PGF1dGhvcj5TdW5kZWxs

LCBLLjwvYXV0aG9yPjxhdXRob3I+UG9vbGUgSG9mZm1hbm4sIFYuPC9hdXRob3I+PGF1dGhvcj5D

YXJsc29uLCBDLjwvYXV0aG9yPjxhdXRob3I+S2hhbm5hLCBSLjwvYXV0aG9yPjxhdXRob3I+TWlu

dHVuLCBNLjwvYXV0aG9yPjxhdXRob3I+RGVNYXR0b3MsIFIuPC9hdXRob3I+PGF1dGhvcj5TZWx6

bGVyLCBLLiBKLjwvYXV0aG9yPjxhdXRob3I+U2llbWVycywgRS48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Gcm9tIHRoZSBEZXBhcnRtZW50IG9mIE5ldXJv

bG9neSBhbmQgVGF1YiBJbnN0aXR1dGUgZm9yIFJlc2VhcmNoIG9uIEFsemhlaW1lciZhcG9zO3Mg

RGlzZWFzZSBhbmQgdGhlIEFnaW5nIEJyYWluLCBDb2x1bWJpYSBVbml2ZXJzaXR5IE1lZGljYWwg

Q2VudGVyLCBOZXcgWW9yayAoTC5TLkguKTsgR2Vyb250b3BvbGUsIENlbnRyZSBIb3NwaXRhbGll

ciBVbml2ZXJzaXRhaXJlIFRvdWxvdXNlLCBVbml0ZSBNaXh0ZSBkZSBSZWNoZXJjaGUgSU5TRVJN

IFVuaXRlIDEwMjcgVW5pdmVyc2l0ZSBUb3Vsb3VzZSBJSUktUGF1bCBTYWJhdGllciwgVG91bG91

c2UsIEZyYW5jZSAoQi5WLik7IEF1c3RpbiBIZWFsdGggQ29udGludWluZyBDYXJlIENsaW5pY2Fs

IFNlcnZpY2UgVW5pdCwgSGVpZGVsYmVyZywgYW5kIHRoZSBVbml2ZXJzaXR5IG9mIE1lbGJvdXJu

ZSwgTWVsYm91cm5lLCBWSUMgLSBib3RoIGluIEF1c3RyYWxpYSAoTS5XLik7IEZ1bmRhY2lvIEFD

RSwgQWx6aGVpbWVyIFJlc2VhcmNoIENlbnRlciBhbmQgTWVtb3J5IENsaW5pYywgSW5zdGl0dXQg

Q2F0YWxhIGRlIE5ldXJvY2llbmNpZXMgQXBsaWNhZGVzLCBCYXJjZWxvbmEgKE0uIEJvYWRhKTsg

S2luZ3NoaWxsIFJlc2VhcmNoIENlbnRyZSwgVmljdG9yaWEgSG9zcGl0YWwsIFN3aW5kb24sIFVu

aXRlZCBLaW5nZG9tIChSLkIuKTsgdGhlIERpdmlzaW9uIG9mIEdlcmlhdHJpYyBNZWRpY2luZSwg

U2NodWxpY2ggU2Nob29sIG9mIE1lZGljaW5lIGFuZCBEZW50aXN0cnksIFdlc3Rlcm4gVW5pdmVy

c2l0eSwgTG9uZG9uLCBPTiwgQ2FuYWRhIChNLiBCb3JyaWUpOyBDbGluaWMgZm9yIE1lZGljaW5l

IG9mIHRoZSBFbGRlcmx5LCBEaWFrb3ZlcmUgSGVucmlldHRlbnN0aWZ0LCBIYW5ub3ZlciwgR2Vy

bWFueSAoSy5ILik7IEthcm9saW5za2EgSW5zdGl0dXRldCBBbHpoZWltZXImYXBvcztzIERpc2Vh

c2UgUmVzZWFyY2ggQ2VudGVyIGFuZCBDbGluaWNhbCBUcmlhbCBVbml0LCBHZXJpYXRyaWMgQ2xp

bmljLCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCBTd2VkZW4gKE4u

QS4pOyB0aGUgRGVwYXJ0bWVudCBvZiBQYXRob3BoeXNpb2xvZ3kgYW5kIFRyYW5zcGxhbnRhdGlv

biwgTmV1cm9sb2d5IFVuaXQsIERpbm8gRmVycmFyaSBDZW50ZXIsIFVuaXZlcnNpdHkgb2YgTWls

YW4sIEZvbmRhemlvbmUgQ2EmYXBvczsgR3JhbmRhLCBJc3RpdHV0byBkaSBSaWNvdmVybyBlIEN1

cmEgYSBDYXJhdHRlcmUgU2NpZW50aWZpY28gT3NwZWRhbGUgUG9saWNsaW5pY28sIE1pbGFuIChF

LiBTY2FycGluaSk7IEVsaSBMaWxseSAoSC5MLi1TLiwgTS5DLiwgQS5ILiwgSy5TLiwgVi5QLkgu

LCBDLkMuLCBSLksuLCBNLk0uLCBSLkQuLCBLLkouUy4sIEUuIFNpZW1lcnMpIGFuZCB0aGUgRGVw

YXJ0bWVudCBvZiBQYXRob2xvZ3kgYW5kIExhYm9yYXRvcnkgTWVkaWNpbmUsIEluZGlhbmEgVW5p

dmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUgKFIuQS5ELikgLSBib3RoIGluIEluZGlhbmFwb2xp

czsgYW5kIEF2aWQgUmFkaW9waGFybWFjZXV0aWNhbHMsIFBoaWxhZGVscGhpYSAoTS5NLikuPC9h

dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VHJpYWwgb2YgU29sYW5lenVtYWIgZm9yIE1pbGQg

RGVtZW50aWEgRHVlIHRvIEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZTwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5OIEVuZ2wgSiBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MzIx

LTMzMDwvcGFnZXM+PHZvbHVtZT4zNzg8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZWRpdGlv

bj4yMDE4LzAxLzI1PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BY3Rpdml0aWVzIG9mIERh

aWx5IExpdmluZzwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQs

IDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2RpYWdub3Np

cy8qZHJ1ZyB0aGVyYXB5L3BzeWNob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRh

LVBlcHRpZGVzL2NlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJvZGll

cywgTW9ub2Nsb25hbCwgSHVtYW5pemVkL2FkdmVyc2UgZWZmZWN0cy8qdGhlcmFwZXV0aWMgdXNl

PC9rZXl3b3JkPjxrZXl3b3JkPkJpb21hcmtlcnMvY2VyZWJyb3NwaW5hbCBmbHVpZDwva2V5d29y

ZD48a2V5d29yZD5Eb3VibGUtQmxpbmQgTWV0aG9kPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwv

a2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+KkltbXVub3RoZXJhcHk8

L2tleXdvcmQ+PGtleXdvcmQ+SW5mdXNpb25zLCBJbnRyYXZlbm91czwva2V5d29yZD48a2V5d29y

ZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbnRhbCBTdGF0dXMgYW5kIERlbWVudGlhIFRlc3Rz

PC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBlcHRpZGUg

RnJhZ21lbnRzL2NlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+UGxhcXVlLCBB

bXlsb2lkL2RydWcgdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Qb3NpdHJvbi1FbWlzc2lvbiBU

b21vZ3JhcGh5PC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBGYWlsdXJlPC9rZXl3b3JkPjwv

a2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KYW4gMjU8

L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTMzLTQ0MDYgKEVsZWN0cm9uaWMpJiN4

RDswMDI4LTQ3OTMgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5MzY1Mjk0PC9hY2Nl

c3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5u

aWguZ292L3B1Ym1lZC8yOTM2NTI5NDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTA1Ni9ORUpNb2ExNzA1OTcxPC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib25pZzwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl

Y051bT4yMDg0PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NTg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDg0PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NjIyMDUiPjIwODQ8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhvbmlnLCBMLiBTLjwvYXV0aG9yPjxhdXRo

b3I+VmVsbGFzLCBCLjwvYXV0aG9yPjxhdXRob3I+V29vZHdhcmQsIE0uPC9hdXRob3I+PGF1dGhv

cj5Cb2FkYSwgTS48L2F1dGhvcj48YXV0aG9yPkJ1bGxvY2ssIFIuPC9hdXRob3I+PGF1dGhvcj5C

b3JyaWUsIE0uPC9hdXRob3I+PGF1dGhvcj5IYWdlciwgSy48L2F1dGhvcj48YXV0aG9yPkFuZHJl

YXNlbiwgTi48L2F1dGhvcj48YXV0aG9yPlNjYXJwaW5pLCBFLjwvYXV0aG9yPjxhdXRob3I+TGl1

LVNlaWZlcnQsIEguPC9hdXRob3I+PGF1dGhvcj5DYXNlLCBNLjwvYXV0aG9yPjxhdXRob3I+RGVh

biwgUi4gQS48L2F1dGhvcj48YXV0aG9yPkhha2UsIEEuPC9hdXRob3I+PGF1dGhvcj5TdW5kZWxs

LCBLLjwvYXV0aG9yPjxhdXRob3I+UG9vbGUgSG9mZm1hbm4sIFYuPC9hdXRob3I+PGF1dGhvcj5D

YXJsc29uLCBDLjwvYXV0aG9yPjxhdXRob3I+S2hhbm5hLCBSLjwvYXV0aG9yPjxhdXRob3I+TWlu

dHVuLCBNLjwvYXV0aG9yPjxhdXRob3I+RGVNYXR0b3MsIFIuPC9hdXRob3I+PGF1dGhvcj5TZWx6

bGVyLCBLLiBKLjwvYXV0aG9yPjxhdXRob3I+U2llbWVycywgRS48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Gcm9tIHRoZSBEZXBhcnRtZW50IG9mIE5ldXJv

bG9neSBhbmQgVGF1YiBJbnN0aXR1dGUgZm9yIFJlc2VhcmNoIG9uIEFsemhlaW1lciZhcG9zO3Mg

RGlzZWFzZSBhbmQgdGhlIEFnaW5nIEJyYWluLCBDb2x1bWJpYSBVbml2ZXJzaXR5IE1lZGljYWwg

Q2VudGVyLCBOZXcgWW9yayAoTC5TLkguKTsgR2Vyb250b3BvbGUsIENlbnRyZSBIb3NwaXRhbGll

ciBVbml2ZXJzaXRhaXJlIFRvdWxvdXNlLCBVbml0ZSBNaXh0ZSBkZSBSZWNoZXJjaGUgSU5TRVJN

IFVuaXRlIDEwMjcgVW5pdmVyc2l0ZSBUb3Vsb3VzZSBJSUktUGF1bCBTYWJhdGllciwgVG91bG91

c2UsIEZyYW5jZSAoQi5WLik7IEF1c3RpbiBIZWFsdGggQ29udGludWluZyBDYXJlIENsaW5pY2Fs

IFNlcnZpY2UgVW5pdCwgSGVpZGVsYmVyZywgYW5kIHRoZSBVbml2ZXJzaXR5IG9mIE1lbGJvdXJu

ZSwgTWVsYm91cm5lLCBWSUMgLSBib3RoIGluIEF1c3RyYWxpYSAoTS5XLik7IEZ1bmRhY2lvIEFD

RSwgQWx6aGVpbWVyIFJlc2VhcmNoIENlbnRlciBhbmQgTWVtb3J5IENsaW5pYywgSW5zdGl0dXQg

Q2F0YWxhIGRlIE5ldXJvY2llbmNpZXMgQXBsaWNhZGVzLCBCYXJjZWxvbmEgKE0uIEJvYWRhKTsg

S2luZ3NoaWxsIFJlc2VhcmNoIENlbnRyZSwgVmljdG9yaWEgSG9zcGl0YWwsIFN3aW5kb24sIFVu

aXRlZCBLaW5nZG9tIChSLkIuKTsgdGhlIERpdmlzaW9uIG9mIEdlcmlhdHJpYyBNZWRpY2luZSwg

U2NodWxpY2ggU2Nob29sIG9mIE1lZGljaW5lIGFuZCBEZW50aXN0cnksIFdlc3Rlcm4gVW5pdmVy

c2l0eSwgTG9uZG9uLCBPTiwgQ2FuYWRhIChNLiBCb3JyaWUpOyBDbGluaWMgZm9yIE1lZGljaW5l

IG9mIHRoZSBFbGRlcmx5LCBEaWFrb3ZlcmUgSGVucmlldHRlbnN0aWZ0LCBIYW5ub3ZlciwgR2Vy

bWFueSAoSy5ILik7IEthcm9saW5za2EgSW5zdGl0dXRldCBBbHpoZWltZXImYXBvcztzIERpc2Vh

c2UgUmVzZWFyY2ggQ2VudGVyIGFuZCBDbGluaWNhbCBUcmlhbCBVbml0LCBHZXJpYXRyaWMgQ2xp

bmljLCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCBTd2VkZW4gKE4u

QS4pOyB0aGUgRGVwYXJ0bWVudCBvZiBQYXRob3BoeXNpb2xvZ3kgYW5kIFRyYW5zcGxhbnRhdGlv

biwgTmV1cm9sb2d5IFVuaXQsIERpbm8gRmVycmFyaSBDZW50ZXIsIFVuaXZlcnNpdHkgb2YgTWls

YW4sIEZvbmRhemlvbmUgQ2EmYXBvczsgR3JhbmRhLCBJc3RpdHV0byBkaSBSaWNvdmVybyBlIEN1

cmEgYSBDYXJhdHRlcmUgU2NpZW50aWZpY28gT3NwZWRhbGUgUG9saWNsaW5pY28sIE1pbGFuIChF

LiBTY2FycGluaSk7IEVsaSBMaWxseSAoSC5MLi1TLiwgTS5DLiwgQS5ILiwgSy5TLiwgVi5QLkgu

LCBDLkMuLCBSLksuLCBNLk0uLCBSLkQuLCBLLkouUy4sIEUuIFNpZW1lcnMpIGFuZCB0aGUgRGVw

YXJ0bWVudCBvZiBQYXRob2xvZ3kgYW5kIExhYm9yYXRvcnkgTWVkaWNpbmUsIEluZGlhbmEgVW5p

dmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUgKFIuQS5ELikgLSBib3RoIGluIEluZGlhbmFwb2xp

czsgYW5kIEF2aWQgUmFkaW9waGFybWFjZXV0aWNhbHMsIFBoaWxhZGVscGhpYSAoTS5NLikuPC9h

dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VHJpYWwgb2YgU29sYW5lenVtYWIgZm9yIE1pbGQg

RGVtZW50aWEgRHVlIHRvIEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZTwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5OIEVuZ2wgSiBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MzIx

LTMzMDwvcGFnZXM+PHZvbHVtZT4zNzg8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZWRpdGlv

bj4yMDE4LzAxLzI1PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BY3Rpdml0aWVzIG9mIERh

aWx5IExpdmluZzwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQs

IDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2RpYWdub3Np

cy8qZHJ1ZyB0aGVyYXB5L3BzeWNob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRh

LVBlcHRpZGVzL2NlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJvZGll

cywgTW9ub2Nsb25hbCwgSHVtYW5pemVkL2FkdmVyc2UgZWZmZWN0cy8qdGhlcmFwZXV0aWMgdXNl

PC9rZXl3b3JkPjxrZXl3b3JkPkJpb21hcmtlcnMvY2VyZWJyb3NwaW5hbCBmbHVpZDwva2V5d29y

ZD48a2V5d29yZD5Eb3VibGUtQmxpbmQgTWV0aG9kPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwv

a2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+KkltbXVub3RoZXJhcHk8

L2tleXdvcmQ+PGtleXdvcmQ+SW5mdXNpb25zLCBJbnRyYXZlbm91czwva2V5d29yZD48a2V5d29y

ZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbnRhbCBTdGF0dXMgYW5kIERlbWVudGlhIFRlc3Rz

PC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBlcHRpZGUg

RnJhZ21lbnRzL2NlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+UGxhcXVlLCBB

bXlsb2lkL2RydWcgdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Qb3NpdHJvbi1FbWlzc2lvbiBU

b21vZ3JhcGh5PC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBGYWlsdXJlPC9rZXl3b3JkPjwv

a2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KYW4gMjU8

L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTMzLTQ0MDYgKEVsZWN0cm9uaWMpJiN4

RDswMDI4LTQ3OTMgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5MzY1Mjk0PC9hY2Nl

c3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5u

aWguZ292L3B1Ym1lZC8yOTM2NTI5NDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTA1Ni9ORUpNb2ExNzA1OTcxPC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 58BAN2401PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb2dvdmluc2t5PC9BdXRob3I+PFllYXI+MjAxNjwvWWVh

cj48UmVjTnVtPjM5MDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2Ny

aXB0Ij42Nzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM5MDk8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjEzOTY2MCI+MzkwOTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TG9nb3ZpbnNreSwgVi48L2F1dGhv

cj48YXV0aG9yPlNhdGxpbiwgQS48L2F1dGhvcj48YXV0aG9yPkxhaSwgUi48L2F1dGhvcj48YXV0

aG9yPlN3YW5zb24sIEMuPC9hdXRob3I+PGF1dGhvcj5LYXBsb3csIEouPC9hdXRob3I+PGF1dGhv

cj5Pc3N3YWxkLCBHLjwvYXV0aG9yPjxhdXRob3I+QmFzdW4sIEguPC9hdXRob3I+PGF1dGhvcj5M

YW5uZmVsdCwgTC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVz

cz5FaXNhaSwgSW5jLiwgMTAwIFRpY2UgQmx2ZCwgV29vZGNsaWZmIExha2UsIE5KLCAwNzY3Nywg

VVNBLiYjeEQ7QmlvQXJjdGljIE5ldXJvc2NpZW5jZSBBQiwgV2FyZnZpbmdlcyB2YWcgMzUsIDEx

MiA1MSwgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFsdGgv

R2VyaWF0cmljcywgVXBwc2FsYSBVbml2ZXJzaXR5LCBEYWcgSGFtbWFyc2tpb2xkcyB2YWcgMTQg

QiwgNzUxIDg1LCBVcHBzYWxhLCBTd2VkZW4uJiN4RDtCaW9BcmN0aWMgTmV1cm9zY2llbmNlIEFC

LCBXYXJmdmluZ2VzIHZhZyAzNSwgMTEyIDUxLCBTdG9ja2hvbG0sIFN3ZWRlbi4gTGFycy5MYW5u

ZmVsdEBwdWJjYXJlLnV1LnNlLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoL0dlcmlh

dHJpY3MsIFVwcHNhbGEgVW5pdmVyc2l0eSwgRGFnIEhhbW1hcnNraW9sZHMgdmFnIDE0IEIsIDc1

MSA4NSwgVXBwc2FsYSwgU3dlZGVuLiBMYXJzLkxhbm5mZWx0QHB1YmNhcmUudXUuc2UuPC9hdXRo

LWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+U2FmZXR5IGFuZCB0b2xlcmFiaWxpdHkgb2YgQkFOMjQw

MS0tYSBjbGluaWNhbCBzdHVkeSBpbiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2Ugd2l0aCBhIHBy

b3RvZmlicmlsIHNlbGVjdGl2ZSBBYmV0YSBhbnRpYm9keTwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5BbHpoZWltZXJzIFJlcyBUaGVyPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+QWx6aGVpbWVycyBSZXMgVGhlcjwvZnVsbC10aXRsZT48L3BlcmlvZGlj

YWw+PHBhZ2VzPjE0PC9wYWdlcz48dm9sdW1lPjg8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48

ZWRpdGlvbj4yMDE2LzA0LzA3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3

b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2Jsb29kLypkcnVnIHRoZXJhcHkvaW1tdW5v

bG9neTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvYmxvb2QvKmltbXVu

b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJvZGllcywgTW9ub2Nsb25hbCwgSHVtYW5pemVk

LyphZHZlcnNlIGVmZmVjdHMvcGhhcm1hY29raW5ldGljcy8qdGhlcmFwZXV0aWM8L2tleXdvcmQ+

PGtleXdvcmQ+dXNlPC9rZXl3b3JkPjxrZXl3b3JkPkJpb21hcmtlcnMvYmxvb2Q8L2tleXdvcmQ+

PGtleXdvcmQ+QnJhaW4vZHJ1ZyBlZmZlY3RzL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5E

b3NlLVJlc3BvbnNlIFJlbGF0aW9uc2hpcCwgRHJ1Zzwva2V5d29yZD48a2V5d29yZD5Eb3VibGUt

QmxpbmQgTWV0aG9kPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5I

dW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5QZXB0aWRlIEZy

YWdtZW50cy9ibG9vZDwva2V5d29yZD48a2V5d29yZD5BcmlhPC9rZXl3b3JkPjxrZXl3b3JkPkFs

emhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkLWJldGE8L2tl

eXdvcmQ+PGtleXdvcmQ+QWJldGE8L2tleXdvcmQ+PGtleXdvcmQ+QmFuMjQwMTwva2V5d29yZD48

a2V5d29yZD5DbGluaWNhbCB0cmlhbDwva2V5d29yZD48a2V5d29yZD5JbW11bm90aGVyYXB5PC9r

ZXl3b3JkPjxrZXl3b3JkPlByb3RvZmlicmlsPC9rZXl3b3JkPjxrZXl3b3JkPm1BYjE1ODwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

QXByIDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNzU4LTkxOTMgKEVsZWN0cm9u

aWMpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3MDQ4MTcwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxy

ZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNzA0

ODE3MDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0ODIyMjk3PC9jdXN0

b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTg2L3MxMzE5NS0wMTYtMDE4MS0yPC9l

bGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb2dvdmluc2t5PC9BdXRob3I+PFllYXI+MjAxNjwvWWVh

cj48UmVjTnVtPjM5MDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2Ny

aXB0Ij42Nzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM5MDk8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjEzOTY2MCI+MzkwOTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TG9nb3ZpbnNreSwgVi48L2F1dGhv

cj48YXV0aG9yPlNhdGxpbiwgQS48L2F1dGhvcj48YXV0aG9yPkxhaSwgUi48L2F1dGhvcj48YXV0

aG9yPlN3YW5zb24sIEMuPC9hdXRob3I+PGF1dGhvcj5LYXBsb3csIEouPC9hdXRob3I+PGF1dGhv

cj5Pc3N3YWxkLCBHLjwvYXV0aG9yPjxhdXRob3I+QmFzdW4sIEguPC9hdXRob3I+PGF1dGhvcj5M

YW5uZmVsdCwgTC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVz

cz5FaXNhaSwgSW5jLiwgMTAwIFRpY2UgQmx2ZCwgV29vZGNsaWZmIExha2UsIE5KLCAwNzY3Nywg

VVNBLiYjeEQ7QmlvQXJjdGljIE5ldXJvc2NpZW5jZSBBQiwgV2FyZnZpbmdlcyB2YWcgMzUsIDEx

MiA1MSwgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFsdGgv

R2VyaWF0cmljcywgVXBwc2FsYSBVbml2ZXJzaXR5LCBEYWcgSGFtbWFyc2tpb2xkcyB2YWcgMTQg

QiwgNzUxIDg1LCBVcHBzYWxhLCBTd2VkZW4uJiN4RDtCaW9BcmN0aWMgTmV1cm9zY2llbmNlIEFC

LCBXYXJmdmluZ2VzIHZhZyAzNSwgMTEyIDUxLCBTdG9ja2hvbG0sIFN3ZWRlbi4gTGFycy5MYW5u

ZmVsdEBwdWJjYXJlLnV1LnNlLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoL0dlcmlh

dHJpY3MsIFVwcHNhbGEgVW5pdmVyc2l0eSwgRGFnIEhhbW1hcnNraW9sZHMgdmFnIDE0IEIsIDc1

MSA4NSwgVXBwc2FsYSwgU3dlZGVuLiBMYXJzLkxhbm5mZWx0QHB1YmNhcmUudXUuc2UuPC9hdXRo

LWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+U2FmZXR5IGFuZCB0b2xlcmFiaWxpdHkgb2YgQkFOMjQw

MS0tYSBjbGluaWNhbCBzdHVkeSBpbiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2Ugd2l0aCBhIHBy

b3RvZmlicmlsIHNlbGVjdGl2ZSBBYmV0YSBhbnRpYm9keTwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5BbHpoZWltZXJzIFJlcyBUaGVyPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+QWx6aGVpbWVycyBSZXMgVGhlcjwvZnVsbC10aXRsZT48L3BlcmlvZGlj

YWw+PHBhZ2VzPjE0PC9wYWdlcz48dm9sdW1lPjg8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48

ZWRpdGlvbj4yMDE2LzA0LzA3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3

b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2Jsb29kLypkcnVnIHRoZXJhcHkvaW1tdW5v

bG9neTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvYmxvb2QvKmltbXVu

b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJvZGllcywgTW9ub2Nsb25hbCwgSHVtYW5pemVk

LyphZHZlcnNlIGVmZmVjdHMvcGhhcm1hY29raW5ldGljcy8qdGhlcmFwZXV0aWM8L2tleXdvcmQ+

PGtleXdvcmQ+dXNlPC9rZXl3b3JkPjxrZXl3b3JkPkJpb21hcmtlcnMvYmxvb2Q8L2tleXdvcmQ+

PGtleXdvcmQ+QnJhaW4vZHJ1ZyBlZmZlY3RzL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5E

b3NlLVJlc3BvbnNlIFJlbGF0aW9uc2hpcCwgRHJ1Zzwva2V5d29yZD48a2V5d29yZD5Eb3VibGUt

QmxpbmQgTWV0aG9kPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5I

dW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5QZXB0aWRlIEZy

YWdtZW50cy9ibG9vZDwva2V5d29yZD48a2V5d29yZD5BcmlhPC9rZXl3b3JkPjxrZXl3b3JkPkFs

emhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkLWJldGE8L2tl

eXdvcmQ+PGtleXdvcmQ+QWJldGE8L2tleXdvcmQ+PGtleXdvcmQ+QmFuMjQwMTwva2V5d29yZD48

a2V5d29yZD5DbGluaWNhbCB0cmlhbDwva2V5d29yZD48a2V5d29yZD5JbW11bm90aGVyYXB5PC9r

ZXl3b3JkPjxrZXl3b3JkPlByb3RvZmlicmlsPC9rZXl3b3JkPjxrZXl3b3JkPm1BYjE1ODwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

QXByIDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNzU4LTkxOTMgKEVsZWN0cm9u

aWMpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3MDQ4MTcwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxy

ZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNzA0

ODE3MDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0ODIyMjk3PC9jdXN0

b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTg2L3MxMzE5NS0wMTYtMDE4MS0yPC9l

bGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 67Increased control of epitope binding affinity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJkPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVj

TnVtPjQyNTQ8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij42

ODwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQyNTQ8L3JlYy1udW1i

ZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBo

cGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjkxNzMwNSI+NDI1NDwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QmFyZCwgRi48L2F1dGhvcj48YXV0aG9yPkJh

cmJvdXIsIFIuPC9hdXRob3I+PGF1dGhvcj5DYW5ub24sIEMuPC9hdXRob3I+PGF1dGhvcj5DYXJy

ZXR0bywgUi48L2F1dGhvcj48YXV0aG9yPkZveCwgTS48L2F1dGhvcj48YXV0aG9yPkdhbWVzLCBE

LjwvYXV0aG9yPjxhdXRob3I+R3VpZG8sIFQuPC9hdXRob3I+PGF1dGhvcj5Ib2Vub3csIEsuPC9h

dXRob3I+PGF1dGhvcj5IdSwgSy48L2F1dGhvcj48YXV0aG9yPkpvaG5zb24tV29vZCwgSy48L2F1

dGhvcj48YXV0aG9yPktoYW4sIEsuPC9hdXRob3I+PGF1dGhvcj5LaG9sb2RlbmtvLCBELjwvYXV0

aG9yPjxhdXRob3I+TGVlLCBDLjwvYXV0aG9yPjxhdXRob3I+TGVlLCBNLjwvYXV0aG9yPjxhdXRo

b3I+TW90dGVyLCBSLjwvYXV0aG9yPjxhdXRob3I+Tmd1eWVuLCBNLjwvYXV0aG9yPjxhdXRob3I+

UmVlZCwgQS48L2F1dGhvcj48YXV0aG9yPlNjaGVuaywgRC48L2F1dGhvcj48YXV0aG9yPlRhbmcs

IFAuPC9hdXRob3I+PGF1dGhvcj5WYXNxdWV6LCBOLjwvYXV0aG9yPjxhdXRob3I+U2V1YmVydCwg

UC48L2F1dGhvcj48YXV0aG9yPlllZG5vY2ssIFQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp

YnV0b3JzPjxhdXRoLWFkZHJlc3M+RWxhbiBQaGFybWFjZXV0aWNhbHMsIDgwMCBHYXRld2F5IEJv

dWxldmFyZCwgU291dGggU2FuIEZyYW5jaXNjbywgQ0EgOTQwODAsIFVTQS4gZnJlZGVyaXF1ZS5i

YXJkQGVsYW4uY29tPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+RXBpdG9wZSBhbmQgaXNv

dHlwZSBzcGVjaWZpY2l0aWVzIG9mIGFudGlib2RpZXMgdG8gYmV0YSAtYW15bG9pZCBwZXB0aWRl

IGZvciBwcm90ZWN0aW9uIGFnYWluc3QgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlLWxpa2UgbmV1

cm9wYXRob2xvZ3k8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2NpIFUg

UyBBPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UHJv

YyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjAy

My04PC9wYWdlcz48dm9sdW1lPjEwMDwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxlZGl0aW9u

PjIwMDMvMDIvMDU8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNl

L2ltbXVub2xvZ3kvKnByZXZlbnRpb24gJmFtcDsgY29udHJvbDwva2V5d29yZD48a2V5d29yZD5B

bWlubyBBY2lkIFNlcXVlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRl

cy8qY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkFudGlib2RpZXMsIE1vbm9jbG9uYWwvKmlt

bXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+KkFudGlib2R5IFNwZWNpZmljaXR5PC9rZXl3b3Jk

PjxrZXl3b3JkPkVwaXRvcGUgTWFwcGluZzwva2V5d29yZD48a2V5d29yZD5FcGl0b3Blcy8qaW1t

dW5vbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TW9sZWN1

bGFyIFNlcXVlbmNlIERhdGE8L2tleXdvcmQ+PGtleXdvcmQ+UGVwdGlkZSBGcmFnbWVudHMvKmlt

bXVub2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMzwveWVhcj48cHVi

LWRhdGVzPjxkYXRlPkZlYiAxODwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMjct

ODQyNCAoUHJpbnQpJiN4RDswMDI3LTg0MjQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVt

PjEyNTY2NTY4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczov

L3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xMjU2NjU2ODwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48Y3VzdG9tMj5QTUMxNDk5NTI8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjEwLjEwNzMvcG5hcy4wNDM2Mjg2MTAwPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3Jl

Y29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJkPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVj

TnVtPjQyNTQ8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij42

ODwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQyNTQ8L3JlYy1udW1i

ZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBo

cGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjkxNzMwNSI+NDI1NDwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QmFyZCwgRi48L2F1dGhvcj48YXV0aG9yPkJh

cmJvdXIsIFIuPC9hdXRob3I+PGF1dGhvcj5DYW5ub24sIEMuPC9hdXRob3I+PGF1dGhvcj5DYXJy

ZXR0bywgUi48L2F1dGhvcj48YXV0aG9yPkZveCwgTS48L2F1dGhvcj48YXV0aG9yPkdhbWVzLCBE

LjwvYXV0aG9yPjxhdXRob3I+R3VpZG8sIFQuPC9hdXRob3I+PGF1dGhvcj5Ib2Vub3csIEsuPC9h

dXRob3I+PGF1dGhvcj5IdSwgSy48L2F1dGhvcj48YXV0aG9yPkpvaG5zb24tV29vZCwgSy48L2F1

dGhvcj48YXV0aG9yPktoYW4sIEsuPC9hdXRob3I+PGF1dGhvcj5LaG9sb2RlbmtvLCBELjwvYXV0

aG9yPjxhdXRob3I+TGVlLCBDLjwvYXV0aG9yPjxhdXRob3I+TGVlLCBNLjwvYXV0aG9yPjxhdXRo

b3I+TW90dGVyLCBSLjwvYXV0aG9yPjxhdXRob3I+Tmd1eWVuLCBNLjwvYXV0aG9yPjxhdXRob3I+

UmVlZCwgQS48L2F1dGhvcj48YXV0aG9yPlNjaGVuaywgRC48L2F1dGhvcj48YXV0aG9yPlRhbmcs

IFAuPC9hdXRob3I+PGF1dGhvcj5WYXNxdWV6LCBOLjwvYXV0aG9yPjxhdXRob3I+U2V1YmVydCwg

UC48L2F1dGhvcj48YXV0aG9yPlllZG5vY2ssIFQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp

YnV0b3JzPjxhdXRoLWFkZHJlc3M+RWxhbiBQaGFybWFjZXV0aWNhbHMsIDgwMCBHYXRld2F5IEJv

dWxldmFyZCwgU291dGggU2FuIEZyYW5jaXNjbywgQ0EgOTQwODAsIFVTQS4gZnJlZGVyaXF1ZS5i

YXJkQGVsYW4uY29tPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+RXBpdG9wZSBhbmQgaXNv

dHlwZSBzcGVjaWZpY2l0aWVzIG9mIGFudGlib2RpZXMgdG8gYmV0YSAtYW15bG9pZCBwZXB0aWRl

IGZvciBwcm90ZWN0aW9uIGFnYWluc3QgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlLWxpa2UgbmV1

cm9wYXRob2xvZ3k8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2NpIFUg

UyBBPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UHJv

YyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjAy

My04PC9wYWdlcz48dm9sdW1lPjEwMDwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxlZGl0aW9u

PjIwMDMvMDIvMDU8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNl

L2ltbXVub2xvZ3kvKnByZXZlbnRpb24gJmFtcDsgY29udHJvbDwva2V5d29yZD48a2V5d29yZD5B

bWlubyBBY2lkIFNlcXVlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRl

cy8qY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkFudGlib2RpZXMsIE1vbm9jbG9uYWwvKmlt

bXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+KkFudGlib2R5IFNwZWNpZmljaXR5PC9rZXl3b3Jk

PjxrZXl3b3JkPkVwaXRvcGUgTWFwcGluZzwva2V5d29yZD48a2V5d29yZD5FcGl0b3Blcy8qaW1t

dW5vbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TW9sZWN1

bGFyIFNlcXVlbmNlIERhdGE8L2tleXdvcmQ+PGtleXdvcmQ+UGVwdGlkZSBGcmFnbWVudHMvKmlt

bXVub2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMzwveWVhcj48cHVi

LWRhdGVzPjxkYXRlPkZlYiAxODwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMjct

ODQyNCAoUHJpbnQpJiN4RDswMDI3LTg0MjQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVt

PjEyNTY2NTY4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczov

L3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xMjU2NjU2ODwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48Y3VzdG9tMj5QTUMxNDk5NTI8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjEwLjEwNzMvcG5hcy4wNDM2Mjg2MTAwPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3Jl

Y29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 68Require continuous reinforcement of the immunization ADDIN EN.CITE <EndNote><Cite><Author>Lemere</Author><Year>2013</Year><RecNum>4247</RecNum><DisplayText><style face="superscript">69</style></DisplayText><record><rec-number>4247</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1536913840">4247</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lemere, C. A.</author></authors></contributors><auth-address>Center for Neurologic Diseases, Brigham and Women&apos;s Hospital, Harvard Medical School, NRB 636F, 77 Avenue Louis Pasteur, Boston 02115, MA, USA. clemere@.</auth-address><titles><title>Immunotherapy for Alzheimer&apos;s disease: hoops and hurdles</title><secondary-title>Mol Neurodegener</secondary-title></titles><periodical><full-title>Mol Neurodegener</full-title></periodical><pages>36</pages><volume>8</volume><edition>2013/10/24</edition><keywords><keyword>Alzheimer Disease/*therapy</keyword><keyword>Alzheimer Vaccines/*pharmacology</keyword><keyword>Animals</keyword><keyword>Humans</keyword><keyword>Immunotherapy/*methods</keyword></keywords><dates><year>2013</year><pub-dates><date>Oct 22</date></pub-dates></dates><isbn>1750-1326 (Electronic)&#xD;1750-1326 (Linking)</isbn><accession-num>24148220</accession-num><urls><related-urls><url>. Due to the need to design, generate and humanize antibodies ADDIN EN.CITE <EndNote><Cite><Author>Panza</Author><Year>2011</Year><RecNum>4253</RecNum><DisplayText><style face="superscript">70</style></DisplayText><record><rec-number>4253</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1536915430">4253</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Panza, F.</author><author>Frisardi, V.</author><author>Imbimbo, B. P.</author><author>Seripa, D.</author><author>Solfrizzi, V.</author><author>Pilotto, A.</author></authors></contributors><titles><title>Monoclonal antibodies against beta-amyloid (Abeta) for the treatment of Alzheimer&apos;s disease: the Abeta target at a crossroads</title><secondary-title>Expert Opin Biol Ther</secondary-title></titles><pages>679-86</pages><volume>11</volume><number>6</number><edition>2011/04/20</edition><keywords><keyword>Alzheimer Disease/immunology/*therapy</keyword><keyword>Amyloid beta-Peptides/*immunology</keyword><keyword>Antibodies, Monoclonal/*immunology</keyword><keyword>Humans</keyword></keywords><dates><year>2011</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1744-7682 (Electronic)&#xD;1471-2598 (Linking)</isbn><accession-num>21501112</accession-num><urls><related-urls><url> to stop therapy if secondary effects are found PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZmVpZmVyPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48

UmVjTnVtPjQyNTU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij43MTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQyNTU8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjkxNzM5MyI+NDI1NTwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+UGZlaWZlciwgTS48L2F1dGhvcj48YXV0

aG9yPkJvbmNyaXN0aWFubywgUy48L2F1dGhvcj48YXV0aG9yPkJvbmRvbGZpLCBMLjwvYXV0aG9y

PjxhdXRob3I+U3RhbGRlciwgQS48L2F1dGhvcj48YXV0aG9yPkRlbGxlciwgVC48L2F1dGhvcj48

YXV0aG9yPlN0YXVmZW5iaWVsLCBNLjwvYXV0aG9yPjxhdXRob3I+TWF0aGV3cywgUC4gTS48L2F1

dGhvcj48YXV0aG9yPkp1Y2tlciwgTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+

PGF1dGgtYWRkcmVzcz5JbnN0aXR1dGUgb2YgUGF0aG9sb2d5LCBVbml2ZXJzaXR5IG9mIEJhc2Vs

LCBDSC00MDAzIEJhc2VsLCBTd2l0emVybGFuZC48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRs

ZT5DZXJlYnJhbCBoZW1vcnJoYWdlIGFmdGVyIHBhc3NpdmUgYW50aS1BYmV0YSBpbW11bm90aGVy

YXB5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlNjaWVuY2U8L3NlY29uZGFyeS10aXRsZT48L3Rp

dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5TY2llbmNlPC9mdWxsLXRpdGxlPjwvcGVyaW9k

aWNhbD48cGFnZXM+MTM3OTwvcGFnZXM+PHZvbHVtZT4yOTg8L3ZvbHVtZT48bnVtYmVyPjU1OTc8

L251bWJlcj48ZWRpdGlvbj4yMDAyLzExLzE2PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5B

bHpoZWltZXIgRGlzZWFzZS9wYXRob2xvZ3kvdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5BbXls

b2lkIGJldGEtUGVwdGlkZXMvYW5hbHlzaXMvKmltbXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BbnRpYm9kaWVzLCBNb25vY2xvbmFsL2ltbXVub2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2FwaWxsYXJ5IFBlcm1lYWJpbGl0eTwva2V5d29yZD48a2V5

d29yZD5DZXJlYnJhbCBBbXlsb2lkIEFuZ2lvcGF0aHkvbWV0YWJvbGlzbS9wYXRob2xvZ3kvKnRo

ZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgSGVtb3JyaGFnZS8qZXRpb2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVuaXphdGlvbiwgUGFz

c2l2ZS8qYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIEcv

aW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8

L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgVHJhbnNnZW5pYzwva2V5d29yZD48a2V5d29yZD5OZW9j

b3J0ZXgvYmxvb2Qgc3VwcGx5L2NoZW1pc3RyeS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

UGVwdGlkZSBGcmFnbWVudHMvYW5hbHlzaXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAwMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdiAxNTwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjEwOTUtOTIwMyAoRWxlY3Ryb25pYykmI3hEOzAwMzYtODA3NSAoTGlua2lu

Zyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTI0MzQwNTM8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJl

bGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzEyNDM0

MDUzPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4x

MC4xMTI2L3NjaWVuY2UuMTA3ODI1OTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+

PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZmVpZmVyPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48

UmVjTnVtPjQyNTU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij43MTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQyNTU8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjkxNzM5MyI+NDI1NTwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+UGZlaWZlciwgTS48L2F1dGhvcj48YXV0

aG9yPkJvbmNyaXN0aWFubywgUy48L2F1dGhvcj48YXV0aG9yPkJvbmRvbGZpLCBMLjwvYXV0aG9y

PjxhdXRob3I+U3RhbGRlciwgQS48L2F1dGhvcj48YXV0aG9yPkRlbGxlciwgVC48L2F1dGhvcj48

YXV0aG9yPlN0YXVmZW5iaWVsLCBNLjwvYXV0aG9yPjxhdXRob3I+TWF0aGV3cywgUC4gTS48L2F1

dGhvcj48YXV0aG9yPkp1Y2tlciwgTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+

PGF1dGgtYWRkcmVzcz5JbnN0aXR1dGUgb2YgUGF0aG9sb2d5LCBVbml2ZXJzaXR5IG9mIEJhc2Vs

LCBDSC00MDAzIEJhc2VsLCBTd2l0emVybGFuZC48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRs

ZT5DZXJlYnJhbCBoZW1vcnJoYWdlIGFmdGVyIHBhc3NpdmUgYW50aS1BYmV0YSBpbW11bm90aGVy

YXB5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlNjaWVuY2U8L3NlY29uZGFyeS10aXRsZT48L3Rp

dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5TY2llbmNlPC9mdWxsLXRpdGxlPjwvcGVyaW9k

aWNhbD48cGFnZXM+MTM3OTwvcGFnZXM+PHZvbHVtZT4yOTg8L3ZvbHVtZT48bnVtYmVyPjU1OTc8

L251bWJlcj48ZWRpdGlvbj4yMDAyLzExLzE2PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5B

bHpoZWltZXIgRGlzZWFzZS9wYXRob2xvZ3kvdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5BbXls

b2lkIGJldGEtUGVwdGlkZXMvYW5hbHlzaXMvKmltbXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BbnRpYm9kaWVzLCBNb25vY2xvbmFsL2ltbXVub2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2FwaWxsYXJ5IFBlcm1lYWJpbGl0eTwva2V5d29yZD48a2V5

d29yZD5DZXJlYnJhbCBBbXlsb2lkIEFuZ2lvcGF0aHkvbWV0YWJvbGlzbS9wYXRob2xvZ3kvKnRo

ZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgSGVtb3JyaGFnZS8qZXRpb2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVuaXphdGlvbiwgUGFz

c2l2ZS8qYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIEcv

aW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8

L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgVHJhbnNnZW5pYzwva2V5d29yZD48a2V5d29yZD5OZW9j

b3J0ZXgvYmxvb2Qgc3VwcGx5L2NoZW1pc3RyeS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

UGVwdGlkZSBGcmFnbWVudHMvYW5hbHlzaXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAwMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdiAxNTwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjEwOTUtOTIwMyAoRWxlY3Ryb25pYykmI3hEOzAwMzYtODA3NSAoTGlua2lu

Zyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTI0MzQwNTM8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJl

bGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzEyNDM0

MDUzPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4x

MC4xMTI2L3NjaWVuY2UuMTA3ODI1OTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+

PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 71 Increased risk of edema/micro bleeds due to repeated infusion PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DcmFuZTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl

Y051bT4yMTkyPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NzI8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMTkyPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ5Mjc3OTMiPjIxOTI8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkNyYW5lLCBBLjwvYXV0aG9yPjxhdXRob3I+

QnJ1YmFrZXIsIFcuIEQuPC9hdXRob3I+PGF1dGhvcj5Kb2hhbnNzb24sIEouIFUuPC9hdXRob3I+

PGF1dGhvcj5UcmlndW5haXRlLCBBLjwvYXV0aG9yPjxhdXRob3I+Q2ViYWxsb3MsIEouPC9hdXRo

b3I+PGF1dGhvcj5CcmFkdCwgQi48L2F1dGhvcj48YXV0aG9yPkdsYXZpcy1CbG9vbSwgQy48L2F1

dGhvcj48YXV0aG9yPldhbGxhY2UsIFQuIEwuPC9hdXRob3I+PGF1dGhvcj5UZW5uZXIsIEEuIEou

PC9hdXRob3I+PGF1dGhvcj5Sb2dlcnMsIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjxhdXRoLWFkZHJlc3M+Qmlvc2NpZW5jZXMgRGl2aXNpb24sIFNSSSBJbnRlcm5hdGlvbmFs

LCBNZW5sbyBQYXJrLCBDQSwgVVNBLiYjeEQ7RGVwYXJ0bWVudHMgb2YgTW9sZWN1bGFyIEJpb2xv

Z3kgYW5kIEJpb2NoZW1pc3RyeSBhbmQgTmV1cm9iaW9sb2d5IGFuZCBCZWhhdmlvciwgVW5pdmVy

c2l0eSBvZiBDYWxpZm9ybmlhLCBJcnZpbmUsIElydmluZSwgQ0EsIFVTQS4mI3hEO0Jpb3NjaWVu

Y2VzIERpdmlzaW9uLCBTUkkgSW50ZXJuYXRpb25hbCwgTWVubG8gUGFyaywgQ0EsIFVTQS4gRWxl

Y3Ryb25pYyBhZGRyZXNzOiBqb3NlcGgucm9nZXJzQHNyaS5jb20uPC9hdXRoLWFkZHJlc3M+PHRp

dGxlcz48dGl0bGU+UGVyaXBoZXJhbCBjb21wbGVtZW50IGludGVyYWN0aW9ucyB3aXRoIGFteWxv

aWQgYmV0YSBwZXB0aWRlIGluIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogMi4gUmVsYXRpb25z

aGlwIHRvIGFteWxvaWQgYmV0YSBpbW11bm90aGVyYXB5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PkFsemhlaW1lcnMgRGVtZW50PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+QWx6aGVpbWVycyBEZW1lbnQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxw

YWdlcz4yNDMtMjUyPC9wYWdlcz48dm9sdW1lPjE0PC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+

PGVkaXRpb24+MjAxNy8wOC8wMjwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVy

JmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YSBwZXB0aWRlPC9r

ZXl3b3JkPjxrZXl3b3JkPkFiZXRhIGltbXVub3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+Qmxv

b2Q8L2tleXdvcmQ+PGtleXdvcmQ+Q29tcGxlbWVudDwva2V5d29yZD48a2V5d29yZD5Db21wbGVt

ZW50IHJlY2VwdG9yIDE8L2tleXdvcmQ+PGtleXdvcmQ+RXJ5dGhyb2N5dGU8L2tleXdvcmQ+PGtl

eXdvcmQ+SHVtYW48L2tleXdvcmQ+PGtleXdvcmQ+TWFjcm9waGFnZTwva2V5d29yZD48L2tleXdv

cmRzPjxkYXRlcz48eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RmViPC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU1Mi01Mjc5IChFbGVjdHJvbmljKSYjeEQ7MTU1Mi01

MjYwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yODc1NTgzOTwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9w

dWJtZWQvMjg3NTU4Mzk8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNTg4

MTU3MTwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmphbHouMjAx

Ny4wNC4wMTU8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5v

dGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DcmFuZTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl

Y051bT4yMTkyPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NzI8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMTkyPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ5Mjc3OTMiPjIxOTI8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkNyYW5lLCBBLjwvYXV0aG9yPjxhdXRob3I+

QnJ1YmFrZXIsIFcuIEQuPC9hdXRob3I+PGF1dGhvcj5Kb2hhbnNzb24sIEouIFUuPC9hdXRob3I+

PGF1dGhvcj5UcmlndW5haXRlLCBBLjwvYXV0aG9yPjxhdXRob3I+Q2ViYWxsb3MsIEouPC9hdXRo

b3I+PGF1dGhvcj5CcmFkdCwgQi48L2F1dGhvcj48YXV0aG9yPkdsYXZpcy1CbG9vbSwgQy48L2F1

dGhvcj48YXV0aG9yPldhbGxhY2UsIFQuIEwuPC9hdXRob3I+PGF1dGhvcj5UZW5uZXIsIEEuIEou

PC9hdXRob3I+PGF1dGhvcj5Sb2dlcnMsIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjxhdXRoLWFkZHJlc3M+Qmlvc2NpZW5jZXMgRGl2aXNpb24sIFNSSSBJbnRlcm5hdGlvbmFs

LCBNZW5sbyBQYXJrLCBDQSwgVVNBLiYjeEQ7RGVwYXJ0bWVudHMgb2YgTW9sZWN1bGFyIEJpb2xv

Z3kgYW5kIEJpb2NoZW1pc3RyeSBhbmQgTmV1cm9iaW9sb2d5IGFuZCBCZWhhdmlvciwgVW5pdmVy

c2l0eSBvZiBDYWxpZm9ybmlhLCBJcnZpbmUsIElydmluZSwgQ0EsIFVTQS4mI3hEO0Jpb3NjaWVu

Y2VzIERpdmlzaW9uLCBTUkkgSW50ZXJuYXRpb25hbCwgTWVubG8gUGFyaywgQ0EsIFVTQS4gRWxl

Y3Ryb25pYyBhZGRyZXNzOiBqb3NlcGgucm9nZXJzQHNyaS5jb20uPC9hdXRoLWFkZHJlc3M+PHRp

dGxlcz48dGl0bGU+UGVyaXBoZXJhbCBjb21wbGVtZW50IGludGVyYWN0aW9ucyB3aXRoIGFteWxv

aWQgYmV0YSBwZXB0aWRlIGluIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogMi4gUmVsYXRpb25z

aGlwIHRvIGFteWxvaWQgYmV0YSBpbW11bm90aGVyYXB5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PkFsemhlaW1lcnMgRGVtZW50PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+QWx6aGVpbWVycyBEZW1lbnQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxw

YWdlcz4yNDMtMjUyPC9wYWdlcz48dm9sdW1lPjE0PC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+

PGVkaXRpb24+MjAxNy8wOC8wMjwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVy

JmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YSBwZXB0aWRlPC9r

ZXl3b3JkPjxrZXl3b3JkPkFiZXRhIGltbXVub3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+Qmxv

b2Q8L2tleXdvcmQ+PGtleXdvcmQ+Q29tcGxlbWVudDwva2V5d29yZD48a2V5d29yZD5Db21wbGVt

ZW50IHJlY2VwdG9yIDE8L2tleXdvcmQ+PGtleXdvcmQ+RXJ5dGhyb2N5dGU8L2tleXdvcmQ+PGtl

eXdvcmQ+SHVtYW48L2tleXdvcmQ+PGtleXdvcmQ+TWFjcm9waGFnZTwva2V5d29yZD48L2tleXdv

cmRzPjxkYXRlcz48eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RmViPC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU1Mi01Mjc5IChFbGVjdHJvbmljKSYjeEQ7MTU1Mi01

MjYwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yODc1NTgzOTwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9w

dWJtZWQvMjg3NTU4Mzk8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNTg4

MTU3MTwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmphbHouMjAx

Ny4wNC4wMTU8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5v

dGU+

ADDIN EN.CITE.DATA 72 Modification of antibodies is possible to improve efficacy ADDIN EN.CITE <EndNote><Cite><Author>Cehlar</Author><Year>2018</Year><RecNum>2187</RecNum><DisplayText><style face="superscript">73</style></DisplayText><record><rec-number>2187</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1534927793">2187</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cehlar, O.</author><author>Skrabana, R.</author><author>Revajova, V.</author><author>Novak, M.</author></authors></contributors><titles><title>Structural aspects of Alzheimer&apos;s disease immunotherapy targeted against amyloid-beta peptide</title><secondary-title>Bratisl Lek Listy</secondary-title></titles><periodical><full-title>Bratisl Lek Listy</full-title></periodical><pages>201-204</pages><volume>119</volume><number>4</number><edition>2018/04/18</edition><keywords><keyword>*Alzheimer&apos;s disease</keyword><keyword>*amyloid beta</keyword><keyword>*immunotherapy antibody-amyloid complex.</keyword></keywords><dates><year>2018</year></dates><isbn>0006-9248 (Print)&#xD;0006-9248 (Linking)</isbn><accession-num>29663816</accession-num><urls><related-urls><url> time is required to reach effective antibody titerPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb2dvdmluc2t5PC9BdXRob3I+PFllYXI+MjAxNjwvWWVh

cj48UmVjTnVtPjM5MDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2Ny

aXB0Ij42Nyw3NDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM5MDk8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjEzOTY2MCI+MzkwOTwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TG9nb3ZpbnNreSwgVi48L2F1

dGhvcj48YXV0aG9yPlNhdGxpbiwgQS48L2F1dGhvcj48YXV0aG9yPkxhaSwgUi48L2F1dGhvcj48

YXV0aG9yPlN3YW5zb24sIEMuPC9hdXRob3I+PGF1dGhvcj5LYXBsb3csIEouPC9hdXRob3I+PGF1

dGhvcj5Pc3N3YWxkLCBHLjwvYXV0aG9yPjxhdXRob3I+QmFzdW4sIEguPC9hdXRob3I+PGF1dGhv

cj5MYW5uZmVsdCwgTC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk

cmVzcz5FaXNhaSwgSW5jLiwgMTAwIFRpY2UgQmx2ZCwgV29vZGNsaWZmIExha2UsIE5KLCAwNzY3

NywgVVNBLiYjeEQ7QmlvQXJjdGljIE5ldXJvc2NpZW5jZSBBQiwgV2FyZnZpbmdlcyB2YWcgMzUs

IDExMiA1MSwgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFs

dGgvR2VyaWF0cmljcywgVXBwc2FsYSBVbml2ZXJzaXR5LCBEYWcgSGFtbWFyc2tpb2xkcyB2YWcg

MTQgQiwgNzUxIDg1LCBVcHBzYWxhLCBTd2VkZW4uJiN4RDtCaW9BcmN0aWMgTmV1cm9zY2llbmNl

IEFCLCBXYXJmdmluZ2VzIHZhZyAzNSwgMTEyIDUxLCBTdG9ja2hvbG0sIFN3ZWRlbi4gTGFycy5M

YW5uZmVsdEBwdWJjYXJlLnV1LnNlLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoL0dl

cmlhdHJpY3MsIFVwcHNhbGEgVW5pdmVyc2l0eSwgRGFnIEhhbW1hcnNraW9sZHMgdmFnIDE0IEIs

IDc1MSA4NSwgVXBwc2FsYSwgU3dlZGVuLiBMYXJzLkxhbm5mZWx0QHB1YmNhcmUudXUuc2UuPC9h

dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+U2FmZXR5IGFuZCB0b2xlcmFiaWxpdHkgb2YgQkFO

MjQwMS0tYSBjbGluaWNhbCBzdHVkeSBpbiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2Ugd2l0aCBh

IHByb3RvZmlicmlsIHNlbGVjdGl2ZSBBYmV0YSBhbnRpYm9keTwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5BbHpoZWltZXJzIFJlcyBUaGVyPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlv

ZGljYWw+PGZ1bGwtdGl0bGU+QWx6aGVpbWVycyBSZXMgVGhlcjwvZnVsbC10aXRsZT48L3Blcmlv

ZGljYWw+PHBhZ2VzPjE0PC9wYWdlcz48dm9sdW1lPjg8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJl

cj48ZWRpdGlvbj4yMDE2LzA0LzA3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9r

ZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2Jsb29kLypkcnVnIHRoZXJhcHkvaW1t

dW5vbG9neTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvYmxvb2QvKmlt

bXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJvZGllcywgTW9ub2Nsb25hbCwgSHVtYW5p

emVkLyphZHZlcnNlIGVmZmVjdHMvcGhhcm1hY29raW5ldGljcy8qdGhlcmFwZXV0aWM8L2tleXdv

cmQ+PGtleXdvcmQ+dXNlPC9rZXl3b3JkPjxrZXl3b3JkPkJpb21hcmtlcnMvYmxvb2Q8L2tleXdv

cmQ+PGtleXdvcmQ+QnJhaW4vZHJ1ZyBlZmZlY3RzL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5Eb3NlLVJlc3BvbnNlIFJlbGF0aW9uc2hpcCwgRHJ1Zzwva2V5d29yZD48a2V5d29yZD5Eb3Vi

bGUtQmxpbmQgTWV0aG9kPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29y

ZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5QZXB0aWRl

IEZyYWdtZW50cy9ibG9vZDwva2V5d29yZD48a2V5d29yZD5BcmlhPC9rZXl3b3JkPjxrZXl3b3Jk

PkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkLWJldGE8

L2tleXdvcmQ+PGtleXdvcmQ+QWJldGE8L2tleXdvcmQ+PGtleXdvcmQ+QmFuMjQwMTwva2V5d29y

ZD48a2V5d29yZD5DbGluaWNhbCB0cmlhbDwva2V5d29yZD48a2V5d29yZD5JbW11bm90aGVyYXB5

PC9rZXl3b3JkPjxrZXl3b3JkPlByb3RvZmlicmlsPC9rZXl3b3JkPjxrZXl3b3JkPm1BYjE1ODwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+QXByIDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNzU4LTkxOTMgKEVsZWN0

cm9uaWMpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3MDQ4MTcwPC9hY2Nlc3Npb24tbnVtPjx1cmxz

PjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8y

NzA0ODE3MDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0ODIyMjk3PC9j

dXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTg2L3MxMzE5NS0wMTYtMDE4MS0y

PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5M

YW5uZmVsdDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJlY051bT4yMjIyPC9SZWNOdW0+PHJl

Y29yZD48cmVjLW51bWJlcj4yMjIyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3Rh

bXA9IjE1MzQ5Mjc3OTYiPjIyMjI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkxhbm5mZWx0LCBMLjwvYXV0aG9yPjxhdXRob3I+TW9sbGVyLCBDLjwvYXV0aG9yPjxhdXRo

b3I+QmFzdW4sIEguPC9hdXRob3I+PGF1dGhvcj5Pc3N3YWxkLCBHLjwvYXV0aG9yPjxhdXRob3I+

U2VobGluLCBELjwvYXV0aG9yPjxhdXRob3I+U2F0bGluLCBBLjwvYXV0aG9yPjxhdXRob3I+TG9n

b3ZpbnNreSwgVi48L2F1dGhvcj48YXV0aG9yPkdlbGxlcmZvcnMsIFAuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVh

bHRoL0dlcmlhdHJpY3MsIFVwcHNhbGEgVW5pdmVyc2l0eSwgRGFnIEhhbW1hcnNrb2xkcyB2YWcg

MTQgQiwgNzUxIDg1IFVwcHNhbGEsIFN3ZWRlbiA7IEJpb0FyY3RpYyBOZXVyb3NjaWVuY2UgQUIs

IFdhcmZ2aW5nZXMgdmFnIDM1LCAxMTIgNTEgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtCaW9BcmN0

aWMgTmV1cm9zY2llbmNlIEFCLCBXYXJmdmluZ2VzIHZhZyAzNSwgMTEyIDUxIFN0b2NraG9sbSwg

U3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoL0dlcmlhdHJpY3MsIFVwcHNh

bGEgVW5pdmVyc2l0eSwgRGFnIEhhbW1hcnNrb2xkcyB2YWcgMTQgQiwgNzUxIDg1IFVwcHNhbGEs

IFN3ZWRlbi4mI3hEO0Vpc2FpLCBJbmMsIDEwMCBUaWNlIEJvdWxldmFyZCwgV29vZGNsaWZmIExh

a2UsIE5KIDA3Njc3LCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UGVyc3BlY3Rp

dmVzIG9uIGZ1dHVyZSBBbHpoZWltZXIgdGhlcmFwaWVzOiBhbXlsb2lkLWJldGEgcHJvdG9maWJy

aWxzIC0gYSBuZXcgdGFyZ2V0IGZvciBpbW11bm90aGVyYXB5IHdpdGggQkFOMjQwMSBpbiBBbHpo

ZWltZXImYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWx6aGVpbWVycyBS

ZXMgVGhlcjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxl

PkFsemhlaW1lcnMgUmVzIFRoZXI8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xNjwv

cGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGVkaXRpb24+MjAxNC8w

Ny8xODwvZWRpdGlvbj48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48L2RhdGVzPjxpc2JuPjE3NTgt

OTE5MyAoUHJpbnQpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1MDMxNjMzPC9hY2Nlc3Npb24tbnVt

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8yNTAzMTYzMzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0MDU0

OTY3PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTg2L2FsenJ0MjQ2PC9l

bGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb2dvdmluc2t5PC9BdXRob3I+PFllYXI+MjAxNjwvWWVh

cj48UmVjTnVtPjM5MDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2Ny

aXB0Ij42Nyw3NDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM5MDk8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjEzOTY2MCI+MzkwOTwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TG9nb3ZpbnNreSwgVi48L2F1

dGhvcj48YXV0aG9yPlNhdGxpbiwgQS48L2F1dGhvcj48YXV0aG9yPkxhaSwgUi48L2F1dGhvcj48

YXV0aG9yPlN3YW5zb24sIEMuPC9hdXRob3I+PGF1dGhvcj5LYXBsb3csIEouPC9hdXRob3I+PGF1

dGhvcj5Pc3N3YWxkLCBHLjwvYXV0aG9yPjxhdXRob3I+QmFzdW4sIEguPC9hdXRob3I+PGF1dGhv

cj5MYW5uZmVsdCwgTC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk

cmVzcz5FaXNhaSwgSW5jLiwgMTAwIFRpY2UgQmx2ZCwgV29vZGNsaWZmIExha2UsIE5KLCAwNzY3

NywgVVNBLiYjeEQ7QmlvQXJjdGljIE5ldXJvc2NpZW5jZSBBQiwgV2FyZnZpbmdlcyB2YWcgMzUs

IDExMiA1MSwgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFs

dGgvR2VyaWF0cmljcywgVXBwc2FsYSBVbml2ZXJzaXR5LCBEYWcgSGFtbWFyc2tpb2xkcyB2YWcg

MTQgQiwgNzUxIDg1LCBVcHBzYWxhLCBTd2VkZW4uJiN4RDtCaW9BcmN0aWMgTmV1cm9zY2llbmNl

IEFCLCBXYXJmdmluZ2VzIHZhZyAzNSwgMTEyIDUxLCBTdG9ja2hvbG0sIFN3ZWRlbi4gTGFycy5M

YW5uZmVsdEBwdWJjYXJlLnV1LnNlLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoL0dl

cmlhdHJpY3MsIFVwcHNhbGEgVW5pdmVyc2l0eSwgRGFnIEhhbW1hcnNraW9sZHMgdmFnIDE0IEIs

IDc1MSA4NSwgVXBwc2FsYSwgU3dlZGVuLiBMYXJzLkxhbm5mZWx0QHB1YmNhcmUudXUuc2UuPC9h

dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+U2FmZXR5IGFuZCB0b2xlcmFiaWxpdHkgb2YgQkFO

MjQwMS0tYSBjbGluaWNhbCBzdHVkeSBpbiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2Ugd2l0aCBh

IHByb3RvZmlicmlsIHNlbGVjdGl2ZSBBYmV0YSBhbnRpYm9keTwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5BbHpoZWltZXJzIFJlcyBUaGVyPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlv

ZGljYWw+PGZ1bGwtdGl0bGU+QWx6aGVpbWVycyBSZXMgVGhlcjwvZnVsbC10aXRsZT48L3Blcmlv

ZGljYWw+PHBhZ2VzPjE0PC9wYWdlcz48dm9sdW1lPjg8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJl

cj48ZWRpdGlvbj4yMDE2LzA0LzA3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9r

ZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2Jsb29kLypkcnVnIHRoZXJhcHkvaW1t

dW5vbG9neTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvYmxvb2QvKmlt

bXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJvZGllcywgTW9ub2Nsb25hbCwgSHVtYW5p

emVkLyphZHZlcnNlIGVmZmVjdHMvcGhhcm1hY29raW5ldGljcy8qdGhlcmFwZXV0aWM8L2tleXdv

cmQ+PGtleXdvcmQ+dXNlPC9rZXl3b3JkPjxrZXl3b3JkPkJpb21hcmtlcnMvYmxvb2Q8L2tleXdv

cmQ+PGtleXdvcmQ+QnJhaW4vZHJ1ZyBlZmZlY3RzL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5Eb3NlLVJlc3BvbnNlIFJlbGF0aW9uc2hpcCwgRHJ1Zzwva2V5d29yZD48a2V5d29yZD5Eb3Vi

bGUtQmxpbmQgTWV0aG9kPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29y

ZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5QZXB0aWRl

IEZyYWdtZW50cy9ibG9vZDwva2V5d29yZD48a2V5d29yZD5BcmlhPC9rZXl3b3JkPjxrZXl3b3Jk

PkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkLWJldGE8

L2tleXdvcmQ+PGtleXdvcmQ+QWJldGE8L2tleXdvcmQ+PGtleXdvcmQ+QmFuMjQwMTwva2V5d29y

ZD48a2V5d29yZD5DbGluaWNhbCB0cmlhbDwva2V5d29yZD48a2V5d29yZD5JbW11bm90aGVyYXB5

PC9rZXl3b3JkPjxrZXl3b3JkPlByb3RvZmlicmlsPC9rZXl3b3JkPjxrZXl3b3JkPm1BYjE1ODwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+QXByIDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNzU4LTkxOTMgKEVsZWN0

cm9uaWMpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3MDQ4MTcwPC9hY2Nlc3Npb24tbnVtPjx1cmxz

PjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8y

NzA0ODE3MDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0ODIyMjk3PC9j

dXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTg2L3MxMzE5NS0wMTYtMDE4MS0y

PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5M

YW5uZmVsdDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJlY051bT4yMjIyPC9SZWNOdW0+PHJl

Y29yZD48cmVjLW51bWJlcj4yMjIyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3Rh

bXA9IjE1MzQ5Mjc3OTYiPjIyMjI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkxhbm5mZWx0LCBMLjwvYXV0aG9yPjxhdXRob3I+TW9sbGVyLCBDLjwvYXV0aG9yPjxhdXRo

b3I+QmFzdW4sIEguPC9hdXRob3I+PGF1dGhvcj5Pc3N3YWxkLCBHLjwvYXV0aG9yPjxhdXRob3I+

U2VobGluLCBELjwvYXV0aG9yPjxhdXRob3I+U2F0bGluLCBBLjwvYXV0aG9yPjxhdXRob3I+TG9n

b3ZpbnNreSwgVi48L2F1dGhvcj48YXV0aG9yPkdlbGxlcmZvcnMsIFAuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVh

bHRoL0dlcmlhdHJpY3MsIFVwcHNhbGEgVW5pdmVyc2l0eSwgRGFnIEhhbW1hcnNrb2xkcyB2YWcg

MTQgQiwgNzUxIDg1IFVwcHNhbGEsIFN3ZWRlbiA7IEJpb0FyY3RpYyBOZXVyb3NjaWVuY2UgQUIs

IFdhcmZ2aW5nZXMgdmFnIDM1LCAxMTIgNTEgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtCaW9BcmN0

aWMgTmV1cm9zY2llbmNlIEFCLCBXYXJmdmluZ2VzIHZhZyAzNSwgMTEyIDUxIFN0b2NraG9sbSwg

U3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoL0dlcmlhdHJpY3MsIFVwcHNh

bGEgVW5pdmVyc2l0eSwgRGFnIEhhbW1hcnNrb2xkcyB2YWcgMTQgQiwgNzUxIDg1IFVwcHNhbGEs

IFN3ZWRlbi4mI3hEO0Vpc2FpLCBJbmMsIDEwMCBUaWNlIEJvdWxldmFyZCwgV29vZGNsaWZmIExh

a2UsIE5KIDA3Njc3LCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UGVyc3BlY3Rp

dmVzIG9uIGZ1dHVyZSBBbHpoZWltZXIgdGhlcmFwaWVzOiBhbXlsb2lkLWJldGEgcHJvdG9maWJy

aWxzIC0gYSBuZXcgdGFyZ2V0IGZvciBpbW11bm90aGVyYXB5IHdpdGggQkFOMjQwMSBpbiBBbHpo

ZWltZXImYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWx6aGVpbWVycyBS

ZXMgVGhlcjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxl

PkFsemhlaW1lcnMgUmVzIFRoZXI8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xNjwv

cGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGVkaXRpb24+MjAxNC8w

Ny8xODwvZWRpdGlvbj48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48L2RhdGVzPjxpc2JuPjE3NTgt

OTE5MyAoUHJpbnQpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1MDMxNjMzPC9hY2Nlc3Npb24tbnVt

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8yNTAzMTYzMzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0MDU0

OTY3PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTg2L2FsenJ0MjQ2PC9l

bGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 67,74Better for targeting Tau oligomer isoforms ADDIN EN.CITE <EndNote><Cite><Author>Bittar</Author><Year>2018</Year><RecNum>4248</RecNum><DisplayText><style face="superscript">75</style></DisplayText><record><rec-number>4248</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1536914009">4248</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bittar, A.</author><author>Sengupta, U.</author><author>Kayed, R.</author></authors></contributors><auth-address>1Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX 77555 USA.0000 0001 1547 9964grid.176731.5&#xD;2Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555 USA.0000 0001 1547 9964grid.176731.5&#xD;3Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555 USA.0000 0001 1547 9964grid.176731.5</auth-address><titles><title>Prospects for strain-specific immunotherapy in Alzheimer&apos;s disease and tauopathies</title><secondary-title>NPJ Vaccines</secondary-title></titles><pages>9</pages><volume>3</volume><edition>2018/03/07</edition><dates><year>2018</year></dates><isbn>2059-0105 (Electronic)&#xD;2059-0105 (Linking)</isbn><accession-num>29507776</accession-num><urls><related-urls><url> Does not require the host immune system. Elderly patients may benefit ADDIN EN.CITE <EndNote><Cite><Author>Wilcock</Author><Year>2004</Year><RecNum>4274</RecNum><DisplayText><style face="superscript">76</style></DisplayText><record><rec-number>4274</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1537200333">4274</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wilcock, D. M.</author><author>Rojiani, A.</author><author>Rosenthal, A.</author><author>Subbarao, S.</author><author>Freeman, M. J.</author><author>Gordon, M. N.</author><author>Morgan, D.</author></authors></contributors><auth-address>Alzheimer&apos;s Research Laboratory, University of South Florida, Department of Pharmacology, 12901 Bruce B Downs Blvd, Tampa, Florida 33612, USA. dmorgan@hsc.usf.edu.</auth-address><titles><title>Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage</title><secondary-title>J Neuroinflammation</secondary-title></titles><periodical><full-title>J Neuroinflammation</full-title></periodical><pages>24</pages><volume>1</volume><number>1</number><edition>2004/12/14</edition><dates><year>2004</year><pub-dates><date>Dec 8</date></pub-dates></dates><isbn>1742-2094 (Electronic)&#xD;1742-2094 (Linking)</isbn><accession-num>15588287</accession-num><urls><related-urls><url> IMMUNOTHERAPIESCAD106PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYW5kZW5iZXJnaGU8L0F1dGhvcj48WWVhcj4yMDE3PC9Z

ZWFyPjxSZWNOdW0+MjE4MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJz

Y3JpcHQiPjc3PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjE4MDwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0OTI3NTg1Ij4yMTgwPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5WYW5kZW5iZXJnaGUsIFIuPC9h

dXRob3I+PGF1dGhvcj5SaXZpZXJlLCBNLiBFLjwvYXV0aG9yPjxhdXRob3I+Q2FwdXRvLCBBLjwv

YXV0aG9yPjxhdXRob3I+U292YWdvLCBKLjwvYXV0aG9yPjxhdXRob3I+TWFndWlyZSwgUi4gUC48

L2F1dGhvcj48YXV0aG9yPkZhcmxvdywgTS48L2F1dGhvcj48YXV0aG9yPk1hcm90dGEsIEcuPC9h

dXRob3I+PGF1dGhvcj5TYW5jaGV6LVZhbGxlLCBSLjwvYXV0aG9yPjxhdXRob3I+U2NoZWx0ZW5z

LCBQLjwvYXV0aG9yPjxhdXRob3I+UnlhbiwgSi4gTS48L2F1dGhvcj48YXV0aG9yPkdyYWYsIEEu

PC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVu

dCBvZiBOZXVyb3NjaWVuY2VzLCBLVSBMZXV2ZW4sIExldXZlbiwgQmVsZ2l1bS4mI3hEO05ldXJv

bG9neSBEZXBhcnRtZW50LCBVbml2ZXJzaXR5IEhvc3BpdGFscyBMZXV2ZW4sIEJlbGdpdW0uJiN4

RDtOZXVyb3NjaWVuY2UsIE5vdmFydGlzIFBoYXJtYSBBRywgQmFzZWwsIFN3aXR6ZXJsYW5kLiYj

eEQ7TmV1cm9zY2llbmNlIFRyYW5zbGF0aW9uYWwgTWVkaWNpbmUsIE5vdmFydGlzIEluc3RpdHV0

ZXMgZm9yIEJpb21lZGljYWwgUmVzZWFyY2gsIEJhc2VsLCBTd2l0emVybGFuZC4mI3hEO0Jpb21h

cmtlciBEZXZlbG9wbWVudCwgQ2xpbmljYWwgSW1hZ2luZywgTm92YXJ0aXMgSW5zdGl0dXRlcyBm

b3IgQmlvbWVkaWNhbCBSZXNlYXJjaCwgQmFzZWwsIFN3aXR6ZXJsYW5kLiYjeEQ7RGVwYXJ0bWVu

dCBvZiBOZXVyb2xvZ3ksIEluZGlhbmEgVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUsIElO

LCBVU0EuJiN4RDtEaXZpc2lvbiBvZiBHZXJpYXRyaWMgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2Yg

VG9yb250bywgVG9yb250bywgQ2FuYWRhLiYjeEQ7QWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlIGFu

ZCBPdGhlciBDb2duaXRpdmUgRGlzb3JkZXJzIFVuaXQsIEhvc3BpdGFsIENsaW5pYywgQmFyY2Vs

b25hLCBTcGFpbi4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9sb2d5IGFuZCBBbHpoZWltZXIgQ2Vu

dGVyLCBWVSBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBBbXN0ZXJkYW0sIFRoZSBOZXRoZXJs

YW5kcy4mI3hEO05vdmFydGlzIFBoYXJtYWNldXRpY2FscyBDb3Jwb3JhdGlvbiwgRWFzdCBIYW5v

dmVyLCBOSiwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkFjdGl2ZSBBYmV0YSBp

bW11bm90aGVyYXB5IENBRDEwNiBpbiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgcGhhc2Ug

MmIgc3R1ZHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWx6aGVpbWVycyBEZW1lbnQgKE4gWSk8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbHpoZWlt

ZXJzIERlbWVudCAoTiBZKTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjEwLTIyPC9w

YWdlcz48dm9sdW1lPjM8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4yMDE3LzEw

LzI3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BY3RpdmUgaW1tdW5vdGhlcmFweTwva2V5

d29yZD48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZC1iZXRhIHBlcHRpZGVzPC9rZXl3b3JkPjxrZXl3b3JkPkJpb2xvZ2ljYWwgYmlvbWFy

a2Vyczwva2V5d29yZD48a2V5d29yZD5DYWQxMDY8L2tleXdvcmQ+PGtleXdvcmQ+U2FmZXR5PC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5KYW48L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4yMzUyLTg3MzcgKFByaW50KSYj

eEQ7MjM1Mi04NzM3IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yOTA2NzMxNjwvYWNj

ZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMjkwNjczMTY8L3VybD48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5p

aC5nb3YvcG1jL2FydGljbGVzL1BNQzU2NTEzNzMvcGRmL21haW4ucGRmPC91cmw+PC9yZWxhdGVk

LXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzU2NTEzNzM8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjEwLjEwMTYvai50cmNpLjIwMTYuMTIuMDAzPC9lbGVjdHJvbmljLXJlc291cmNl

LW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYW5kZW5iZXJnaGU8L0F1dGhvcj48WWVhcj4yMDE3PC9Z

ZWFyPjxSZWNOdW0+MjE4MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJz

Y3JpcHQiPjc3PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjE4MDwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0OTI3NTg1Ij4yMTgwPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5WYW5kZW5iZXJnaGUsIFIuPC9h

dXRob3I+PGF1dGhvcj5SaXZpZXJlLCBNLiBFLjwvYXV0aG9yPjxhdXRob3I+Q2FwdXRvLCBBLjwv

YXV0aG9yPjxhdXRob3I+U292YWdvLCBKLjwvYXV0aG9yPjxhdXRob3I+TWFndWlyZSwgUi4gUC48

L2F1dGhvcj48YXV0aG9yPkZhcmxvdywgTS48L2F1dGhvcj48YXV0aG9yPk1hcm90dGEsIEcuPC9h

dXRob3I+PGF1dGhvcj5TYW5jaGV6LVZhbGxlLCBSLjwvYXV0aG9yPjxhdXRob3I+U2NoZWx0ZW5z

LCBQLjwvYXV0aG9yPjxhdXRob3I+UnlhbiwgSi4gTS48L2F1dGhvcj48YXV0aG9yPkdyYWYsIEEu

PC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVu

dCBvZiBOZXVyb3NjaWVuY2VzLCBLVSBMZXV2ZW4sIExldXZlbiwgQmVsZ2l1bS4mI3hEO05ldXJv

bG9neSBEZXBhcnRtZW50LCBVbml2ZXJzaXR5IEhvc3BpdGFscyBMZXV2ZW4sIEJlbGdpdW0uJiN4

RDtOZXVyb3NjaWVuY2UsIE5vdmFydGlzIFBoYXJtYSBBRywgQmFzZWwsIFN3aXR6ZXJsYW5kLiYj

eEQ7TmV1cm9zY2llbmNlIFRyYW5zbGF0aW9uYWwgTWVkaWNpbmUsIE5vdmFydGlzIEluc3RpdHV0

ZXMgZm9yIEJpb21lZGljYWwgUmVzZWFyY2gsIEJhc2VsLCBTd2l0emVybGFuZC4mI3hEO0Jpb21h

cmtlciBEZXZlbG9wbWVudCwgQ2xpbmljYWwgSW1hZ2luZywgTm92YXJ0aXMgSW5zdGl0dXRlcyBm

b3IgQmlvbWVkaWNhbCBSZXNlYXJjaCwgQmFzZWwsIFN3aXR6ZXJsYW5kLiYjeEQ7RGVwYXJ0bWVu

dCBvZiBOZXVyb2xvZ3ksIEluZGlhbmEgVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUsIElO

LCBVU0EuJiN4RDtEaXZpc2lvbiBvZiBHZXJpYXRyaWMgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2Yg

VG9yb250bywgVG9yb250bywgQ2FuYWRhLiYjeEQ7QWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlIGFu

ZCBPdGhlciBDb2duaXRpdmUgRGlzb3JkZXJzIFVuaXQsIEhvc3BpdGFsIENsaW5pYywgQmFyY2Vs

b25hLCBTcGFpbi4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9sb2d5IGFuZCBBbHpoZWltZXIgQ2Vu

dGVyLCBWVSBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBBbXN0ZXJkYW0sIFRoZSBOZXRoZXJs

YW5kcy4mI3hEO05vdmFydGlzIFBoYXJtYWNldXRpY2FscyBDb3Jwb3JhdGlvbiwgRWFzdCBIYW5v

dmVyLCBOSiwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkFjdGl2ZSBBYmV0YSBp

bW11bm90aGVyYXB5IENBRDEwNiBpbiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgcGhhc2Ug

MmIgc3R1ZHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWx6aGVpbWVycyBEZW1lbnQgKE4gWSk8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbHpoZWlt

ZXJzIERlbWVudCAoTiBZKTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjEwLTIyPC9w

YWdlcz48dm9sdW1lPjM8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4yMDE3LzEw

LzI3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BY3RpdmUgaW1tdW5vdGhlcmFweTwva2V5

d29yZD48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZC1iZXRhIHBlcHRpZGVzPC9rZXl3b3JkPjxrZXl3b3JkPkJpb2xvZ2ljYWwgYmlvbWFy

a2Vyczwva2V5d29yZD48a2V5d29yZD5DYWQxMDY8L2tleXdvcmQ+PGtleXdvcmQ+U2FmZXR5PC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5KYW48L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4yMzUyLTg3MzcgKFByaW50KSYj

eEQ7MjM1Mi04NzM3IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yOTA2NzMxNjwvYWNj

ZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMjkwNjczMTY8L3VybD48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5p

aC5nb3YvcG1jL2FydGljbGVzL1BNQzU2NTEzNzMvcGRmL21haW4ucGRmPC91cmw+PC9yZWxhdGVk

LXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzU2NTEzNzM8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjEwLjEwMTYvai50cmNpLjIwMTYuMTIuMDAzPC9lbGVjdHJvbmljLXJlc291cmNl

LW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 77AADvac1PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ob3ZhazwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

Y051bT4yMDgzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTc8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDgzPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NjE1NzUiPjIwODM8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk5vdmFrLCBQLjwvYXV0aG9yPjxhdXRob3I+

U2NobWlkdCwgUi48L2F1dGhvcj48YXV0aG9yPktvbnRzZWtvdmEsIEUuPC9hdXRob3I+PGF1dGhv

cj5aaWxrYSwgTi48L2F1dGhvcj48YXV0aG9yPktvdmFjZWNoLCBCLjwvYXV0aG9yPjxhdXRob3I+

U2tyYWJhbmEsIFIuPC9hdXRob3I+PGF1dGhvcj5WaW5jZS1LYXptZXJvdmEsIFouPC9hdXRob3I+

PGF1dGhvcj5LYXRpbmEsIFMuPC9hdXRob3I+PGF1dGhvcj5GaWFsb3ZhLCBMLjwvYXV0aG9yPjxh

dXRob3I+UHJjaW5hLCBNLjwvYXV0aG9yPjxhdXRob3I+UGFycmFrLCBWLjwvYXV0aG9yPjxhdXRo

b3I+RGFsLUJpYW5jbywgUC48L2F1dGhvcj48YXV0aG9yPkJydW5uZXIsIE0uPC9hdXRob3I+PGF1

dGhvcj5TdGFmZmVuLCBXLjwvYXV0aG9yPjxhdXRob3I+UmFpbmVyLCBNLjwvYXV0aG9yPjxhdXRo

b3I+T25kcnVzLCBNLjwvYXV0aG9yPjxhdXRob3I+Um9wZWxlLCBTLjwvYXV0aG9yPjxhdXRob3I+

U21pc2VrLCBNLjwvYXV0aG9yPjxhdXRob3I+U2l2YWssIFIuPC9hdXRob3I+PGF1dGhvcj5XaW5i

bGFkLCBCLjwvYXV0aG9yPjxhdXRob3I+Tm92YWssIE0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+QVhPTiBOZXVyb3NjaWVuY2UgU0UsIEJyYXRpc2xhdmEs

IFNsb3Zha2lhLiBFbGVjdHJvbmljIGFkZHJlc3M6IHBldHIubm92YWtAYXhvbi1uZXVyb3NjaWVu

Y2UuZXUuJiN4RDtDbGluaWNhbCBEaXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIERlcGFydG1l

bnQgb2YgTmV1cm9sb2d5LCBNZWRpY2FsIFVuaXZlcnNpdHkgR3JheiwgR3JheiwgQXVzdHJpYS4m

I3hEO0FYT04gTmV1cm9zY2llbmNlIFNFLCBCcmF0aXNsYXZhLCBTbG92YWtpYS4mI3hEO1VuaXZl

cnNpdHkgQ2xpbmljIG9mIE5ldXJvbG9neSwgTWVkaWNhbCBVbml2ZXJzaXR5IG9mIFZpZW5uYSwg

Vmllbm5hLCBBdXN0cmlhLiYjeEQ7VW5pdmVyc2l0eSBDbGluaWMgb2YgQ2xpbmljYWwgUGhhcm1h

Y29sb2d5LCBNZWRpY2FsIFVuaXZlcnNpdHkgb2YgVmllbm5hLCBWaWVubmEsIEF1c3RyaWEuJiN4

RDtVbml2ZXJzaXR5IENsaW5pYyBvZiBOZXVyb2xvZ3ksIENocmlzdGlhbi1Eb3BwbGVyLUNsaW5p

YywgU2FsemJ1cmcsIEF1c3RyaWEuJiN4RDtTb2NpYWwgYW5kIE1lZGljYWwgQ2VudHJlIEVhc3Qs

IERhbnViZSBIb3NwaXRhbCwgS2FybCBMYW5kc3RlaW5lciBJbnN0aXR1dGUgZm9yIE1lbW9yeSBh

bmQgQWx6aGVpbWVyIFJlc2VhcmNoLCBWaWVubmEsIEF1c3RyaWEuJiN4RDtEaXZpc2lvbiBvZiBH

ZW5lcmFsIE5ldXJvbG9neSwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIE1lZGljYWwgVW5pdmVy

c2l0eSBHcmF6LCBHcmF6LCBBdXN0cmlhLiYjeEQ7S2Fyb2xpbnNrYSBJbnN0aXR1dGUgQWx6aGVp

bWVyIERpc2Vhc2UgUmVzZWFyY2ggQ2VudHJlIGFuZCBDbGluaWNhbCBUcmlhbCBVbml0LCBHZXJp

YXRyaWMgQ2xpbmljLCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCBT

d2VkZW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+U2FmZXR5IGFuZCBpbW11bm9nZW5p

Y2l0eSBvZiB0aGUgdGF1IHZhY2NpbmUgQUFEdmFjMSBpbiBwYXRpZW50cyB3aXRoIEFsemhlaW1l

ciZhcG9zO3MgZGlzZWFzZTogYSByYW5kb21pc2VkLCBkb3VibGUtYmxpbmQsIHBsYWNlYm8tY29u

dHJvbGxlZCwgcGhhc2UgMSB0cmlhbDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5MYW5jZXQgTmV1

cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEyMy0xMzQ8L3BhZ2VzPjx2b2x1

bWU+MTY8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48ZWRpdGlvbj4yMDE2LzEyLzE0PC9lZGl0

aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFu

ZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLyp0aGVyYXB5PC9rZXl3

b3JkPjxrZXl3b3JkPkFsemhlaW1lciBWYWNjaW5lcy9hZHZlcnNlIGVmZmVjdHMvKnBoYXJtYWNv

bG9neTwva2V5d29yZD48a2V5d29yZD5Eb3VibGUtQmxpbmQgTWV0aG9kPC9rZXl3b3JkPjxrZXl3

b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1t

dW5vdGhlcmFweS9hZHZlcnNlIGVmZmVjdHMvKm1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFs

ZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD4qT3V0Y29t

ZSBBc3Nlc3NtZW50IChIZWFsdGggQ2FyZSk8L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5z

LyppbW11bm9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5GZWI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDc0

LTQ0NjUgKEVsZWN0cm9uaWMpJiN4RDsxNDc0LTQ0MjIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI3OTU1OTk1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNzk1NTk5NTwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMTQ3NC00NDIy

KDE2KTMwMzMxLTM8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0Vu

ZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ob3ZhazwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

Y051bT4yMDgzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTc8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDgzPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ4NjE1NzUiPjIwODM8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk5vdmFrLCBQLjwvYXV0aG9yPjxhdXRob3I+

U2NobWlkdCwgUi48L2F1dGhvcj48YXV0aG9yPktvbnRzZWtvdmEsIEUuPC9hdXRob3I+PGF1dGhv

cj5aaWxrYSwgTi48L2F1dGhvcj48YXV0aG9yPktvdmFjZWNoLCBCLjwvYXV0aG9yPjxhdXRob3I+

U2tyYWJhbmEsIFIuPC9hdXRob3I+PGF1dGhvcj5WaW5jZS1LYXptZXJvdmEsIFouPC9hdXRob3I+

PGF1dGhvcj5LYXRpbmEsIFMuPC9hdXRob3I+PGF1dGhvcj5GaWFsb3ZhLCBMLjwvYXV0aG9yPjxh

dXRob3I+UHJjaW5hLCBNLjwvYXV0aG9yPjxhdXRob3I+UGFycmFrLCBWLjwvYXV0aG9yPjxhdXRo

b3I+RGFsLUJpYW5jbywgUC48L2F1dGhvcj48YXV0aG9yPkJydW5uZXIsIE0uPC9hdXRob3I+PGF1

dGhvcj5TdGFmZmVuLCBXLjwvYXV0aG9yPjxhdXRob3I+UmFpbmVyLCBNLjwvYXV0aG9yPjxhdXRo

b3I+T25kcnVzLCBNLjwvYXV0aG9yPjxhdXRob3I+Um9wZWxlLCBTLjwvYXV0aG9yPjxhdXRob3I+

U21pc2VrLCBNLjwvYXV0aG9yPjxhdXRob3I+U2l2YWssIFIuPC9hdXRob3I+PGF1dGhvcj5XaW5i

bGFkLCBCLjwvYXV0aG9yPjxhdXRob3I+Tm92YWssIE0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+QVhPTiBOZXVyb3NjaWVuY2UgU0UsIEJyYXRpc2xhdmEs

IFNsb3Zha2lhLiBFbGVjdHJvbmljIGFkZHJlc3M6IHBldHIubm92YWtAYXhvbi1uZXVyb3NjaWVu

Y2UuZXUuJiN4RDtDbGluaWNhbCBEaXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIERlcGFydG1l

bnQgb2YgTmV1cm9sb2d5LCBNZWRpY2FsIFVuaXZlcnNpdHkgR3JheiwgR3JheiwgQXVzdHJpYS4m

I3hEO0FYT04gTmV1cm9zY2llbmNlIFNFLCBCcmF0aXNsYXZhLCBTbG92YWtpYS4mI3hEO1VuaXZl

cnNpdHkgQ2xpbmljIG9mIE5ldXJvbG9neSwgTWVkaWNhbCBVbml2ZXJzaXR5IG9mIFZpZW5uYSwg

Vmllbm5hLCBBdXN0cmlhLiYjeEQ7VW5pdmVyc2l0eSBDbGluaWMgb2YgQ2xpbmljYWwgUGhhcm1h

Y29sb2d5LCBNZWRpY2FsIFVuaXZlcnNpdHkgb2YgVmllbm5hLCBWaWVubmEsIEF1c3RyaWEuJiN4

RDtVbml2ZXJzaXR5IENsaW5pYyBvZiBOZXVyb2xvZ3ksIENocmlzdGlhbi1Eb3BwbGVyLUNsaW5p

YywgU2FsemJ1cmcsIEF1c3RyaWEuJiN4RDtTb2NpYWwgYW5kIE1lZGljYWwgQ2VudHJlIEVhc3Qs

IERhbnViZSBIb3NwaXRhbCwgS2FybCBMYW5kc3RlaW5lciBJbnN0aXR1dGUgZm9yIE1lbW9yeSBh

bmQgQWx6aGVpbWVyIFJlc2VhcmNoLCBWaWVubmEsIEF1c3RyaWEuJiN4RDtEaXZpc2lvbiBvZiBH

ZW5lcmFsIE5ldXJvbG9neSwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIE1lZGljYWwgVW5pdmVy

c2l0eSBHcmF6LCBHcmF6LCBBdXN0cmlhLiYjeEQ7S2Fyb2xpbnNrYSBJbnN0aXR1dGUgQWx6aGVp

bWVyIERpc2Vhc2UgUmVzZWFyY2ggQ2VudHJlIGFuZCBDbGluaWNhbCBUcmlhbCBVbml0LCBHZXJp

YXRyaWMgQ2xpbmljLCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCBT

d2VkZW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+U2FmZXR5IGFuZCBpbW11bm9nZW5p

Y2l0eSBvZiB0aGUgdGF1IHZhY2NpbmUgQUFEdmFjMSBpbiBwYXRpZW50cyB3aXRoIEFsemhlaW1l

ciZhcG9zO3MgZGlzZWFzZTogYSByYW5kb21pc2VkLCBkb3VibGUtYmxpbmQsIHBsYWNlYm8tY29u

dHJvbGxlZCwgcGhhc2UgMSB0cmlhbDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5MYW5jZXQgTmV1

cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEyMy0xMzQ8L3BhZ2VzPjx2b2x1

bWU+MTY8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48ZWRpdGlvbj4yMDE2LzEyLzE0PC9lZGl0

aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFu

ZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLyp0aGVyYXB5PC9rZXl3

b3JkPjxrZXl3b3JkPkFsemhlaW1lciBWYWNjaW5lcy9hZHZlcnNlIGVmZmVjdHMvKnBoYXJtYWNv

bG9neTwva2V5d29yZD48a2V5d29yZD5Eb3VibGUtQmxpbmQgTWV0aG9kPC9rZXl3b3JkPjxrZXl3

b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1t

dW5vdGhlcmFweS9hZHZlcnNlIGVmZmVjdHMvKm1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFs

ZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD4qT3V0Y29t

ZSBBc3Nlc3NtZW50IChIZWFsdGggQ2FyZSk8L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5z

LyppbW11bm9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5GZWI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDc0

LTQ0NjUgKEVsZWN0cm9uaWMpJiN4RDsxNDc0LTQ0MjIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI3OTU1OTk1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNzk1NTk5NTwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMTQ3NC00NDIy

KDE2KTMwMzMxLTM8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0Vu

ZE5vdGU+

ADDIN EN.CITE.DATA 17Slightly different epitopes can be recognized for each individual, tailoring antibody responsePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PcmdvZ296bzwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+

PFJlY051bT40NjQwPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+NjUsNzgsNzk8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40NjQw

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDM4NTYwNDIiPjQ2NDA8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk9yZ29nb3pvLCBKLiBNLjwv

YXV0aG9yPjxhdXRob3I+R2lsbWFuLCBTLjwvYXV0aG9yPjxhdXRob3I+RGFydGlndWVzLCBKLiBG

LjwvYXV0aG9yPjxhdXRob3I+TGF1cmVudCwgQi48L2F1dGhvcj48YXV0aG9yPlB1ZWwsIE0uPC9h

dXRob3I+PGF1dGhvcj5LaXJieSwgTC4gQy48L2F1dGhvcj48YXV0aG9yPkpvdWFubnksIFAuPC9h

dXRob3I+PGF1dGhvcj5EdWJvaXMsIEIuPC9hdXRob3I+PGF1dGhvcj5FaXNuZXIsIEwuPC9hdXRo

b3I+PGF1dGhvcj5GbGl0bWFuLCBTLjwvYXV0aG9yPjxhdXRob3I+TWljaGVsLCBCLiBGLjwvYXV0

aG9yPjxhdXRob3I+Qm9hZGEsIE0uPC9hdXRob3I+PGF1dGhvcj5GcmFuaywgQS48L2F1dGhvcj48

YXV0aG9yPkhvY2ssIEMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk

ZHJlc3M+RmVkZXJhdGlvbiBvZiBOZXVyb2xvZ3ksIENIVSBQZWxsZWdyaW4sIEJvcmRlYXV4LCBG

cmFuY2UuIGoubS5vcmdvZ296b0BuZXVyby51LWJvcmRlYXV4Mi5mcjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPlN1YmFjdXRlIG1lbmluZ29lbmNlcGhhbGl0aXMgaW4gYSBzdWJzZXQgb2Yg

cGF0aWVudHMgd2l0aCBBRCBhZnRlciBBYmV0YTQyIGltbXVuaXphdGlvbjwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5OZXVyb2xvZ3k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh

bD48ZnVsbC10aXRsZT5OZXVyb2xvZ3k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz40

Ni01NDwvcGFnZXM+PHZvbHVtZT42MTwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxlZGl0aW9u

PjIwMDMvMDcvMDk8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkcmVuYWwgQ29ydGV4IEhv

cm1vbmVzL2FkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZTwva2V5d29yZD48a2V5d29yZD5BZ2Vk

PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFs

emhlaW1lciBEaXNlYXNlL2NvbXBsaWNhdGlvbnMvKmltbXVub2xvZ3kvdGhlcmFweTwva2V5d29y

ZD48a2V5d29yZD5BbHpoZWltZXIgVmFjY2luZXMvYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdl

LyphZHZlcnNlIGVmZmVjdHMvaW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJl

dGEtUGVwdGlkZXMvYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlLyphZHZlcnNlIGVmZmVjdHMv

aW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5BbnRpYm9kaWVzL2Jsb29kPC9rZXl3b3JkPjxr

ZXl3b3JkPkJyYWluL3BhdGhvbG9neS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

RGlzZWFzZSBQcm9ncmVzc2lvbjwva2V5d29yZD48a2V5d29yZD5FdXJvcGU8L2tleXdvcmQ+PGtl

eXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5N

YWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3Jk

PjxrZXl3b3JkPk1lbmluZ29lbmNlcGhhbGl0aXMvZGlhZ25vc2lzL2RydWcgdGhlcmFweS9ldGlv

bG9neS8qaW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48

a2V5d29yZD5OZXVyb3BzeWNob2xvZ2ljYWwgVGVzdHM8L2tleXdvcmQ+PGtleXdvcmQ+UGVwdGlk

ZSBGcmFnbWVudHMvKmFkdmVyc2UgZWZmZWN0cy9pbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PlBpbG90IFByb2plY3RzPC9rZXl3b3JkPjxrZXl3b3JkPlBsYXNtYXBoZXJlc2lzPC9rZXl3b3Jk

PjxrZXl3b3JkPlNhZmV0eTwva2V5d29yZD48a2V5d29yZD5UcmVhdG1lbnQgT3V0Y29tZTwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDAzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

SnVsIDg8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTI2LTYzMlggKEVsZWN0cm9u

aWMpJiN4RDswMDI4LTM4NzggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjEyODQ3MTU1

PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3B1Ym1lZC8xMjg0NzE1NTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48

L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5Nb3JnYW48L0F1dGhvcj48WWVhcj4yMDA2PC9Z

ZWFyPjxSZWNOdW0+NDYzOTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+NDYzOTwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTQzODU1OTk4Ij40NjM5PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Nb3JnYW4sIEQuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+QWx6aGVpbWVyIFJlc2VhcmNoIExhYm9y

YXRvcnksIERlcGFydG1lbnQgb2YgUGhhcm1hY29sb2d5IGFuZCBNb2xlY3VsYXIgVGhlcmFwZXV0

aWNzLCBVbml2ZXJzaXR5IG9mIFNvdXRoIEZsb3JpZGEsIE1EQyBCb3ggOSwgVGFtcGEsIEZMIDMz

NjEyLCBVbml0ZWQgU3RhdGVzLiBkbW9yZ2FuQGhzYy51c2YuZWR1PC9hdXRoLWFkZHJlc3M+PHRp

dGxlcz48dGl0bGU+TW9kdWxhdGlvbiBvZiBtaWNyb2dsaWFsIGFjdGl2YXRpb24gc3RhdGUgZm9s

bG93aW5nIHBhc3NpdmUgaW1tdW5pemF0aW9uIGluIGFteWxvaWQgZGVwb3NpdGluZyB0cmFuc2dl

bmljIG1pY2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmV1cm9jaGVtIEludDwvc2Vjb25kYXJ5

LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvY2hlbSBJbnQ8L2Z1

bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xOTAtNDwvcGFnZXM+PHZvbHVtZT40OTwvdm9s

dW1lPjxudW1iZXI+MjwvbnVtYmVyPjxlZGl0aW9uPjIwMDYvMDYvMDM8L2VkaXRpb24+PGtleXdv

cmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2dlbmV0aWNzL2ltbXVub2xvZ3kvKnRoZXJh

cHk8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzLyphbnRhZ29uaXN0cyAm

YW1wOyBpbmhpYml0b3JzL2ltbXVub2xvZ3kvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5B

bmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkFudGlib2RpZXMvaW1tdW5vbG9neS8qcGhhcm1hY29s

b2d5L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5CcmFpbi8qaW1tdW5vbG9neS9w

aHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFuaW1hbDwv

a2V5d29yZD48a2V5d29yZD5FbmNlcGhhbGl0aXMvaW1tdW5vbG9neS9wcmV2ZW50aW9uICZhbXA7

IGNvbnRyb2wvdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5HbGlvc2lzL2ltbXVub2xvZ3kvcHJl

dmVudGlvbiAmYW1wOyBjb250cm9sL3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9r

ZXl3b3JkPjxrZXl3b3JkPkltbXVuaXphdGlvbiwgUGFzc2l2ZS8qbWV0aG9kcy90cmVuZHM8L2tl

eXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFuc2dlbmljL2dl

bmV0aWNzLyppbW11bm9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TWljcm9nbGlh

L2ltbXVub2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNjwveWVhcj48

cHViLWRhdGVzPjxkYXRlPkp1bDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAxOTct

MDE4NiAoUHJpbnQpJiN4RDswMTk3LTAxODYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVt

PjE2NzQwMzQyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczov

L3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNjc0MDM0MjwvdXJsPjx1cmw+aHR0cHM6Ly9h

Yy5lbHMtY2RuLmNvbS9TMDE5NzAxODYwNjAwMTY5MC8xLXMyLjAtUzAxOTcwMTg2MDYwMDE2OTAt

bWFpbi5wZGY/X3RpZD1mZjcxMjVhZi0zZmU1LTQ3NTEtOWZjNi1hMGUxNGU3NTlkZDcmYW1wO2Fj

ZG5hdD0xNTQzODU2MTk1XzQ0MDgzNzQ1MTU3ZmMwMzc4NTBlOTc1ZWMyNDEwNDZkPC91cmw+PC9y

ZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2oubmV1

aW50LjIwMDYuMDMuMDE3PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+

PENpdGU+PEF1dGhvcj5Nb3JnYW48L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxSZWNOdW0+MTI8

L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+

PGtleSBhcHA9IkVOIiBkYi1pZD0iemZ0ZnZ0eGVmeHN2MDFldHBzdDV6c3NlejI5d3QwMHN4cHJ2

IiB0aW1lc3RhbXA9IjE1NDM5MjAxNTciPjEyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5Nb3JnYW4sIEQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxh

dXRoLWFkZHJlc3M+QWx6aGVpbWVyJmFwb3M7cyBJbnN0aXR1dGUsIFVuaXZlcnNpdHkgb2YgU291

dGggRmxvcmlkYSwgVGFtcGEsIEZMIDMzNjEzLCBVU0EuIHNjaWVudGlzdC5kYXZlQGdtYWlsLmNv

bTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkltbXVub3RoZXJhcHkgZm9yIEFsemhlaW1l

ciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEludGVybiBNZWQ8L3Nl

Y29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NTQtNjM8L3BhZ2VzPjx2b2x1bWU+MjY5PC92

b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGVkaXRpb24+MjAxMC8xMi8xNzwvZWRpdGlvbj48a2V5

d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvaW1tdW5vbG9neS9wYXRob2xvZ3kvKnRo

ZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIFZhY2NpbmVzL3RoZXJhcGV1dGljIHVz

ZTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL3BhdGhvbG9neTwv

a2V5d29yZD48a2V5d29yZD5EaXNlYXNlIE1vZGVscywgQW5pbWFsPC9rZXl3b3JkPjxrZXl3b3Jk

Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bml6YXRpb24sIFBhc3NpdmUvbWV0aG9kczwv

a2V5d29yZD48a2V5d29yZD5JbW11bm90aGVyYXB5LyptZXRob2RzL3RyZW5kczwva2V5d29yZD48

a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIFRyYW5zZ2VuaWM8L2tleXdvcmQ+

PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkphbjwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjEzNjUtMjc5NiAoRWxlY3Ryb25pYykmI3hE

OzA5NTQtNjgyMCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjExNTg5Nzg8L2FjY2Vz

c2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5p

aC5nb3YvcHVibWVkLzIxMTU4OTc4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20y

PlBNQzMwNzQ5Njc8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExMTEvai4x

MzY1LTI3OTYuMjAxMC4wMjMxNS54PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48

L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PcmdvZ296bzwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+

PFJlY051bT40NjQwPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+NjUsNzgsNzk8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40NjQw

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDM4NTYwNDIiPjQ2NDA8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk9yZ29nb3pvLCBKLiBNLjwv

YXV0aG9yPjxhdXRob3I+R2lsbWFuLCBTLjwvYXV0aG9yPjxhdXRob3I+RGFydGlndWVzLCBKLiBG

LjwvYXV0aG9yPjxhdXRob3I+TGF1cmVudCwgQi48L2F1dGhvcj48YXV0aG9yPlB1ZWwsIE0uPC9h

dXRob3I+PGF1dGhvcj5LaXJieSwgTC4gQy48L2F1dGhvcj48YXV0aG9yPkpvdWFubnksIFAuPC9h

dXRob3I+PGF1dGhvcj5EdWJvaXMsIEIuPC9hdXRob3I+PGF1dGhvcj5FaXNuZXIsIEwuPC9hdXRo

b3I+PGF1dGhvcj5GbGl0bWFuLCBTLjwvYXV0aG9yPjxhdXRob3I+TWljaGVsLCBCLiBGLjwvYXV0

aG9yPjxhdXRob3I+Qm9hZGEsIE0uPC9hdXRob3I+PGF1dGhvcj5GcmFuaywgQS48L2F1dGhvcj48

YXV0aG9yPkhvY2ssIEMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk

ZHJlc3M+RmVkZXJhdGlvbiBvZiBOZXVyb2xvZ3ksIENIVSBQZWxsZWdyaW4sIEJvcmRlYXV4LCBG

cmFuY2UuIGoubS5vcmdvZ296b0BuZXVyby51LWJvcmRlYXV4Mi5mcjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPlN1YmFjdXRlIG1lbmluZ29lbmNlcGhhbGl0aXMgaW4gYSBzdWJzZXQgb2Yg

cGF0aWVudHMgd2l0aCBBRCBhZnRlciBBYmV0YTQyIGltbXVuaXphdGlvbjwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5OZXVyb2xvZ3k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh

bD48ZnVsbC10aXRsZT5OZXVyb2xvZ3k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz40

Ni01NDwvcGFnZXM+PHZvbHVtZT42MTwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxlZGl0aW9u

PjIwMDMvMDcvMDk8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkcmVuYWwgQ29ydGV4IEhv

cm1vbmVzL2FkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZTwva2V5d29yZD48a2V5d29yZD5BZ2Vk

PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFs

emhlaW1lciBEaXNlYXNlL2NvbXBsaWNhdGlvbnMvKmltbXVub2xvZ3kvdGhlcmFweTwva2V5d29y

ZD48a2V5d29yZD5BbHpoZWltZXIgVmFjY2luZXMvYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdl

LyphZHZlcnNlIGVmZmVjdHMvaW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJl

dGEtUGVwdGlkZXMvYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlLyphZHZlcnNlIGVmZmVjdHMv

aW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5BbnRpYm9kaWVzL2Jsb29kPC9rZXl3b3JkPjxr

ZXl3b3JkPkJyYWluL3BhdGhvbG9neS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

RGlzZWFzZSBQcm9ncmVzc2lvbjwva2V5d29yZD48a2V5d29yZD5FdXJvcGU8L2tleXdvcmQ+PGtl

eXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5N

YWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3Jk

PjxrZXl3b3JkPk1lbmluZ29lbmNlcGhhbGl0aXMvZGlhZ25vc2lzL2RydWcgdGhlcmFweS9ldGlv

bG9neS8qaW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48

a2V5d29yZD5OZXVyb3BzeWNob2xvZ2ljYWwgVGVzdHM8L2tleXdvcmQ+PGtleXdvcmQ+UGVwdGlk

ZSBGcmFnbWVudHMvKmFkdmVyc2UgZWZmZWN0cy9pbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PlBpbG90IFByb2plY3RzPC9rZXl3b3JkPjxrZXl3b3JkPlBsYXNtYXBoZXJlc2lzPC9rZXl3b3Jk

PjxrZXl3b3JkPlNhZmV0eTwva2V5d29yZD48a2V5d29yZD5UcmVhdG1lbnQgT3V0Y29tZTwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDAzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

SnVsIDg8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTI2LTYzMlggKEVsZWN0cm9u

aWMpJiN4RDswMDI4LTM4NzggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjEyODQ3MTU1

PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3B1Ym1lZC8xMjg0NzE1NTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48

L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5Nb3JnYW48L0F1dGhvcj48WWVhcj4yMDA2PC9Z

ZWFyPjxSZWNOdW0+NDYzOTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+NDYzOTwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTQzODU1OTk4Ij40NjM5PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Nb3JnYW4sIEQuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+QWx6aGVpbWVyIFJlc2VhcmNoIExhYm9y

YXRvcnksIERlcGFydG1lbnQgb2YgUGhhcm1hY29sb2d5IGFuZCBNb2xlY3VsYXIgVGhlcmFwZXV0

aWNzLCBVbml2ZXJzaXR5IG9mIFNvdXRoIEZsb3JpZGEsIE1EQyBCb3ggOSwgVGFtcGEsIEZMIDMz

NjEyLCBVbml0ZWQgU3RhdGVzLiBkbW9yZ2FuQGhzYy51c2YuZWR1PC9hdXRoLWFkZHJlc3M+PHRp

dGxlcz48dGl0bGU+TW9kdWxhdGlvbiBvZiBtaWNyb2dsaWFsIGFjdGl2YXRpb24gc3RhdGUgZm9s

bG93aW5nIHBhc3NpdmUgaW1tdW5pemF0aW9uIGluIGFteWxvaWQgZGVwb3NpdGluZyB0cmFuc2dl

bmljIG1pY2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmV1cm9jaGVtIEludDwvc2Vjb25kYXJ5

LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvY2hlbSBJbnQ8L2Z1

bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xOTAtNDwvcGFnZXM+PHZvbHVtZT40OTwvdm9s

dW1lPjxudW1iZXI+MjwvbnVtYmVyPjxlZGl0aW9uPjIwMDYvMDYvMDM8L2VkaXRpb24+PGtleXdv

cmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2dlbmV0aWNzL2ltbXVub2xvZ3kvKnRoZXJh

cHk8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzLyphbnRhZ29uaXN0cyAm

YW1wOyBpbmhpYml0b3JzL2ltbXVub2xvZ3kvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5B

bmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkFudGlib2RpZXMvaW1tdW5vbG9neS8qcGhhcm1hY29s

b2d5L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5CcmFpbi8qaW1tdW5vbG9neS9w

aHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFuaW1hbDwv

a2V5d29yZD48a2V5d29yZD5FbmNlcGhhbGl0aXMvaW1tdW5vbG9neS9wcmV2ZW50aW9uICZhbXA7

IGNvbnRyb2wvdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5HbGlvc2lzL2ltbXVub2xvZ3kvcHJl

dmVudGlvbiAmYW1wOyBjb250cm9sL3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9r

ZXl3b3JkPjxrZXl3b3JkPkltbXVuaXphdGlvbiwgUGFzc2l2ZS8qbWV0aG9kcy90cmVuZHM8L2tl

eXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFuc2dlbmljL2dl

bmV0aWNzLyppbW11bm9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TWljcm9nbGlh

L2ltbXVub2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNjwveWVhcj48

cHViLWRhdGVzPjxkYXRlPkp1bDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAxOTct

MDE4NiAoUHJpbnQpJiN4RDswMTk3LTAxODYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVt

PjE2NzQwMzQyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczov

L3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNjc0MDM0MjwvdXJsPjx1cmw+aHR0cHM6Ly9h

Yy5lbHMtY2RuLmNvbS9TMDE5NzAxODYwNjAwMTY5MC8xLXMyLjAtUzAxOTcwMTg2MDYwMDE2OTAt

bWFpbi5wZGY/X3RpZD1mZjcxMjVhZi0zZmU1LTQ3NTEtOWZjNi1hMGUxNGU3NTlkZDcmYW1wO2Fj

ZG5hdD0xNTQzODU2MTk1XzQ0MDgzNzQ1MTU3ZmMwMzc4NTBlOTc1ZWMyNDEwNDZkPC91cmw+PC9y

ZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2oubmV1

aW50LjIwMDYuMDMuMDE3PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+

PENpdGU+PEF1dGhvcj5Nb3JnYW48L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxSZWNOdW0+MTI8

L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+

PGtleSBhcHA9IkVOIiBkYi1pZD0iemZ0ZnZ0eGVmeHN2MDFldHBzdDV6c3NlejI5d3QwMHN4cHJ2

IiB0aW1lc3RhbXA9IjE1NDM5MjAxNTciPjEyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5Nb3JnYW4sIEQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxh

dXRoLWFkZHJlc3M+QWx6aGVpbWVyJmFwb3M7cyBJbnN0aXR1dGUsIFVuaXZlcnNpdHkgb2YgU291

dGggRmxvcmlkYSwgVGFtcGEsIEZMIDMzNjEzLCBVU0EuIHNjaWVudGlzdC5kYXZlQGdtYWlsLmNv

bTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkltbXVub3RoZXJhcHkgZm9yIEFsemhlaW1l

ciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEludGVybiBNZWQ8L3Nl

Y29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NTQtNjM8L3BhZ2VzPjx2b2x1bWU+MjY5PC92

b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGVkaXRpb24+MjAxMC8xMi8xNzwvZWRpdGlvbj48a2V5

d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvaW1tdW5vbG9neS9wYXRob2xvZ3kvKnRo

ZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIFZhY2NpbmVzL3RoZXJhcGV1dGljIHVz

ZTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL3BhdGhvbG9neTwv

a2V5d29yZD48a2V5d29yZD5EaXNlYXNlIE1vZGVscywgQW5pbWFsPC9rZXl3b3JkPjxrZXl3b3Jk

Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bml6YXRpb24sIFBhc3NpdmUvbWV0aG9kczwv

a2V5d29yZD48a2V5d29yZD5JbW11bm90aGVyYXB5LyptZXRob2RzL3RyZW5kczwva2V5d29yZD48

a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIFRyYW5zZ2VuaWM8L2tleXdvcmQ+

PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkphbjwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjEzNjUtMjc5NiAoRWxlY3Ryb25pYykmI3hE

OzA5NTQtNjgyMCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjExNTg5Nzg8L2FjY2Vz

c2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5p

aC5nb3YvcHVibWVkLzIxMTU4OTc4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20y

PlBNQzMwNzQ5Njc8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExMTEvai4x

MzY1LTI3OTYuMjAxMC4wMjMxNS54PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48

L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 65,78,79Reduced control over epitope choice and specificity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJkPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVj

TnVtPjQyNTQ8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij42

ODwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQyNTQ8L3JlYy1udW1i

ZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBo

cGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjkxNzMwNSI+NDI1NDwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QmFyZCwgRi48L2F1dGhvcj48YXV0aG9yPkJh

cmJvdXIsIFIuPC9hdXRob3I+PGF1dGhvcj5DYW5ub24sIEMuPC9hdXRob3I+PGF1dGhvcj5DYXJy

ZXR0bywgUi48L2F1dGhvcj48YXV0aG9yPkZveCwgTS48L2F1dGhvcj48YXV0aG9yPkdhbWVzLCBE

LjwvYXV0aG9yPjxhdXRob3I+R3VpZG8sIFQuPC9hdXRob3I+PGF1dGhvcj5Ib2Vub3csIEsuPC9h

dXRob3I+PGF1dGhvcj5IdSwgSy48L2F1dGhvcj48YXV0aG9yPkpvaG5zb24tV29vZCwgSy48L2F1

dGhvcj48YXV0aG9yPktoYW4sIEsuPC9hdXRob3I+PGF1dGhvcj5LaG9sb2RlbmtvLCBELjwvYXV0

aG9yPjxhdXRob3I+TGVlLCBDLjwvYXV0aG9yPjxhdXRob3I+TGVlLCBNLjwvYXV0aG9yPjxhdXRo

b3I+TW90dGVyLCBSLjwvYXV0aG9yPjxhdXRob3I+Tmd1eWVuLCBNLjwvYXV0aG9yPjxhdXRob3I+

UmVlZCwgQS48L2F1dGhvcj48YXV0aG9yPlNjaGVuaywgRC48L2F1dGhvcj48YXV0aG9yPlRhbmcs

IFAuPC9hdXRob3I+PGF1dGhvcj5WYXNxdWV6LCBOLjwvYXV0aG9yPjxhdXRob3I+U2V1YmVydCwg

UC48L2F1dGhvcj48YXV0aG9yPlllZG5vY2ssIFQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp

YnV0b3JzPjxhdXRoLWFkZHJlc3M+RWxhbiBQaGFybWFjZXV0aWNhbHMsIDgwMCBHYXRld2F5IEJv

dWxldmFyZCwgU291dGggU2FuIEZyYW5jaXNjbywgQ0EgOTQwODAsIFVTQS4gZnJlZGVyaXF1ZS5i

YXJkQGVsYW4uY29tPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+RXBpdG9wZSBhbmQgaXNv

dHlwZSBzcGVjaWZpY2l0aWVzIG9mIGFudGlib2RpZXMgdG8gYmV0YSAtYW15bG9pZCBwZXB0aWRl

IGZvciBwcm90ZWN0aW9uIGFnYWluc3QgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlLWxpa2UgbmV1

cm9wYXRob2xvZ3k8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2NpIFUg

UyBBPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UHJv

YyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjAy

My04PC9wYWdlcz48dm9sdW1lPjEwMDwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxlZGl0aW9u

PjIwMDMvMDIvMDU8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNl

L2ltbXVub2xvZ3kvKnByZXZlbnRpb24gJmFtcDsgY29udHJvbDwva2V5d29yZD48a2V5d29yZD5B

bWlubyBBY2lkIFNlcXVlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRl

cy8qY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkFudGlib2RpZXMsIE1vbm9jbG9uYWwvKmlt

bXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+KkFudGlib2R5IFNwZWNpZmljaXR5PC9rZXl3b3Jk

PjxrZXl3b3JkPkVwaXRvcGUgTWFwcGluZzwva2V5d29yZD48a2V5d29yZD5FcGl0b3Blcy8qaW1t

dW5vbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TW9sZWN1

bGFyIFNlcXVlbmNlIERhdGE8L2tleXdvcmQ+PGtleXdvcmQ+UGVwdGlkZSBGcmFnbWVudHMvKmlt

bXVub2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMzwveWVhcj48cHVi

LWRhdGVzPjxkYXRlPkZlYiAxODwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMjct

ODQyNCAoUHJpbnQpJiN4RDswMDI3LTg0MjQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVt

PjEyNTY2NTY4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczov

L3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xMjU2NjU2ODwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48Y3VzdG9tMj5QTUMxNDk5NTI8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjEwLjEwNzMvcG5hcy4wNDM2Mjg2MTAwPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3Jl

Y29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJkPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVj

TnVtPjQyNTQ8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij42

ODwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQyNTQ8L3JlYy1udW1i

ZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBo

cGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjkxNzMwNSI+NDI1NDwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QmFyZCwgRi48L2F1dGhvcj48YXV0aG9yPkJh

cmJvdXIsIFIuPC9hdXRob3I+PGF1dGhvcj5DYW5ub24sIEMuPC9hdXRob3I+PGF1dGhvcj5DYXJy

ZXR0bywgUi48L2F1dGhvcj48YXV0aG9yPkZveCwgTS48L2F1dGhvcj48YXV0aG9yPkdhbWVzLCBE

LjwvYXV0aG9yPjxhdXRob3I+R3VpZG8sIFQuPC9hdXRob3I+PGF1dGhvcj5Ib2Vub3csIEsuPC9h

dXRob3I+PGF1dGhvcj5IdSwgSy48L2F1dGhvcj48YXV0aG9yPkpvaG5zb24tV29vZCwgSy48L2F1

dGhvcj48YXV0aG9yPktoYW4sIEsuPC9hdXRob3I+PGF1dGhvcj5LaG9sb2RlbmtvLCBELjwvYXV0

aG9yPjxhdXRob3I+TGVlLCBDLjwvYXV0aG9yPjxhdXRob3I+TGVlLCBNLjwvYXV0aG9yPjxhdXRo

b3I+TW90dGVyLCBSLjwvYXV0aG9yPjxhdXRob3I+Tmd1eWVuLCBNLjwvYXV0aG9yPjxhdXRob3I+

UmVlZCwgQS48L2F1dGhvcj48YXV0aG9yPlNjaGVuaywgRC48L2F1dGhvcj48YXV0aG9yPlRhbmcs

IFAuPC9hdXRob3I+PGF1dGhvcj5WYXNxdWV6LCBOLjwvYXV0aG9yPjxhdXRob3I+U2V1YmVydCwg

UC48L2F1dGhvcj48YXV0aG9yPlllZG5vY2ssIFQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp

YnV0b3JzPjxhdXRoLWFkZHJlc3M+RWxhbiBQaGFybWFjZXV0aWNhbHMsIDgwMCBHYXRld2F5IEJv

dWxldmFyZCwgU291dGggU2FuIEZyYW5jaXNjbywgQ0EgOTQwODAsIFVTQS4gZnJlZGVyaXF1ZS5i

YXJkQGVsYW4uY29tPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+RXBpdG9wZSBhbmQgaXNv

dHlwZSBzcGVjaWZpY2l0aWVzIG9mIGFudGlib2RpZXMgdG8gYmV0YSAtYW15bG9pZCBwZXB0aWRl

IGZvciBwcm90ZWN0aW9uIGFnYWluc3QgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlLWxpa2UgbmV1

cm9wYXRob2xvZ3k8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2NpIFUg

UyBBPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UHJv

YyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjAy

My04PC9wYWdlcz48dm9sdW1lPjEwMDwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxlZGl0aW9u

PjIwMDMvMDIvMDU8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNl

L2ltbXVub2xvZ3kvKnByZXZlbnRpb24gJmFtcDsgY29udHJvbDwva2V5d29yZD48a2V5d29yZD5B

bWlubyBBY2lkIFNlcXVlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRl

cy8qY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkFudGlib2RpZXMsIE1vbm9jbG9uYWwvKmlt

bXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+KkFudGlib2R5IFNwZWNpZmljaXR5PC9rZXl3b3Jk

PjxrZXl3b3JkPkVwaXRvcGUgTWFwcGluZzwva2V5d29yZD48a2V5d29yZD5FcGl0b3Blcy8qaW1t

dW5vbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TW9sZWN1

bGFyIFNlcXVlbmNlIERhdGE8L2tleXdvcmQ+PGtleXdvcmQ+UGVwdGlkZSBGcmFnbWVudHMvKmlt

bXVub2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMzwveWVhcj48cHVi

LWRhdGVzPjxkYXRlPkZlYiAxODwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMjct

ODQyNCAoUHJpbnQpJiN4RDswMDI3LTg0MjQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVt

PjEyNTY2NTY4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczov

L3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xMjU2NjU2ODwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48Y3VzdG9tMj5QTUMxNDk5NTI8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjEwLjEwNzMvcG5hcy4wNDM2Mjg2MTAwPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3Jl

Y29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 68Lower than passive immunotherapies.The host produces own antibodies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZW1lcmU8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

ZWNOdW0+NDI1MTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

Pjc3LDgwLTgyPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDI1MTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2OTE1MTQ1Ij40MjUxPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5MZW1lcmUsIEMuIEEuPC9hdXRo

b3I+PGF1dGhvcj5NYXNsaWFoLCBFLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48

YXV0aC1hZGRyZXNzPkNlbnRlciBmb3IgTmV1cm9sb2dpYyBEaXNlYXNlcywgRGVwYXJ0bWVudCBv

ZiBOZXVyb2xvZ3ksIEJyaWdoYW0gYW5kIFdvbWVuJmFwb3M7cyBIb3NwaXRhbCwgTmV3IFJlc2Vh

cmNoIEJ1aWxkaW5nIDYzNkYsIEJvc3RvbiwgTUEgMDIxMTUsIFVTQS4gY2xlbWVyZUByaWNzLmJ3

aC5oYXJ2YXJkLmVkdTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNhbiBBbHpoZWltZXIg

ZGlzZWFzZSBiZSBwcmV2ZW50ZWQgYnkgYW15bG9pZC1iZXRhIGltbXVub3RoZXJhcHk/PC90aXRs

ZT48c2Vjb25kYXJ5LXRpdGxlPk5hdCBSZXYgTmV1cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRs

ZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmF0IFJldiBOZXVyb2w8L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxwYWdlcz4xMDgtMTk8L3BhZ2VzPjx2b2x1bWU+Njwvdm9sdW1lPjxudW1iZXI+

MjwvbnVtYmVyPjxlZGl0aW9uPjIwMTAvMDIvMDk8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PkFsemhlaW1lciBEaXNlYXNlL2ltbXVub2xvZ3kvKnByZXZlbnRpb24gJmFtcDsgY29udHJvbDwv

a2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvaW1tdW5vbG9neTwva2V5d29y

ZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkNsaW5pY2FsIFRyaWFscyBhcyBU

b3BpYzwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vdGhl

cmFweS8qbWV0aG9kczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEwPC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+RmViPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTc1

OS00NzY2IChFbGVjdHJvbmljKSYjeEQ7MTc1OS00NzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNz

aW9uLW51bT4yMDE0MDAwMDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+

aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjAxNDAwMDA8L3VybD48L3JlbGF0

ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMjg2NDA4OTwvY3VzdG9tMj48ZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+MTAuMTAzOC9ucm5ldXJvbC4yMDA5LjIxOTwvZWxlY3Ryb25pYy1yZXNvdXJj

ZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+VmFuZGVuYmVyZ2hlPC9BdXRob3I+

PFllYXI+MjAxNzwvWWVhcj48UmVjTnVtPjIxODA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVy

PjIxODA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ew

cng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDkyNzU4NSI+

MjE4MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi

PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+VmFuZGVuYmVyZ2hl

LCBSLjwvYXV0aG9yPjxhdXRob3I+Uml2aWVyZSwgTS4gRS48L2F1dGhvcj48YXV0aG9yPkNhcHV0

bywgQS48L2F1dGhvcj48YXV0aG9yPlNvdmFnbywgSi48L2F1dGhvcj48YXV0aG9yPk1hZ3VpcmUs

IFIuIFAuPC9hdXRob3I+PGF1dGhvcj5GYXJsb3csIE0uPC9hdXRob3I+PGF1dGhvcj5NYXJvdHRh

LCBHLjwvYXV0aG9yPjxhdXRob3I+U2FuY2hlei1WYWxsZSwgUi48L2F1dGhvcj48YXV0aG9yPlNj

aGVsdGVucywgUC48L2F1dGhvcj48YXV0aG9yPlJ5YW4sIEouIE0uPC9hdXRob3I+PGF1dGhvcj5H

cmFmLCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRl

cGFydG1lbnQgb2YgTmV1cm9zY2llbmNlcywgS1UgTGV1dmVuLCBMZXV2ZW4sIEJlbGdpdW0uJiN4

RDtOZXVyb2xvZ3kgRGVwYXJ0bWVudCwgVW5pdmVyc2l0eSBIb3NwaXRhbHMgTGV1dmVuLCBCZWxn

aXVtLiYjeEQ7TmV1cm9zY2llbmNlLCBOb3ZhcnRpcyBQaGFybWEgQUcsIEJhc2VsLCBTd2l0emVy

bGFuZC4mI3hEO05ldXJvc2NpZW5jZSBUcmFuc2xhdGlvbmFsIE1lZGljaW5lLCBOb3ZhcnRpcyBJ

bnN0aXR1dGVzIGZvciBCaW9tZWRpY2FsIFJlc2VhcmNoLCBCYXNlbCwgU3dpdHplcmxhbmQuJiN4

RDtCaW9tYXJrZXIgRGV2ZWxvcG1lbnQsIENsaW5pY2FsIEltYWdpbmcsIE5vdmFydGlzIEluc3Rp

dHV0ZXMgZm9yIEJpb21lZGljYWwgUmVzZWFyY2gsIEJhc2VsLCBTd2l0emVybGFuZC4mI3hEO0Rl

cGFydG1lbnQgb2YgTmV1cm9sb2d5LCBJbmRpYW5hIFVuaXZlcnNpdHkgU2Nob29sIG9mIE1lZGlj

aW5lLCBJTiwgVVNBLiYjeEQ7RGl2aXNpb24gb2YgR2VyaWF0cmljIE1lZGljaW5lLCBVbml2ZXJz

aXR5IG9mIFRvcm9udG8sIFRvcm9udG8sIENhbmFkYS4mI3hEO0FsemhlaW1lciZhcG9zO3MgRGlz

ZWFzZSBhbmQgT3RoZXIgQ29nbml0aXZlIERpc29yZGVycyBVbml0LCBIb3NwaXRhbCBDbGluaWMs

IEJhcmNlbG9uYSwgU3BhaW4uJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvbG9neSBhbmQgQWx6aGVp

bWVyIENlbnRlciwgVlUgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRlciwgQW1zdGVyZGFtLCBUaGUg

TmV0aGVybGFuZHMuJiN4RDtOb3ZhcnRpcyBQaGFybWFjZXV0aWNhbHMgQ29ycG9yYXRpb24sIEVh

c3QgSGFub3ZlciwgTkosIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BY3RpdmUg

QWJldGEgaW1tdW5vdGhlcmFweSBDQUQxMDYgaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlOiBB

IHBoYXNlIDJiIHN0dWR5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFsemhlaW1lcnMgRGVtZW50

IChOIFkpPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+

QWx6aGVpbWVycyBEZW1lbnQgKE4gWSk8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4x

MC0yMjwvcGFnZXM+PHZvbHVtZT4zPC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGVkaXRpb24+

MjAxNy8xMC8yNzwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWN0aXZlIGltbXVub3RoZXJh

cHk8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxr

ZXl3b3JkPkFteWxvaWQtYmV0YSBwZXB0aWRlczwva2V5d29yZD48a2V5d29yZD5CaW9sb2dpY2Fs

IGJpb21hcmtlcnM8L2tleXdvcmQ+PGtleXdvcmQ+Q2FkMTA2PC9rZXl3b3JkPjxrZXl3b3JkPlNh

ZmV0eTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE3PC95ZWFyPjxwdWItZGF0

ZXM+PGRhdGU+SmFuPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MjM1Mi04NzM3IChQ

cmludCkmI3hEOzIzNTItODczNyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjkwNjcz

MTY8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5j

YmkubmxtLm5paC5nb3YvcHVibWVkLzI5MDY3MzE2PC91cmw+PHVybD5odHRwczovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3BtYy9hcnRpY2xlcy9QTUM1NjUxMzczL3BkZi9tYWluLnBkZjwvdXJsPjwv

cmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM1NjUxMzczPC9jdXN0b20yPjxlbGVjdHJv

bmljLXJlc291cmNlLW51bT4xMC4xMDE2L2oudHJjaS4yMDE2LjEyLjAwMzwvZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+RmFybG93PC9BdXRob3I+

PFllYXI+MjAxNTwvWWVhcj48UmVjTnVtPjIxODE8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVy

PjIxODE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ew

cng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDkyNzU4NSI+

MjE4MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi

PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RmFybG93LCBNLiBS

LjwvYXV0aG9yPjxhdXRob3I+QW5kcmVhc2VuLCBOLjwvYXV0aG9yPjxhdXRob3I+Uml2aWVyZSwg

TS4gRS48L2F1dGhvcj48YXV0aG9yPlZvc3RpYXIsIEkuPC9hdXRob3I+PGF1dGhvcj5WaXRhbGl0

aSwgQS48L2F1dGhvcj48YXV0aG9yPlNvdmFnbywgSi48L2F1dGhvcj48YXV0aG9yPkNhcHV0bywg

QS48L2F1dGhvcj48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5HcmFmLCBBLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQg

b2YgTmV1cm9sb2d5LCBJbmRpYW5hIFVuaXZlcnNpdHkgU2Nob29sIG9mIE1lZGljaW5lLCAzNTUg

V2VzdCAxNnRoIFN0cmVldCwgU3VpdGUgNDcwMCwgSW5kaWFuYXBvbGlzLCBJTiA0NjIwMiBVU0Eu

JiN4RDtLYXJvbGluc2thIEluc3RpdHV0ZXQsIERlcHQgTlZTLCBDZW50ZXIgZm9yIEFsemhlaW1l

ciBSZXNlYXJjaCwgRGl2aXNpb24gZm9yIE5ldXJvZ2VyaWF0cmljcywgTm92dW0sIEh1ZGRpbmdl

LCBTRS0xNDEgNTcgU3RvY2tob2xtIFN3ZWRlbiA7IEthcm9saW5za2EgVW5pdmVyc2l0eSBIb3Nw

aXRhbCBIdWRkaW5nZSwgR2VyaWF0cmljIENsaW5pYywgQ2xpbmljYWwgVHJpYWwgVW5pdCwgU0Ut

MTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7Tm92YXJ0aXMgUGhhcm1hIEFHLCBCYXNlbCwg

Q0gtNDAwMiBTd2l0emVybGFuZC48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Mb25nLXRl

cm0gdHJlYXRtZW50IHdpdGggYWN0aXZlIEFiZXRhIGltbXVub3RoZXJhcHkgd2l0aCBDQUQxMDYg

aW4gbWlsZCBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+

QWx6aGVpbWVycyBSZXMgVGhlcjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPkFsemhlaW1lcnMgUmVzIFRoZXI8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz4yMzwvcGFnZXM+PHZvbHVtZT43PC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGVk

aXRpb24+MjAxNS8wNC8yOTwvZWRpdGlvbj48ZGF0ZXM+PHllYXI+MjAxNTwveWVhcj48L2RhdGVz

Pjxpc2JuPjE3NTgtOTE5MyAoUHJpbnQpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1OTE4NTU2PC9h

Y2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5s

bS5uaWguZ292L3B1Ym1lZC8yNTkxODU1NjwvdXJsPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wbWMvYXJ0aWNsZXMvUE1DNDQxMDQ2MC9wZGYvMTMxOTVfMjAxNV9BcnRpY2xlXzEw

OC5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNDQxMDQ2MDwvY3Vz

dG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTE4Ni9zMTMxOTUtMDE1LTAxMDgtMzwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+V2lu

YmxhZDwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJlY051bT4yMTgzPC9SZWNOdW0+PHJlY29y

ZD48cmVjLW51bWJlcj4yMTgzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9

IjE1MzQ5Mjc1ODUiPjIxODM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5BbmRyZWFzZW4sIE4uPC9hdXRob3I+PGF1dGhv

cj5NaW50aG9uLCBMLjwvYXV0aG9yPjxhdXRob3I+RmxvZXNzZXIsIEEuPC9hdXRob3I+PGF1dGhv

cj5JbWJlcnQsIEcuPC9hdXRob3I+PGF1dGhvcj5EdW1vcnRpZXIsIFQuPC9hdXRob3I+PGF1dGhv

cj5NYWd1aXJlLCBSLiBQLjwvYXV0aG9yPjxhdXRob3I+Qmxlbm5vdywgSy48L2F1dGhvcj48YXV0

aG9yPkx1bmRtYXJrLCBKLjwvYXV0aG9yPjxhdXRob3I+U3RhdWZlbmJpZWwsIE0uPC9hdXRob3I+

PGF1dGhvcj5PcmdvZ296bywgSi4gTS48L2F1dGhvcj48YXV0aG9yPkdyYWYsIEEuPC9hdXRob3I+

PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+S2Fyb2xpbnNrYSBJbnN0aXR1

dGV0IEFsemhlaW1lciBEaXNlYXNlIFJlc2VhcmNoIENlbnRyZSBhbmQgQ2xpbmljYWwgVHJpYWwg

VW5pdCwgR2VyaWF0cmljIENsaW5pYywgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBI

dWRkaW5nZSwgU3dlZGVuLiBiZW5ndC53aW5ibGFkQGtpLnNlPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+U2FmZXR5LCB0b2xlcmFiaWxpdHksIGFuZCBhbnRpYm9keSByZXNwb25zZSBvZiBh

Y3RpdmUgQWJldGEgaW1tdW5vdGhlcmFweSB3aXRoIENBRDEwNiBpbiBwYXRpZW50cyB3aXRoIEFs

emhlaW1lciZhcG9zO3MgZGlzZWFzZTogcmFuZG9taXNlZCwgZG91YmxlLWJsaW5kLCBwbGFjZWJv

LWNvbnRyb2xsZWQsIGZpcnN0LWluLWh1bWFuIHN0dWR5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PkxhbmNldCBOZXVyb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NTk3LTYwNDwv

cGFnZXM+PHZvbHVtZT4xMTwvdm9sdW1lPjxudW1iZXI+NzwvbnVtYmVyPjxlZGl0aW9uPjIwMTIv

MDYvMDk8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+

QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvYmxv

b2QvKmRydWcgdGhlcmFweS8qaW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJl

dGEtUGVwdGlkZXMvKmltbXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJvZHkgRm9ybWF0

aW9uL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5CaW9tYXJrZXJzL2Jsb29kPC9rZXl3

b3JkPjxrZXl3b3JkPkRvdWJsZS1CbGluZCBNZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxl

PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxp

biBHL2Jsb29kPC9rZXl3b3JkPjxrZXl3b3JkPipJbW11bm90aGVyYXB5PC9rZXl3b3JkPjxrZXl3

b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+

VHJlYXRtZW50IE91dGNvbWU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMjwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju

PjE0NzQtNDQ2NSAoRWxlY3Ryb25pYykmI3hEOzE0NzQtNDQyMiAoTGlua2luZyk8L2lzYm4+PGFj

Y2Vzc2lvbi1udW0+MjI2NzcyNTg8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48

dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIyNjc3MjU4PC91cmw+PHVy

bD5odHRwczovL2FjLmVscy1jZG4uY29tL1MxNDc0NDQyMjEyNzAxNDAwLzEtczIuMC1TMTQ3NDQ0

MjIxMjcwMTQwMC1tYWluLnBkZj9fdGlkPWY4ZjEwN2YzLTg0MjAtNDczYi04Zjg1LWM4NjZmMmRj

YjZiNSZhbXA7YWNkbmF0PTE1MzQ5MjkxOTFfNTQyN2RmYzA1OGZlMzBhYWJhZmJhMDRlN2RjYjhh

YjE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEw

LjEwMTYvUzE0NzQtNDQyMigxMik3MDE0MC0wPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3Jl

Y29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZW1lcmU8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

ZWNOdW0+NDI1MTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

Pjc3LDgwLTgyPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDI1MTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2OTE1MTQ1Ij40MjUxPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5MZW1lcmUsIEMuIEEuPC9hdXRo

b3I+PGF1dGhvcj5NYXNsaWFoLCBFLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48

YXV0aC1hZGRyZXNzPkNlbnRlciBmb3IgTmV1cm9sb2dpYyBEaXNlYXNlcywgRGVwYXJ0bWVudCBv

ZiBOZXVyb2xvZ3ksIEJyaWdoYW0gYW5kIFdvbWVuJmFwb3M7cyBIb3NwaXRhbCwgTmV3IFJlc2Vh

cmNoIEJ1aWxkaW5nIDYzNkYsIEJvc3RvbiwgTUEgMDIxMTUsIFVTQS4gY2xlbWVyZUByaWNzLmJ3

aC5oYXJ2YXJkLmVkdTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNhbiBBbHpoZWltZXIg

ZGlzZWFzZSBiZSBwcmV2ZW50ZWQgYnkgYW15bG9pZC1iZXRhIGltbXVub3RoZXJhcHk/PC90aXRs

ZT48c2Vjb25kYXJ5LXRpdGxlPk5hdCBSZXYgTmV1cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRs

ZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmF0IFJldiBOZXVyb2w8L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxwYWdlcz4xMDgtMTk8L3BhZ2VzPjx2b2x1bWU+Njwvdm9sdW1lPjxudW1iZXI+

MjwvbnVtYmVyPjxlZGl0aW9uPjIwMTAvMDIvMDk8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PkFsemhlaW1lciBEaXNlYXNlL2ltbXVub2xvZ3kvKnByZXZlbnRpb24gJmFtcDsgY29udHJvbDwv

a2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvaW1tdW5vbG9neTwva2V5d29y

ZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkNsaW5pY2FsIFRyaWFscyBhcyBU

b3BpYzwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vdGhl

cmFweS8qbWV0aG9kczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEwPC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+RmViPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTc1

OS00NzY2IChFbGVjdHJvbmljKSYjeEQ7MTc1OS00NzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNz

aW9uLW51bT4yMDE0MDAwMDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+

aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjAxNDAwMDA8L3VybD48L3JlbGF0

ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMjg2NDA4OTwvY3VzdG9tMj48ZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+MTAuMTAzOC9ucm5ldXJvbC4yMDA5LjIxOTwvZWxlY3Ryb25pYy1yZXNvdXJj

ZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+VmFuZGVuYmVyZ2hlPC9BdXRob3I+

PFllYXI+MjAxNzwvWWVhcj48UmVjTnVtPjIxODA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVy

PjIxODA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ew

cng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDkyNzU4NSI+

MjE4MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi

PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+VmFuZGVuYmVyZ2hl

LCBSLjwvYXV0aG9yPjxhdXRob3I+Uml2aWVyZSwgTS4gRS48L2F1dGhvcj48YXV0aG9yPkNhcHV0

bywgQS48L2F1dGhvcj48YXV0aG9yPlNvdmFnbywgSi48L2F1dGhvcj48YXV0aG9yPk1hZ3VpcmUs

IFIuIFAuPC9hdXRob3I+PGF1dGhvcj5GYXJsb3csIE0uPC9hdXRob3I+PGF1dGhvcj5NYXJvdHRh

LCBHLjwvYXV0aG9yPjxhdXRob3I+U2FuY2hlei1WYWxsZSwgUi48L2F1dGhvcj48YXV0aG9yPlNj

aGVsdGVucywgUC48L2F1dGhvcj48YXV0aG9yPlJ5YW4sIEouIE0uPC9hdXRob3I+PGF1dGhvcj5H

cmFmLCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRl

cGFydG1lbnQgb2YgTmV1cm9zY2llbmNlcywgS1UgTGV1dmVuLCBMZXV2ZW4sIEJlbGdpdW0uJiN4

RDtOZXVyb2xvZ3kgRGVwYXJ0bWVudCwgVW5pdmVyc2l0eSBIb3NwaXRhbHMgTGV1dmVuLCBCZWxn

aXVtLiYjeEQ7TmV1cm9zY2llbmNlLCBOb3ZhcnRpcyBQaGFybWEgQUcsIEJhc2VsLCBTd2l0emVy

bGFuZC4mI3hEO05ldXJvc2NpZW5jZSBUcmFuc2xhdGlvbmFsIE1lZGljaW5lLCBOb3ZhcnRpcyBJ

bnN0aXR1dGVzIGZvciBCaW9tZWRpY2FsIFJlc2VhcmNoLCBCYXNlbCwgU3dpdHplcmxhbmQuJiN4

RDtCaW9tYXJrZXIgRGV2ZWxvcG1lbnQsIENsaW5pY2FsIEltYWdpbmcsIE5vdmFydGlzIEluc3Rp

dHV0ZXMgZm9yIEJpb21lZGljYWwgUmVzZWFyY2gsIEJhc2VsLCBTd2l0emVybGFuZC4mI3hEO0Rl

cGFydG1lbnQgb2YgTmV1cm9sb2d5LCBJbmRpYW5hIFVuaXZlcnNpdHkgU2Nob29sIG9mIE1lZGlj

aW5lLCBJTiwgVVNBLiYjeEQ7RGl2aXNpb24gb2YgR2VyaWF0cmljIE1lZGljaW5lLCBVbml2ZXJz

aXR5IG9mIFRvcm9udG8sIFRvcm9udG8sIENhbmFkYS4mI3hEO0FsemhlaW1lciZhcG9zO3MgRGlz

ZWFzZSBhbmQgT3RoZXIgQ29nbml0aXZlIERpc29yZGVycyBVbml0LCBIb3NwaXRhbCBDbGluaWMs

IEJhcmNlbG9uYSwgU3BhaW4uJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvbG9neSBhbmQgQWx6aGVp

bWVyIENlbnRlciwgVlUgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRlciwgQW1zdGVyZGFtLCBUaGUg

TmV0aGVybGFuZHMuJiN4RDtOb3ZhcnRpcyBQaGFybWFjZXV0aWNhbHMgQ29ycG9yYXRpb24sIEVh

c3QgSGFub3ZlciwgTkosIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BY3RpdmUg

QWJldGEgaW1tdW5vdGhlcmFweSBDQUQxMDYgaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlOiBB

IHBoYXNlIDJiIHN0dWR5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFsemhlaW1lcnMgRGVtZW50

IChOIFkpPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+

QWx6aGVpbWVycyBEZW1lbnQgKE4gWSk8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4x

MC0yMjwvcGFnZXM+PHZvbHVtZT4zPC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGVkaXRpb24+

MjAxNy8xMC8yNzwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWN0aXZlIGltbXVub3RoZXJh

cHk8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxr

ZXl3b3JkPkFteWxvaWQtYmV0YSBwZXB0aWRlczwva2V5d29yZD48a2V5d29yZD5CaW9sb2dpY2Fs

IGJpb21hcmtlcnM8L2tleXdvcmQ+PGtleXdvcmQ+Q2FkMTA2PC9rZXl3b3JkPjxrZXl3b3JkPlNh

ZmV0eTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE3PC95ZWFyPjxwdWItZGF0

ZXM+PGRhdGU+SmFuPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MjM1Mi04NzM3IChQ

cmludCkmI3hEOzIzNTItODczNyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjkwNjcz

MTY8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5j

YmkubmxtLm5paC5nb3YvcHVibWVkLzI5MDY3MzE2PC91cmw+PHVybD5odHRwczovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3BtYy9hcnRpY2xlcy9QTUM1NjUxMzczL3BkZi9tYWluLnBkZjwvdXJsPjwv

cmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM1NjUxMzczPC9jdXN0b20yPjxlbGVjdHJv

bmljLXJlc291cmNlLW51bT4xMC4xMDE2L2oudHJjaS4yMDE2LjEyLjAwMzwvZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+RmFybG93PC9BdXRob3I+

PFllYXI+MjAxNTwvWWVhcj48UmVjTnVtPjIxODE8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVy

PjIxODE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ew

cng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDkyNzU4NSI+

MjE4MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi

PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RmFybG93LCBNLiBS

LjwvYXV0aG9yPjxhdXRob3I+QW5kcmVhc2VuLCBOLjwvYXV0aG9yPjxhdXRob3I+Uml2aWVyZSwg

TS4gRS48L2F1dGhvcj48YXV0aG9yPlZvc3RpYXIsIEkuPC9hdXRob3I+PGF1dGhvcj5WaXRhbGl0

aSwgQS48L2F1dGhvcj48YXV0aG9yPlNvdmFnbywgSi48L2F1dGhvcj48YXV0aG9yPkNhcHV0bywg

QS48L2F1dGhvcj48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5HcmFmLCBBLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQg

b2YgTmV1cm9sb2d5LCBJbmRpYW5hIFVuaXZlcnNpdHkgU2Nob29sIG9mIE1lZGljaW5lLCAzNTUg

V2VzdCAxNnRoIFN0cmVldCwgU3VpdGUgNDcwMCwgSW5kaWFuYXBvbGlzLCBJTiA0NjIwMiBVU0Eu

JiN4RDtLYXJvbGluc2thIEluc3RpdHV0ZXQsIERlcHQgTlZTLCBDZW50ZXIgZm9yIEFsemhlaW1l

ciBSZXNlYXJjaCwgRGl2aXNpb24gZm9yIE5ldXJvZ2VyaWF0cmljcywgTm92dW0sIEh1ZGRpbmdl

LCBTRS0xNDEgNTcgU3RvY2tob2xtIFN3ZWRlbiA7IEthcm9saW5za2EgVW5pdmVyc2l0eSBIb3Nw

aXRhbCBIdWRkaW5nZSwgR2VyaWF0cmljIENsaW5pYywgQ2xpbmljYWwgVHJpYWwgVW5pdCwgU0Ut

MTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7Tm92YXJ0aXMgUGhhcm1hIEFHLCBCYXNlbCwg

Q0gtNDAwMiBTd2l0emVybGFuZC48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Mb25nLXRl

cm0gdHJlYXRtZW50IHdpdGggYWN0aXZlIEFiZXRhIGltbXVub3RoZXJhcHkgd2l0aCBDQUQxMDYg

aW4gbWlsZCBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+

QWx6aGVpbWVycyBSZXMgVGhlcjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPkFsemhlaW1lcnMgUmVzIFRoZXI8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz4yMzwvcGFnZXM+PHZvbHVtZT43PC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGVk

aXRpb24+MjAxNS8wNC8yOTwvZWRpdGlvbj48ZGF0ZXM+PHllYXI+MjAxNTwveWVhcj48L2RhdGVz

Pjxpc2JuPjE3NTgtOTE5MyAoUHJpbnQpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1OTE4NTU2PC9h

Y2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5s

bS5uaWguZ292L3B1Ym1lZC8yNTkxODU1NjwvdXJsPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wbWMvYXJ0aWNsZXMvUE1DNDQxMDQ2MC9wZGYvMTMxOTVfMjAxNV9BcnRpY2xlXzEw

OC5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNDQxMDQ2MDwvY3Vz

dG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTE4Ni9zMTMxOTUtMDE1LTAxMDgtMzwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+V2lu

YmxhZDwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJlY051bT4yMTgzPC9SZWNOdW0+PHJlY29y

ZD48cmVjLW51bWJlcj4yMTgzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9

IjE1MzQ5Mjc1ODUiPjIxODM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5BbmRyZWFzZW4sIE4uPC9hdXRob3I+PGF1dGhv

cj5NaW50aG9uLCBMLjwvYXV0aG9yPjxhdXRob3I+RmxvZXNzZXIsIEEuPC9hdXRob3I+PGF1dGhv

cj5JbWJlcnQsIEcuPC9hdXRob3I+PGF1dGhvcj5EdW1vcnRpZXIsIFQuPC9hdXRob3I+PGF1dGhv

cj5NYWd1aXJlLCBSLiBQLjwvYXV0aG9yPjxhdXRob3I+Qmxlbm5vdywgSy48L2F1dGhvcj48YXV0

aG9yPkx1bmRtYXJrLCBKLjwvYXV0aG9yPjxhdXRob3I+U3RhdWZlbmJpZWwsIE0uPC9hdXRob3I+

PGF1dGhvcj5PcmdvZ296bywgSi4gTS48L2F1dGhvcj48YXV0aG9yPkdyYWYsIEEuPC9hdXRob3I+

PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+S2Fyb2xpbnNrYSBJbnN0aXR1

dGV0IEFsemhlaW1lciBEaXNlYXNlIFJlc2VhcmNoIENlbnRyZSBhbmQgQ2xpbmljYWwgVHJpYWwg

VW5pdCwgR2VyaWF0cmljIENsaW5pYywgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBI

dWRkaW5nZSwgU3dlZGVuLiBiZW5ndC53aW5ibGFkQGtpLnNlPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+U2FmZXR5LCB0b2xlcmFiaWxpdHksIGFuZCBhbnRpYm9keSByZXNwb25zZSBvZiBh

Y3RpdmUgQWJldGEgaW1tdW5vdGhlcmFweSB3aXRoIENBRDEwNiBpbiBwYXRpZW50cyB3aXRoIEFs

emhlaW1lciZhcG9zO3MgZGlzZWFzZTogcmFuZG9taXNlZCwgZG91YmxlLWJsaW5kLCBwbGFjZWJv

LWNvbnRyb2xsZWQsIGZpcnN0LWluLWh1bWFuIHN0dWR5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PkxhbmNldCBOZXVyb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NTk3LTYwNDwv

cGFnZXM+PHZvbHVtZT4xMTwvdm9sdW1lPjxudW1iZXI+NzwvbnVtYmVyPjxlZGl0aW9uPjIwMTIv

MDYvMDk8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+

QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvYmxv

b2QvKmRydWcgdGhlcmFweS8qaW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJl

dGEtUGVwdGlkZXMvKmltbXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJvZHkgRm9ybWF0

aW9uL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5CaW9tYXJrZXJzL2Jsb29kPC9rZXl3

b3JkPjxrZXl3b3JkPkRvdWJsZS1CbGluZCBNZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxl

PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxp

biBHL2Jsb29kPC9rZXl3b3JkPjxrZXl3b3JkPipJbW11bm90aGVyYXB5PC9rZXl3b3JkPjxrZXl3

b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+

VHJlYXRtZW50IE91dGNvbWU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMjwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju

PjE0NzQtNDQ2NSAoRWxlY3Ryb25pYykmI3hEOzE0NzQtNDQyMiAoTGlua2luZyk8L2lzYm4+PGFj

Y2Vzc2lvbi1udW0+MjI2NzcyNTg8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48

dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIyNjc3MjU4PC91cmw+PHVy

bD5odHRwczovL2FjLmVscy1jZG4uY29tL1MxNDc0NDQyMjEyNzAxNDAwLzEtczIuMC1TMTQ3NDQ0

MjIxMjcwMTQwMC1tYWluLnBkZj9fdGlkPWY4ZjEwN2YzLTg0MjAtNDczYi04Zjg1LWM4NjZmMmRj

YjZiNSZhbXA7YWNkbmF0PTE1MzQ5MjkxOTFfNTQyN2RmYzA1OGZlMzBhYWJhZmJhMDRlN2RjYjhh

YjE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEw

LjEwMTYvUzE0NzQtNDQyMigxMik3MDE0MC0wPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3Jl

Y29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 77,80-82Fewer treatments needed to achieve therapeutic effect ADDIN EN.CITE <EndNote><Cite><Author>Winblad</Author><Year>2014</Year><RecNum>4246</RecNum><DisplayText><style face="superscript">83</style></DisplayText><record><rec-number>4246</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1536913467">4246</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Winblad, B.</author><author>Graf, A.</author><author>Riviere, M. E.</author><author>Andreasen, N.</author><author>Ryan, J. M.</author></authors></contributors><auth-address>Karolinska Institutet Alzheimer Disease Research Center, Department NVS, Karolinska Institutet, Novum, floor 5, Stockholm SE-141 86, Sweden.&#xD;Novartis Pharma AG, Basel CH-4002, Switzerland.&#xD;Clinical Trial Unit, Geriatric Clinic, Karolinska University Hospital, Stockholm, Huddinge SE-141 86, Sweden.&#xD;Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, USA.</auth-address><titles><title>Active immunotherapy options for Alzheimer&apos;s disease</title><secondary-title>Alzheimers Res Ther</secondary-title></titles><periodical><full-title>Alzheimers Res Ther</full-title></periodical><pages>7</pages><volume>6</volume><number>1</number><edition>2014/01/31</edition><dates><year>2014</year></dates><isbn>1758-9193 (Print)</isbn><accession-num>24476230</accession-num><urls><related-urls><url> to reverse immune response if secondary effects are found ADDIN EN.CITE <EndNote><Cite><Author>Lemere</Author><Year>2013</Year><RecNum>4247</RecNum><DisplayText><style face="superscript">69</style></DisplayText><record><rec-number>4247</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1536913840">4247</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lemere, C. A.</author></authors></contributors><auth-address>Center for Neurologic Diseases, Brigham and Women&apos;s Hospital, Harvard Medical School, NRB 636F, 77 Avenue Louis Pasteur, Boston 02115, MA, USA. clemere@.</auth-address><titles><title>Immunotherapy for Alzheimer&apos;s disease: hoops and hurdles</title><secondary-title>Mol Neurodegener</secondary-title></titles><periodical><full-title>Mol Neurodegener</full-title></periodical><pages>36</pages><volume>8</volume><edition>2013/10/24</edition><keywords><keyword>Alzheimer Disease/*therapy</keyword><keyword>Alzheimer Vaccines/*pharmacology</keyword><keyword>Animals</keyword><keyword>Humans</keyword><keyword>Immunotherapy/*methods</keyword></keywords><dates><year>2013</year><pub-dates><date>Oct 22</date></pub-dates></dates><isbn>1750-1326 (Electronic)&#xD;1750-1326 (Linking)</isbn><accession-num>24148220</accession-num><urls><related-urls><url> Reduced risk for allergic reactions to foreign molecules ADDIN EN.CITE <EndNote><Cite><Author>Winblad</Author><Year>2014</Year><RecNum>4246</RecNum><DisplayText><style face="superscript">83</style></DisplayText><record><rec-number>4246</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1536913467">4246</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Winblad, B.</author><author>Graf, A.</author><author>Riviere, M. E.</author><author>Andreasen, N.</author><author>Ryan, J. M.</author></authors></contributors><auth-address>Karolinska Institutet Alzheimer Disease Research Center, Department NVS, Karolinska Institutet, Novum, floor 5, Stockholm SE-141 86, Sweden.&#xD;Novartis Pharma AG, Basel CH-4002, Switzerland.&#xD;Clinical Trial Unit, Geriatric Clinic, Karolinska University Hospital, Stockholm, Huddinge SE-141 86, Sweden.&#xD;Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, USA.</auth-address><titles><title>Active immunotherapy options for Alzheimer&apos;s disease</title><secondary-title>Alzheimers Res Ther</secondary-title></titles><periodical><full-title>Alzheimers Res Ther</full-title></periodical><pages>7</pages><volume>6</volume><number>1</number><edition>2014/01/31</edition><dates><year>2014</year></dates><isbn>1758-9193 (Print)</isbn><accession-num>24476230</accession-num><urls><related-urls><url> Elderly patients may have hypo-responsiveness to immunization ADDIN EN.CITE <EndNote><Cite><Author>Menendez-Gonzalez</Author><Year>2011</Year><RecNum>2268</RecNum><DisplayText><style face="superscript">84</style></DisplayText><record><rec-number>2268</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1534927804">2268</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Menendez-Gonzalez, M.</author><author>Perez-Pinera, P.</author><author>Martinez-Rivera, M.</author><author>Muniz, A. L.</author><author>Vega, J. A.</author></authors></contributors><auth-address>Departamento de Morfologia y Biologia Celular, Universidad de Oviedo, Oviedo, Spain. manuelmenendez@</auth-address><titles><title>Immunotherapy for Alzheimer&apos;s disease: rational basis in ongoing clinical trials</title><secondary-title>Curr Pharm Des</secondary-title></titles><periodical><full-title>Curr Pharm Des</full-title></periodical><pages>508-20</pages><volume>17</volume><number>5</number><edition>2011/03/08</edition><keywords><keyword>Alzheimer Disease/*drug therapy/immunology/metabolism</keyword><keyword>Alzheimer Vaccines/*adverse effects/*therapeutic use</keyword><keyword>Amyloid beta-Peptides/*immunology/metabolism</keyword><keyword>Animals</keyword><keyword>Clinical Trials as Topic/adverse effects/*methods</keyword><keyword>Disease Models, Animal</keyword><keyword>Humans</keyword><keyword>Immunization, Passive/*methods</keyword><keyword>Immunotherapy, Active/*methods</keyword><keyword>Models, Immunological</keyword></keywords><dates><year>2011</year></dates><isbn>1873-4286 (Electronic)&#xD;1381-6128 (Linking)</isbn><accession-num>21375481</accession-num><urls><related-urls><url> better candidate for early prophylactic approachTable 1. Advantages and disadvantages of passive and active immunotherapies for AD. Many clinical trials aiming at controlling the amyloid cascade propose diverse strategies and targets, but so far, there is no consensus about a universal target or approach for any form of AD. Studies performed in Sweden, working with Novartis as the sponsor yielded an active immunotherapy against Aβ using the CAD106, a small six-residue Aβ fragment recognized by B-cells, administered together with an adjuvant of viral origin PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

UmVjTnVtPjIxODM8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij44Miw4NTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjIxODM8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDkyNzU4NSI+MjE4Mzwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48

YXV0aG9yPkFuZHJlYXNlbiwgTi48L2F1dGhvcj48YXV0aG9yPk1pbnRob24sIEwuPC9hdXRob3I+

PGF1dGhvcj5GbG9lc3NlciwgQS48L2F1dGhvcj48YXV0aG9yPkltYmVydCwgRy48L2F1dGhvcj48

YXV0aG9yPkR1bW9ydGllciwgVC48L2F1dGhvcj48YXV0aG9yPk1hZ3VpcmUsIFIuIFAuPC9hdXRo

b3I+PGF1dGhvcj5CbGVubm93LCBLLjwvYXV0aG9yPjxhdXRob3I+THVuZG1hcmssIEouPC9hdXRo

b3I+PGF1dGhvcj5TdGF1ZmVuYmllbCwgTS48L2F1dGhvcj48YXV0aG9yPk9yZ29nb3pvLCBKLiBN

LjwvYXV0aG9yPjxhdXRob3I+R3JhZiwgQS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5LYXJvbGluc2thIEluc3RpdHV0ZXQgQWx6aGVpbWVyIERpc2Vhc2Ug

UmVzZWFyY2ggQ2VudHJlIGFuZCBDbGluaWNhbCBUcmlhbCBVbml0LCBHZXJpYXRyaWMgQ2xpbmlj

LCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCBTd2VkZW4uIGJlbmd0

LndpbmJsYWRAa2kuc2U8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5TYWZldHksIHRvbGVy

YWJpbGl0eSwgYW5kIGFudGlib2R5IHJlc3BvbnNlIG9mIGFjdGl2ZSBBYmV0YSBpbW11bm90aGVy

YXB5IHdpdGggQ0FEMTA2IGluIHBhdGllbnRzIHdpdGggQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNl

OiByYW5kb21pc2VkLCBkb3VibGUtYmxpbmQsIHBsYWNlYm8tY29udHJvbGxlZCwgZmlyc3QtaW4t

aHVtYW4gc3R1ZHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TGFuY2V0IE5ldXJvbDwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz41OTctNjA0PC9wYWdlcz48dm9sdW1lPjExPC92b2x1

bWU+PG51bWJlcj43PC9udW1iZXI+PGVkaXRpb24+MjAxMi8wNi8wOTwvZWRpdGlvbj48a2V5d29y

ZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5

d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9ibG9vZC8qZHJ1ZyB0aGVyYXB5LyppbW11

bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy8qaW1tdW5vbG9n

eTwva2V5d29yZD48a2V5d29yZD5BbnRpYm9keSBGb3JtYXRpb24vZHJ1ZyBlZmZlY3RzPC9rZXl3

b3JkPjxrZXl3b3JkPkJpb21hcmtlcnMvYmxvb2Q8L2tleXdvcmQ+PGtleXdvcmQ+RG91YmxlLUJs

aW5kIE1ldGhvZDwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVt

YW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIEcvYmxvb2Q8L2tleXdvcmQ+PGtl

eXdvcmQ+KkltbXVub3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5

d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5UcmVhdG1lbnQgT3V0Y29tZTwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

SnVsPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ3NC00NDY1IChFbGVjdHJvbmlj

KSYjeEQ7MTQ3NC00NDIyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMjY3NzI1ODwv

YWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5u

bG0ubmloLmdvdi9wdWJtZWQvMjI2NzcyNTg8L3VybD48dXJsPmh0dHBzOi8vYWMuZWxzLWNkbi5j

b20vUzE0NzQ0NDIyMTI3MDE0MDAvMS1zMi4wLVMxNDc0NDQyMjEyNzAxNDAwLW1haW4ucGRmP190

aWQ9ZjhmMTA3ZjMtODQyMC00NzNiLThmODUtYzg2NmYyZGNiNmI1JmFtcDthY2RuYXQ9MTUzNDky

OTE5MV81NDI3ZGZjMDU4ZmUzMGFhYmFmYmEwNGU3ZGNiOGFiMTwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMTQ3NC00NDIyKDEyKTcw

MTQwLTA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPldpZXNzbmVyPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVjTnVtPjIxODQ8L1JlY051

bT48cmVjb3JkPjxyZWMtbnVtYmVyPjIxODQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5

IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRp

bWVzdGFtcD0iMTUzNDkyNzU4NSI+MjE4NDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBu

YW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3Jz

PjxhdXRob3I+V2llc3NuZXIsIEMuPC9hdXRob3I+PGF1dGhvcj5XaWVkZXJob2xkLCBLLiBILjwv

YXV0aG9yPjxhdXRob3I+VGlzc290LCBBLiBDLjwvYXV0aG9yPjxhdXRob3I+RnJleSwgUC48L2F1

dGhvcj48YXV0aG9yPkRhbm5lciwgUy48L2F1dGhvcj48YXV0aG9yPkphY29ic29uLCBMLiBILjwv

YXV0aG9yPjxhdXRob3I+SmVubmluZ3MsIEcuIFQuPC9hdXRob3I+PGF1dGhvcj5MdW9uZCwgUi48

L2F1dGhvcj48YXV0aG9yPk9ydG1hbm4sIFIuPC9hdXRob3I+PGF1dGhvcj5SZWljaHdhbGQsIEou

PC9hdXRob3I+PGF1dGhvcj5adXJpbmksIE0uPC9hdXRob3I+PGF1dGhvcj5NaXIsIEEuPC9hdXRo

b3I+PGF1dGhvcj5CYWNobWFubiwgTS4gRi48L2F1dGhvcj48YXV0aG9yPlN0YXVmZW5iaWVsLCBN

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPk5vdmFydGlz

IEluc3RpdHV0ZXMgZm9yIEJpb21lZGljYWwgUmVzZWFyY2gsIENILTQwNTYgQmFzZWwsIFN3aXR6

ZXJsYW5kLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSBzZWNvbmQtZ2VuZXJhdGlv

biBhY3RpdmUgQWJldGEgaW1tdW5vdGhlcmFweSBDQUQxMDYgcmVkdWNlcyBhbXlsb2lkIGFjY3Vt

dWxhdGlvbiBpbiBBUFAgdHJhbnNnZW5pYyBtaWNlIHdoaWxlIG1pbmltaXppbmcgcG90ZW50aWFs

IHNpZGUgZWZmZWN0czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIE5ldXJvc2NpPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBOZXVyb3NjaTwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjkzMjMtMzE8L3BhZ2VzPjx2b2x1bWU+MzE8L3Zv

bHVtZT48bnVtYmVyPjI1PC9udW1iZXI+PGVkaXRpb24+MjAxMS8wNi8yNDwvZWRpdGlvbj48a2V5

d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcgdGhlcmFweS9pbW11bm9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9hZHZlcnNlIGVmZmVjdHMv

KnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUHJvdGVpbiBQ

cmVjdXJzb3IvKmdlbmV0aWNzLyppbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8

L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVkPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVu

b3RoZXJhcHkvKm1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29y

ZD5NaWNlLCBUcmFuc2dlbmljPC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBPdXRjb21lPC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5KdW4gMjI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTI5LTI0MDEgKEVsZWN0

cm9uaWMpJiN4RDswMjcwLTY0NzQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIxNjk3

MzgyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMTY5NzM4MjwvdXJsPjx1cmw+aHR0cDovL3d3dy5qbmV1

cm9zY2kub3JnL2NvbnRlbnQvam5ldXJvLzMxLzI1LzkzMjMuZnVsbC5wZGY8L3VybD48L3JlbGF0

ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjE1MjMvSk5FVVJPU0NJ

LjAyOTMtMTEuMjAxMTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwv

RW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

UmVjTnVtPjIxODM8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij44Miw4NTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjIxODM8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDkyNzU4NSI+MjE4Mzwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48

YXV0aG9yPkFuZHJlYXNlbiwgTi48L2F1dGhvcj48YXV0aG9yPk1pbnRob24sIEwuPC9hdXRob3I+

PGF1dGhvcj5GbG9lc3NlciwgQS48L2F1dGhvcj48YXV0aG9yPkltYmVydCwgRy48L2F1dGhvcj48

YXV0aG9yPkR1bW9ydGllciwgVC48L2F1dGhvcj48YXV0aG9yPk1hZ3VpcmUsIFIuIFAuPC9hdXRo

b3I+PGF1dGhvcj5CbGVubm93LCBLLjwvYXV0aG9yPjxhdXRob3I+THVuZG1hcmssIEouPC9hdXRo

b3I+PGF1dGhvcj5TdGF1ZmVuYmllbCwgTS48L2F1dGhvcj48YXV0aG9yPk9yZ29nb3pvLCBKLiBN

LjwvYXV0aG9yPjxhdXRob3I+R3JhZiwgQS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5LYXJvbGluc2thIEluc3RpdHV0ZXQgQWx6aGVpbWVyIERpc2Vhc2Ug

UmVzZWFyY2ggQ2VudHJlIGFuZCBDbGluaWNhbCBUcmlhbCBVbml0LCBHZXJpYXRyaWMgQ2xpbmlj

LCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCBTd2VkZW4uIGJlbmd0

LndpbmJsYWRAa2kuc2U8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5TYWZldHksIHRvbGVy

YWJpbGl0eSwgYW5kIGFudGlib2R5IHJlc3BvbnNlIG9mIGFjdGl2ZSBBYmV0YSBpbW11bm90aGVy

YXB5IHdpdGggQ0FEMTA2IGluIHBhdGllbnRzIHdpdGggQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNl

OiByYW5kb21pc2VkLCBkb3VibGUtYmxpbmQsIHBsYWNlYm8tY29udHJvbGxlZCwgZmlyc3QtaW4t

aHVtYW4gc3R1ZHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TGFuY2V0IE5ldXJvbDwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz41OTctNjA0PC9wYWdlcz48dm9sdW1lPjExPC92b2x1

bWU+PG51bWJlcj43PC9udW1iZXI+PGVkaXRpb24+MjAxMi8wNi8wOTwvZWRpdGlvbj48a2V5d29y

ZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5

d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9ibG9vZC8qZHJ1ZyB0aGVyYXB5LyppbW11

bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy8qaW1tdW5vbG9n

eTwva2V5d29yZD48a2V5d29yZD5BbnRpYm9keSBGb3JtYXRpb24vZHJ1ZyBlZmZlY3RzPC9rZXl3

b3JkPjxrZXl3b3JkPkJpb21hcmtlcnMvYmxvb2Q8L2tleXdvcmQ+PGtleXdvcmQ+RG91YmxlLUJs

aW5kIE1ldGhvZDwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVt

YW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIEcvYmxvb2Q8L2tleXdvcmQ+PGtl

eXdvcmQ+KkltbXVub3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5

d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5UcmVhdG1lbnQgT3V0Y29tZTwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

SnVsPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ3NC00NDY1IChFbGVjdHJvbmlj

KSYjeEQ7MTQ3NC00NDIyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMjY3NzI1ODwv

YWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5u

bG0ubmloLmdvdi9wdWJtZWQvMjI2NzcyNTg8L3VybD48dXJsPmh0dHBzOi8vYWMuZWxzLWNkbi5j

b20vUzE0NzQ0NDIyMTI3MDE0MDAvMS1zMi4wLVMxNDc0NDQyMjEyNzAxNDAwLW1haW4ucGRmP190

aWQ9ZjhmMTA3ZjMtODQyMC00NzNiLThmODUtYzg2NmYyZGNiNmI1JmFtcDthY2RuYXQ9MTUzNDky

OTE5MV81NDI3ZGZjMDU4ZmUzMGFhYmFmYmEwNGU3ZGNiOGFiMTwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMTQ3NC00NDIyKDEyKTcw

MTQwLTA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPldpZXNzbmVyPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVjTnVtPjIxODQ8L1JlY051

bT48cmVjb3JkPjxyZWMtbnVtYmVyPjIxODQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5

IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRp

bWVzdGFtcD0iMTUzNDkyNzU4NSI+MjE4NDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBu

YW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3Jz

PjxhdXRob3I+V2llc3NuZXIsIEMuPC9hdXRob3I+PGF1dGhvcj5XaWVkZXJob2xkLCBLLiBILjwv

YXV0aG9yPjxhdXRob3I+VGlzc290LCBBLiBDLjwvYXV0aG9yPjxhdXRob3I+RnJleSwgUC48L2F1

dGhvcj48YXV0aG9yPkRhbm5lciwgUy48L2F1dGhvcj48YXV0aG9yPkphY29ic29uLCBMLiBILjwv

YXV0aG9yPjxhdXRob3I+SmVubmluZ3MsIEcuIFQuPC9hdXRob3I+PGF1dGhvcj5MdW9uZCwgUi48

L2F1dGhvcj48YXV0aG9yPk9ydG1hbm4sIFIuPC9hdXRob3I+PGF1dGhvcj5SZWljaHdhbGQsIEou

PC9hdXRob3I+PGF1dGhvcj5adXJpbmksIE0uPC9hdXRob3I+PGF1dGhvcj5NaXIsIEEuPC9hdXRo

b3I+PGF1dGhvcj5CYWNobWFubiwgTS4gRi48L2F1dGhvcj48YXV0aG9yPlN0YXVmZW5iaWVsLCBN

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPk5vdmFydGlz

IEluc3RpdHV0ZXMgZm9yIEJpb21lZGljYWwgUmVzZWFyY2gsIENILTQwNTYgQmFzZWwsIFN3aXR6

ZXJsYW5kLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSBzZWNvbmQtZ2VuZXJhdGlv

biBhY3RpdmUgQWJldGEgaW1tdW5vdGhlcmFweSBDQUQxMDYgcmVkdWNlcyBhbXlsb2lkIGFjY3Vt

dWxhdGlvbiBpbiBBUFAgdHJhbnNnZW5pYyBtaWNlIHdoaWxlIG1pbmltaXppbmcgcG90ZW50aWFs

IHNpZGUgZWZmZWN0czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIE5ldXJvc2NpPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBOZXVyb3NjaTwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjkzMjMtMzE8L3BhZ2VzPjx2b2x1bWU+MzE8L3Zv

bHVtZT48bnVtYmVyPjI1PC9udW1iZXI+PGVkaXRpb24+MjAxMS8wNi8yNDwvZWRpdGlvbj48a2V5

d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcgdGhlcmFweS9pbW11bm9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9hZHZlcnNlIGVmZmVjdHMv

KnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUHJvdGVpbiBQ

cmVjdXJzb3IvKmdlbmV0aWNzLyppbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8

L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVkPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVu

b3RoZXJhcHkvKm1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29y

ZD5NaWNlLCBUcmFuc2dlbmljPC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBPdXRjb21lPC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5KdW4gMjI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTI5LTI0MDEgKEVsZWN0

cm9uaWMpJiN4RDswMjcwLTY0NzQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIxNjk3

MzgyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMTY5NzM4MjwvdXJsPjx1cmw+aHR0cDovL3d3dy5qbmV1

cm9zY2kub3JnL2NvbnRlbnQvam5ldXJvLzMxLzI1LzkzMjMuZnVsbC5wZGY8L3VybD48L3JlbGF0

ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjE1MjMvSk5FVVJPU0NJ

LjAyOTMtMTEuMjAxMTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwv

RW5kTm90ZT5=

ADDIN EN.CITE.DATA 82,85. In order to have a clinical effect, a specific concentration of the IGG A-Beta titer is required. After three or four injections, produced a significant antibody titer; however, it was not sustained long enough to induce a therapeutic antibody response. A recent phase II study with CAD106 showed target engagement and tolerability, however, no improvement in MMSE scores was obtained, possibly because of the small size of the control cohort (14 patients) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYW5kZW5iZXJnaGU8L0F1dGhvcj48WWVhcj4yMDE3PC9Z

ZWFyPjxSZWNOdW0+MjE4MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJz

Y3JpcHQiPjc3PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjE4MDwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0OTI3NTg1Ij4yMTgwPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5WYW5kZW5iZXJnaGUsIFIuPC9h

dXRob3I+PGF1dGhvcj5SaXZpZXJlLCBNLiBFLjwvYXV0aG9yPjxhdXRob3I+Q2FwdXRvLCBBLjwv

YXV0aG9yPjxhdXRob3I+U292YWdvLCBKLjwvYXV0aG9yPjxhdXRob3I+TWFndWlyZSwgUi4gUC48

L2F1dGhvcj48YXV0aG9yPkZhcmxvdywgTS48L2F1dGhvcj48YXV0aG9yPk1hcm90dGEsIEcuPC9h

dXRob3I+PGF1dGhvcj5TYW5jaGV6LVZhbGxlLCBSLjwvYXV0aG9yPjxhdXRob3I+U2NoZWx0ZW5z

LCBQLjwvYXV0aG9yPjxhdXRob3I+UnlhbiwgSi4gTS48L2F1dGhvcj48YXV0aG9yPkdyYWYsIEEu

PC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVu

dCBvZiBOZXVyb3NjaWVuY2VzLCBLVSBMZXV2ZW4sIExldXZlbiwgQmVsZ2l1bS4mI3hEO05ldXJv

bG9neSBEZXBhcnRtZW50LCBVbml2ZXJzaXR5IEhvc3BpdGFscyBMZXV2ZW4sIEJlbGdpdW0uJiN4

RDtOZXVyb3NjaWVuY2UsIE5vdmFydGlzIFBoYXJtYSBBRywgQmFzZWwsIFN3aXR6ZXJsYW5kLiYj

eEQ7TmV1cm9zY2llbmNlIFRyYW5zbGF0aW9uYWwgTWVkaWNpbmUsIE5vdmFydGlzIEluc3RpdHV0

ZXMgZm9yIEJpb21lZGljYWwgUmVzZWFyY2gsIEJhc2VsLCBTd2l0emVybGFuZC4mI3hEO0Jpb21h

cmtlciBEZXZlbG9wbWVudCwgQ2xpbmljYWwgSW1hZ2luZywgTm92YXJ0aXMgSW5zdGl0dXRlcyBm

b3IgQmlvbWVkaWNhbCBSZXNlYXJjaCwgQmFzZWwsIFN3aXR6ZXJsYW5kLiYjeEQ7RGVwYXJ0bWVu

dCBvZiBOZXVyb2xvZ3ksIEluZGlhbmEgVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUsIElO

LCBVU0EuJiN4RDtEaXZpc2lvbiBvZiBHZXJpYXRyaWMgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2Yg

VG9yb250bywgVG9yb250bywgQ2FuYWRhLiYjeEQ7QWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlIGFu

ZCBPdGhlciBDb2duaXRpdmUgRGlzb3JkZXJzIFVuaXQsIEhvc3BpdGFsIENsaW5pYywgQmFyY2Vs

b25hLCBTcGFpbi4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9sb2d5IGFuZCBBbHpoZWltZXIgQ2Vu

dGVyLCBWVSBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBBbXN0ZXJkYW0sIFRoZSBOZXRoZXJs

YW5kcy4mI3hEO05vdmFydGlzIFBoYXJtYWNldXRpY2FscyBDb3Jwb3JhdGlvbiwgRWFzdCBIYW5v

dmVyLCBOSiwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkFjdGl2ZSBBYmV0YSBp

bW11bm90aGVyYXB5IENBRDEwNiBpbiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgcGhhc2Ug

MmIgc3R1ZHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWx6aGVpbWVycyBEZW1lbnQgKE4gWSk8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbHpoZWlt

ZXJzIERlbWVudCAoTiBZKTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjEwLTIyPC9w

YWdlcz48dm9sdW1lPjM8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4yMDE3LzEw

LzI3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BY3RpdmUgaW1tdW5vdGhlcmFweTwva2V5

d29yZD48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZC1iZXRhIHBlcHRpZGVzPC9rZXl3b3JkPjxrZXl3b3JkPkJpb2xvZ2ljYWwgYmlvbWFy

a2Vyczwva2V5d29yZD48a2V5d29yZD5DYWQxMDY8L2tleXdvcmQ+PGtleXdvcmQ+U2FmZXR5PC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5KYW48L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4yMzUyLTg3MzcgKFByaW50KSYj

eEQ7MjM1Mi04NzM3IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yOTA2NzMxNjwvYWNj

ZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMjkwNjczMTY8L3VybD48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5p

aC5nb3YvcG1jL2FydGljbGVzL1BNQzU2NTEzNzMvcGRmL21haW4ucGRmPC91cmw+PC9yZWxhdGVk

LXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzU2NTEzNzM8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjEwLjEwMTYvai50cmNpLjIwMTYuMTIuMDAzPC9lbGVjdHJvbmljLXJlc291cmNl

LW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYW5kZW5iZXJnaGU8L0F1dGhvcj48WWVhcj4yMDE3PC9Z

ZWFyPjxSZWNOdW0+MjE4MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJz

Y3JpcHQiPjc3PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjE4MDwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0OTI3NTg1Ij4yMTgwPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5WYW5kZW5iZXJnaGUsIFIuPC9h

dXRob3I+PGF1dGhvcj5SaXZpZXJlLCBNLiBFLjwvYXV0aG9yPjxhdXRob3I+Q2FwdXRvLCBBLjwv

YXV0aG9yPjxhdXRob3I+U292YWdvLCBKLjwvYXV0aG9yPjxhdXRob3I+TWFndWlyZSwgUi4gUC48

L2F1dGhvcj48YXV0aG9yPkZhcmxvdywgTS48L2F1dGhvcj48YXV0aG9yPk1hcm90dGEsIEcuPC9h

dXRob3I+PGF1dGhvcj5TYW5jaGV6LVZhbGxlLCBSLjwvYXV0aG9yPjxhdXRob3I+U2NoZWx0ZW5z

LCBQLjwvYXV0aG9yPjxhdXRob3I+UnlhbiwgSi4gTS48L2F1dGhvcj48YXV0aG9yPkdyYWYsIEEu

PC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVu

dCBvZiBOZXVyb3NjaWVuY2VzLCBLVSBMZXV2ZW4sIExldXZlbiwgQmVsZ2l1bS4mI3hEO05ldXJv

bG9neSBEZXBhcnRtZW50LCBVbml2ZXJzaXR5IEhvc3BpdGFscyBMZXV2ZW4sIEJlbGdpdW0uJiN4

RDtOZXVyb3NjaWVuY2UsIE5vdmFydGlzIFBoYXJtYSBBRywgQmFzZWwsIFN3aXR6ZXJsYW5kLiYj

eEQ7TmV1cm9zY2llbmNlIFRyYW5zbGF0aW9uYWwgTWVkaWNpbmUsIE5vdmFydGlzIEluc3RpdHV0

ZXMgZm9yIEJpb21lZGljYWwgUmVzZWFyY2gsIEJhc2VsLCBTd2l0emVybGFuZC4mI3hEO0Jpb21h

cmtlciBEZXZlbG9wbWVudCwgQ2xpbmljYWwgSW1hZ2luZywgTm92YXJ0aXMgSW5zdGl0dXRlcyBm

b3IgQmlvbWVkaWNhbCBSZXNlYXJjaCwgQmFzZWwsIFN3aXR6ZXJsYW5kLiYjeEQ7RGVwYXJ0bWVu

dCBvZiBOZXVyb2xvZ3ksIEluZGlhbmEgVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUsIElO

LCBVU0EuJiN4RDtEaXZpc2lvbiBvZiBHZXJpYXRyaWMgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2Yg

VG9yb250bywgVG9yb250bywgQ2FuYWRhLiYjeEQ7QWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlIGFu

ZCBPdGhlciBDb2duaXRpdmUgRGlzb3JkZXJzIFVuaXQsIEhvc3BpdGFsIENsaW5pYywgQmFyY2Vs

b25hLCBTcGFpbi4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9sb2d5IGFuZCBBbHpoZWltZXIgQ2Vu

dGVyLCBWVSBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBBbXN0ZXJkYW0sIFRoZSBOZXRoZXJs

YW5kcy4mI3hEO05vdmFydGlzIFBoYXJtYWNldXRpY2FscyBDb3Jwb3JhdGlvbiwgRWFzdCBIYW5v

dmVyLCBOSiwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkFjdGl2ZSBBYmV0YSBp

bW11bm90aGVyYXB5IENBRDEwNiBpbiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgcGhhc2Ug

MmIgc3R1ZHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWx6aGVpbWVycyBEZW1lbnQgKE4gWSk8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbHpoZWlt

ZXJzIERlbWVudCAoTiBZKTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjEwLTIyPC9w

YWdlcz48dm9sdW1lPjM8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4yMDE3LzEw

LzI3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BY3RpdmUgaW1tdW5vdGhlcmFweTwva2V5

d29yZD48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZC1iZXRhIHBlcHRpZGVzPC9rZXl3b3JkPjxrZXl3b3JkPkJpb2xvZ2ljYWwgYmlvbWFy

a2Vyczwva2V5d29yZD48a2V5d29yZD5DYWQxMDY8L2tleXdvcmQ+PGtleXdvcmQ+U2FmZXR5PC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5KYW48L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4yMzUyLTg3MzcgKFByaW50KSYj

eEQ7MjM1Mi04NzM3IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yOTA2NzMxNjwvYWNj

ZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMjkwNjczMTY8L3VybD48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5p

aC5nb3YvcG1jL2FydGljbGVzL1BNQzU2NTEzNzMvcGRmL21haW4ucGRmPC91cmw+PC9yZWxhdGVk

LXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzU2NTEzNzM8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjEwLjEwMTYvai50cmNpLjIwMTYuMTIuMDAzPC9lbGVjdHJvbmljLXJlc291cmNl

LW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 77. Swiss researchers created aducanumab, an interesting antibody under BIOGEN development. Aducanumab is an antibody derived from healthy elderly subjects with no decline in cognition and from cognitively impaired elderly subjects with an unusually slow decline rate. From these subjects, memory B cells were isolated from lymphocyte libraries and their produced antibody screened for their ability to bind to Aβ, in a process known as reverse translational medicine PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZXZpZ255PC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjIzODk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij44Njwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjIzODk8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDkyOTU2OCI+MjM4OTwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U2V2aWdueSwgSi48L2F1dGhvcj48YXV0

aG9yPkNoaWFvLCBQLjwvYXV0aG9yPjxhdXRob3I+QnVzc2llcmUsIFQuPC9hdXRob3I+PGF1dGhv

cj5XZWlucmViLCBQLiBILjwvYXV0aG9yPjxhdXRob3I+V2lsbGlhbXMsIEwuPC9hdXRob3I+PGF1

dGhvcj5NYWllciwgTS48L2F1dGhvcj48YXV0aG9yPkR1bnN0YW4sIFIuPC9hdXRob3I+PGF1dGhv

cj5TYWxsb3dheSwgUy48L2F1dGhvcj48YXV0aG9yPkNoZW4sIFQuPC9hdXRob3I+PGF1dGhvcj5M

aW5nLCBZLjwvYXV0aG9yPjxhdXRob3I+TyZhcG9zO0dvcm1hbiwgSi48L2F1dGhvcj48YXV0aG9y

PlFpYW4sIEYuPC9hdXRob3I+PGF1dGhvcj5BcmFzdHUsIE0uPC9hdXRob3I+PGF1dGhvcj5MaSwg

TS48L2F1dGhvcj48YXV0aG9yPkNob2xsYXRlLCBTLjwvYXV0aG9yPjxhdXRob3I+QnJlbm5hbiwg

TS4gUy48L2F1dGhvcj48YXV0aG9yPlF1aW50ZXJvLU1vbnpvbiwgTy48L2F1dGhvcj48YXV0aG9y

PlNjYW5uZXZpbiwgUi4gSC48L2F1dGhvcj48YXV0aG9yPkFybm9sZCwgSC4gTS48L2F1dGhvcj48

YXV0aG9yPkVuZ2JlciwgVC48L2F1dGhvcj48YXV0aG9yPlJob2RlcywgSy48L2F1dGhvcj48YXV0

aG9yPkZlcnJlcm8sIEouPC9hdXRob3I+PGF1dGhvcj5IYW5nLCBZLjwvYXV0aG9yPjxhdXRob3I+

TWlrdWxza2lzLCBBLjwvYXV0aG9yPjxhdXRob3I+R3JpbW0sIEouPC9hdXRob3I+PGF1dGhvcj5I

b2NrLCBDLjwvYXV0aG9yPjxhdXRob3I+Tml0c2NoLCBSLiBNLjwvYXV0aG9yPjxhdXRob3I+U2Fu

ZHJvY2ssIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+

QmlvZ2VuLCBDYW1icmlkZ2UsIE1hc3NhY2h1c2V0dHMgMDIxNDIsIFVTQS4mI3hEO05ldXJpbW11

bmUsIFNjaGxpZXJlbi1adXJpY2ggODk1MiwgU3dpdHplcmxhbmQuJiN4RDtCdXRsZXIgSG9zcGl0

YWwsIFByb3ZpZGVuY2UsIFJob2RlIElzbGFuZCAwMjkwNiwgVVNBLiYjeEQ7SW5zdGl0dXRlIGZv

ciBSZWdlbmVyYXRpdmUgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgWnVyaWNoLCBadXJpY2ggODk1

MiwgU3dpdHplcmxhbmQuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGhlIGFudGlib2R5

IGFkdWNhbnVtYWIgcmVkdWNlcyBBYmV0YSBwbGFxdWVzIGluIEFsemhlaW1lciZhcG9zO3MgZGlz

ZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OYXR1cmU8L3NlY29uZGFyeS10aXRsZT48L3Rp

dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OYXR1cmU8L2Z1bGwtdGl0bGU+PC9wZXJpb2Rp

Y2FsPjxwYWdlcz41MC02PC9wYWdlcz48dm9sdW1lPjUzNzwvdm9sdW1lPjxudW1iZXI+NzYxODwv

bnVtYmVyPjxlZGl0aW9uPjIwMTYvMDkvMDI8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFn

ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+

QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcgdGhlcmFweS9tZXRhYm9saXNtL3BhdGhvbG9neS8qcHN5

Y2hvbG9neTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkL2RydWcgZWZmZWN0cy9tZXRhYm9saXNt

PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy8qYW50YWdvbmlzdHMgJmFt

cDsgaW5oaWJpdG9ycy9jaGVtaXN0cnkvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW5p

bWFsczwva2V5d29yZD48a2V5d29yZD5BbnRpYm9kaWVzLCBNb25vY2xvbmFsLCBIdW1hbml6ZWQv

YWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlL2FkdmVyc2U8L2tleXdvcmQ+PGtleXdvcmQ+ZWZm

ZWN0cy9waGFybWFjb2tpbmV0aWNzLyp0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+

QnJhaW4vZHJ1ZyBlZmZlY3RzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q2xpbmljYWwg

VHJpYWxzLCBQaGFzZSBJSUkgYXMgVG9waWM8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2Rl

bHMsIEFuaW1hbDwva2V5d29yZD48a2V5d29yZD5Eb3NlLVJlc3BvbnNlIFJlbGF0aW9uc2hpcCwg

RHJ1Zzwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9r

ZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5

d29yZD5NaWNlLCBUcmFuc2dlbmljPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3

b3JkPjxrZXl3b3JkPk1vZGVscywgQmlvbG9naWNhbDwva2V5d29yZD48a2V5d29yZD5QbGFxdWUs

IEFteWxvaWQvKmRydWcgdGhlcmFweS8qbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+UHJvdGVpbiBBZ2dyZWdhdGlvbiwgUGF0aG9sb2dpY2FsL2RydWcgdGhlcmFweTwva2V5

d29yZD48a2V5d29yZD5Tb2x1YmlsaXR5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFy

PjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxpc2JuPjE0NzYtNDY4NyAoRWxlY3Ryb25pYykmI3hEOzAwMjgtMDgzNiAoTGlua2luZyk8

L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjc1ODIyMjA8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0

ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI3NTgyMjIw

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4x

MDM4L25hdHVyZTE5MzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+

PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZXZpZ255PC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjIzODk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij44Njwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjIzODk8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDkyOTU2OCI+MjM4OTwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U2V2aWdueSwgSi48L2F1dGhvcj48YXV0

aG9yPkNoaWFvLCBQLjwvYXV0aG9yPjxhdXRob3I+QnVzc2llcmUsIFQuPC9hdXRob3I+PGF1dGhv

cj5XZWlucmViLCBQLiBILjwvYXV0aG9yPjxhdXRob3I+V2lsbGlhbXMsIEwuPC9hdXRob3I+PGF1

dGhvcj5NYWllciwgTS48L2F1dGhvcj48YXV0aG9yPkR1bnN0YW4sIFIuPC9hdXRob3I+PGF1dGhv

cj5TYWxsb3dheSwgUy48L2F1dGhvcj48YXV0aG9yPkNoZW4sIFQuPC9hdXRob3I+PGF1dGhvcj5M

aW5nLCBZLjwvYXV0aG9yPjxhdXRob3I+TyZhcG9zO0dvcm1hbiwgSi48L2F1dGhvcj48YXV0aG9y

PlFpYW4sIEYuPC9hdXRob3I+PGF1dGhvcj5BcmFzdHUsIE0uPC9hdXRob3I+PGF1dGhvcj5MaSwg

TS48L2F1dGhvcj48YXV0aG9yPkNob2xsYXRlLCBTLjwvYXV0aG9yPjxhdXRob3I+QnJlbm5hbiwg

TS4gUy48L2F1dGhvcj48YXV0aG9yPlF1aW50ZXJvLU1vbnpvbiwgTy48L2F1dGhvcj48YXV0aG9y

PlNjYW5uZXZpbiwgUi4gSC48L2F1dGhvcj48YXV0aG9yPkFybm9sZCwgSC4gTS48L2F1dGhvcj48

YXV0aG9yPkVuZ2JlciwgVC48L2F1dGhvcj48YXV0aG9yPlJob2RlcywgSy48L2F1dGhvcj48YXV0

aG9yPkZlcnJlcm8sIEouPC9hdXRob3I+PGF1dGhvcj5IYW5nLCBZLjwvYXV0aG9yPjxhdXRob3I+

TWlrdWxza2lzLCBBLjwvYXV0aG9yPjxhdXRob3I+R3JpbW0sIEouPC9hdXRob3I+PGF1dGhvcj5I

b2NrLCBDLjwvYXV0aG9yPjxhdXRob3I+Tml0c2NoLCBSLiBNLjwvYXV0aG9yPjxhdXRob3I+U2Fu

ZHJvY2ssIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+

QmlvZ2VuLCBDYW1icmlkZ2UsIE1hc3NhY2h1c2V0dHMgMDIxNDIsIFVTQS4mI3hEO05ldXJpbW11

bmUsIFNjaGxpZXJlbi1adXJpY2ggODk1MiwgU3dpdHplcmxhbmQuJiN4RDtCdXRsZXIgSG9zcGl0

YWwsIFByb3ZpZGVuY2UsIFJob2RlIElzbGFuZCAwMjkwNiwgVVNBLiYjeEQ7SW5zdGl0dXRlIGZv

ciBSZWdlbmVyYXRpdmUgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgWnVyaWNoLCBadXJpY2ggODk1

MiwgU3dpdHplcmxhbmQuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGhlIGFudGlib2R5

IGFkdWNhbnVtYWIgcmVkdWNlcyBBYmV0YSBwbGFxdWVzIGluIEFsemhlaW1lciZhcG9zO3MgZGlz

ZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OYXR1cmU8L3NlY29uZGFyeS10aXRsZT48L3Rp

dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OYXR1cmU8L2Z1bGwtdGl0bGU+PC9wZXJpb2Rp

Y2FsPjxwYWdlcz41MC02PC9wYWdlcz48dm9sdW1lPjUzNzwvdm9sdW1lPjxudW1iZXI+NzYxODwv

bnVtYmVyPjxlZGl0aW9uPjIwMTYvMDkvMDI8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFn

ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+

QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcgdGhlcmFweS9tZXRhYm9saXNtL3BhdGhvbG9neS8qcHN5

Y2hvbG9neTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkL2RydWcgZWZmZWN0cy9tZXRhYm9saXNt

PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy8qYW50YWdvbmlzdHMgJmFt

cDsgaW5oaWJpdG9ycy9jaGVtaXN0cnkvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW5p

bWFsczwva2V5d29yZD48a2V5d29yZD5BbnRpYm9kaWVzLCBNb25vY2xvbmFsLCBIdW1hbml6ZWQv

YWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlL2FkdmVyc2U8L2tleXdvcmQ+PGtleXdvcmQ+ZWZm

ZWN0cy9waGFybWFjb2tpbmV0aWNzLyp0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+

QnJhaW4vZHJ1ZyBlZmZlY3RzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q2xpbmljYWwg

VHJpYWxzLCBQaGFzZSBJSUkgYXMgVG9waWM8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2Rl

bHMsIEFuaW1hbDwva2V5d29yZD48a2V5d29yZD5Eb3NlLVJlc3BvbnNlIFJlbGF0aW9uc2hpcCwg

RHJ1Zzwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9r

ZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5

d29yZD5NaWNlLCBUcmFuc2dlbmljPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3

b3JkPjxrZXl3b3JkPk1vZGVscywgQmlvbG9naWNhbDwva2V5d29yZD48a2V5d29yZD5QbGFxdWUs

IEFteWxvaWQvKmRydWcgdGhlcmFweS8qbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+UHJvdGVpbiBBZ2dyZWdhdGlvbiwgUGF0aG9sb2dpY2FsL2RydWcgdGhlcmFweTwva2V5

d29yZD48a2V5d29yZD5Tb2x1YmlsaXR5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFy

PjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxpc2JuPjE0NzYtNDY4NyAoRWxlY3Ryb25pYykmI3hEOzAwMjgtMDgzNiAoTGlua2luZyk8

L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjc1ODIyMjA8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0

ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI3NTgyMjIw

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4x

MDM4L25hdHVyZTE5MzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+

PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 86. In a very late phase I study with its highest doses, aducanumab could reduce Aβ levels by 90%, as shown by PET imaging ADDIN EN.CITE <EndNote><Cite><Author>Sevigny</Author><Year>2017</Year><RecNum>2388</RecNum><DisplayText><style face="superscript">87</style></DisplayText><record><rec-number>2388</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1534929568">2388</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sevigny, J.</author><author>Chiao, P.</author><author>Bussiere, T.</author><author>Weinreb, P. H.</author><author>Williams, L.</author><author>Maier, M.</author><author>Dunstan, R.</author><author>Salloway, S.</author><author>Chen, T.</author><author>Ling, Y.</author><author>O&apos;Gorman, J.</author><author>Qian, F.</author><author>Arastu, M.</author><author>Li, M.</author><author>Chollate, S.</author><author>Brennan, M. S.</author><author>Quintero-Monzon, O.</author><author>Scannevin, R. H.</author><author>Arnold, H. M.</author><author>Engber, T.</author><author>Rhodes, K.</author><author>Ferrero, J.</author><author>Hang, Y.</author><author>Mikulskis, A.</author><author>Grimm, J.</author><author>Hock, C.</author><author>Nitsch, R. M.</author><author>Sandrock, A.</author></authors></contributors><titles><title>Addendum: The antibody aducanumab reduces Abeta plaques in Alzheimer&apos;s disease</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title></periodical><pages>564</pages><volume>546</volume><number>7659</number><edition>2017/06/24</edition><dates><year>2017</year><pub-dates><date>Jun 21</date></pub-dates></dates><isbn>1476-4687 (Electronic)&#xD;0028-0836 (Linking)</isbn><accession-num>28640269</accession-num><urls><related-urls><url>. Currently, aducanuab is in phase III clinical trials for early AD with the ENGAGE (NTC02484547) and EMERGE (NCT02484547) studies. Discussion from previous clinical trials has pointed out that the main challenges to overcome for aducanumab are to inhibit amyloid aggregation avoiding cerebral angiopathy, and achieve improvement in cognition PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QaWF6emE8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxS

ZWNOdW0+MjM5MTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

Pjg4LDg5PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjM5MTwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0OTMwNzY2Ij4yMzkxPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5QaWF6emEsIEYuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+KE1vbnphLCBJdGFseSkuPC9hdXRo

LWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UmVhZGVyIHJlc3BvbnNlOiBBIHBoYXNlIDMgdHJpYWwg

b2YgSVYgaW1tdW5vZ2xvYnVsaW4gZm9yIEFsemhlaW1lciBkaXNlYXNlPC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPk5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPk5ldXJvbG9neTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjE0

NC0xNDU8L3BhZ2VzPjx2b2x1bWU+OTA8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48ZWRpdGlv

bj4yMDE4LzAxLzE4PC9lZGl0aW9uPjxkYXRlcz48eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0ZXM+

PGRhdGU+SmFuIDE2PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUyNi02MzJYIChF

bGVjdHJvbmljKSYjeEQ7MDAyOC0zODc4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4y

OTMzNTMwODwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93

d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjkzMzUzMDg8L3VybD48L3JlbGF0ZWQtdXJscz48

L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEyMTIvV05MLjAwMDAwMDAwMDAwMDQ4

MjQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9y

PlJlbGtpbjwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJlY051bT4yMzkzPC9SZWNOdW0+PHJl

Y29yZD48cmVjLW51bWJlcj4yMzkzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3Rh

bXA9IjE1MzQ5MzA3NjYiPjIzOTM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPlJlbGtpbiwgTi4gUi48L2F1dGhvcj48YXV0aG9yPlRob21hcywgUi4gRy48L2F1dGhvcj48

YXV0aG9yPlJpc3NtYW4sIFIuIEEuPC9hdXRob3I+PGF1dGhvcj5CcmV3ZXIsIEouIEIuPC9hdXRo

b3I+PGF1dGhvcj5SYWZpaSwgTS4gUy48L2F1dGhvcj48YXV0aG9yPnZhbiBEeWNrLCBDLiBILjwv

YXV0aG9yPjxhdXRob3I+SmFjaywgQy4gUi48L2F1dGhvcj48YXV0aG9yPlNhbm8sIE0uPC9hdXRo

b3I+PGF1dGhvcj5Lbm9wbWFuLCBELiBTLjwvYXV0aG9yPjxhdXRob3I+UmFtYW4sIFIuPC9hdXRo

b3I+PGF1dGhvcj5TemFibywgUC48L2F1dGhvcj48YXV0aG9yPkdlbG1vbnQsIEQuIE0uPC9hdXRo

b3I+PGF1dGhvcj5Gcml0c2NoLCBTLjwvYXV0aG9yPjxhdXRob3I+QWlzZW4sIFAuIFMuPC9hdXRo

b3I+PGF1dGhvcj5BbHpoZWltZXImYXBvcztzIERpc2Vhc2UgQ29vcGVyYXRpdmUsIFN0dWR5PC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RnJvbSBXZWlsbCBD

b3JuZWxsIE1lZGljaW5lIChOLlIuUi4sIFAuUy4pLCBOZXcgWW9yaywgTlk7IFVuaXZlcnNpdHkg

b2YgQ2FsaWZvcm5pYSAoUi5HLlQuLCBSLkEuUi4sIEouQi5CLiksIFNhbiBEaWVnbzsgVW5pdmVy

c2l0eSBvZiBTb3V0aGVybiBDYWxpZm9ybmlhIChNLlMuUi4sIFIuUi4sIFAuUy5BLiksIExvcyBB

bmdlbGVzOyBZYWxlIFVuaXZlcnNpdHkgKEMuSC52LkQuKSwgTmV3IEhhdmVuLCBDVDsgTWF5byBD

bGluaWMgKEMuUi5KLiwgRC5TLksuKSwgUm9jaGVzdGVyLCBNTjsgTW91bnQgU2luYWkgU2Nob29s

IG9mIE1lZGljaW5lIChNLlMuKSwgTmV3IFlvcmssIE5ZOyBhbmQgQmF4YWx0YSAoRC5NLkcuLCBT

LkYuKSwgQmFubm9ja2J1cm4sIElMLiYjeEQ7RnJvbSBXZWlsbCBDb3JuZWxsIE1lZGljaW5lIChO

LlIuUi4sIFAuUy4pLCBOZXcgWW9yaywgTlk7IFVuaXZlcnNpdHkgb2YgQ2FsaWZvcm5pYSAoUi5H

LlQuLCBSLkEuUi4sIEouQi5CLiksIFNhbiBEaWVnbzsgVW5pdmVyc2l0eSBvZiBTb3V0aGVybiBD

YWxpZm9ybmlhIChNLlMuUi4sIFIuUi4sIFAuUy5BLiksIExvcyBBbmdlbGVzOyBZYWxlIFVuaXZl

cnNpdHkgKEMuSC52LkQuKSwgTmV3IEhhdmVuLCBDVDsgTWF5byBDbGluaWMgKEMuUi5KLiwgRC5T

LksuKSwgUm9jaGVzdGVyLCBNTjsgTW91bnQgU2luYWkgU2Nob29sIG9mIE1lZGljaW5lIChNLlMu

KSwgTmV3IFlvcmssIE5ZOyBhbmQgQmF4YWx0YSAoRC5NLkcuLCBTLkYuKSwgQmFubm9ja2J1cm4s

IElMLiBwYWlzZW5AdXNjLmVkdS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BIHBoYXNl

IDMgdHJpYWwgb2YgSVYgaW1tdW5vZ2xvYnVsaW4gZm9yIEFsemhlaW1lciBkaXNlYXNlPC90aXRs

ZT48c2Vjb25kYXJ5LXRpdGxlPk5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxw

ZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvbG9neTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+

PHBhZ2VzPjE3NjgtMTc3NTwvcGFnZXM+PHZvbHVtZT44ODwvdm9sdW1lPjxudW1iZXI+MTg8L251

bWJlcj48ZWRpdGlvbj4yMDE3LzA0LzA3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2Vk

PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFs

emhlaW1lciBEaXNlYXNlL2RpYWdub3N0aWMgaW1hZ2luZy8qZHJ1ZyB0aGVyYXB5L2dlbmV0aWNz

PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9ibG9vZDwva2V5d29yZD48

a2V5d29yZD5BcG9saXBvcHJvdGVpbiBFNC9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5CaW9t

YXJrZXJzL2Jsb29kPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL2RpYWdub3N0aWMgaW1hZ2luZy9k

cnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2FuYWRhPC9rZXl3b3JkPjxrZXl3b3JkPkNv

Z25pdGlvbi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+RG91YmxlLUJsaW5kIE1ldGhv

ZDwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3

b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGlucywgSW50cmF2ZW5vdXMvYWR2ZXJzZSBlZmZlY3Rz

Lyp0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29y

ZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5Ob290cm9waWMgQWdlbnRzL2FkdmVyc2Ug

ZWZmZWN0cy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPlBlcHRpZGUgRnJhZ21l

bnRzL2Jsb29kPC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBGYWlsdXJlPC9rZXl3b3JkPjxr

ZXl3b3JkPlVuaXRlZCBTdGF0ZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAx

NzwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1heSAyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGlzYm4+MTUyNi02MzJYIChFbGVjdHJvbmljKSYjeEQ7MDAyOC0zODc4IChMaW5raW5nKTwvaXNi

bj48YWNjZXNzaW9uLW51bT4yODM4MTUwNjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11

cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjgzODE1MDY8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNTQwOTg0NjwvY3VzdG9tMj48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTIxMi9XTkwuMDAwMDAwMDAwMDAwMzkwNDwvZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QaWF6emE8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxS

ZWNOdW0+MjM5MTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

Pjg4LDg5PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjM5MTwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0OTMwNzY2Ij4yMzkxPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5QaWF6emEsIEYuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+KE1vbnphLCBJdGFseSkuPC9hdXRo

LWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UmVhZGVyIHJlc3BvbnNlOiBBIHBoYXNlIDMgdHJpYWwg

b2YgSVYgaW1tdW5vZ2xvYnVsaW4gZm9yIEFsemhlaW1lciBkaXNlYXNlPC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPk5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPk5ldXJvbG9neTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjE0

NC0xNDU8L3BhZ2VzPjx2b2x1bWU+OTA8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48ZWRpdGlv

bj4yMDE4LzAxLzE4PC9lZGl0aW9uPjxkYXRlcz48eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0ZXM+

PGRhdGU+SmFuIDE2PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUyNi02MzJYIChF

bGVjdHJvbmljKSYjeEQ7MDAyOC0zODc4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4y

OTMzNTMwODwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93

d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjkzMzUzMDg8L3VybD48L3JlbGF0ZWQtdXJscz48

L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEyMTIvV05MLjAwMDAwMDAwMDAwMDQ4

MjQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9y

PlJlbGtpbjwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJlY051bT4yMzkzPC9SZWNOdW0+PHJl

Y29yZD48cmVjLW51bWJlcj4yMzkzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3Rh

bXA9IjE1MzQ5MzA3NjYiPjIzOTM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPlJlbGtpbiwgTi4gUi48L2F1dGhvcj48YXV0aG9yPlRob21hcywgUi4gRy48L2F1dGhvcj48

YXV0aG9yPlJpc3NtYW4sIFIuIEEuPC9hdXRob3I+PGF1dGhvcj5CcmV3ZXIsIEouIEIuPC9hdXRo

b3I+PGF1dGhvcj5SYWZpaSwgTS4gUy48L2F1dGhvcj48YXV0aG9yPnZhbiBEeWNrLCBDLiBILjwv

YXV0aG9yPjxhdXRob3I+SmFjaywgQy4gUi48L2F1dGhvcj48YXV0aG9yPlNhbm8sIE0uPC9hdXRo

b3I+PGF1dGhvcj5Lbm9wbWFuLCBELiBTLjwvYXV0aG9yPjxhdXRob3I+UmFtYW4sIFIuPC9hdXRo

b3I+PGF1dGhvcj5TemFibywgUC48L2F1dGhvcj48YXV0aG9yPkdlbG1vbnQsIEQuIE0uPC9hdXRo

b3I+PGF1dGhvcj5Gcml0c2NoLCBTLjwvYXV0aG9yPjxhdXRob3I+QWlzZW4sIFAuIFMuPC9hdXRo

b3I+PGF1dGhvcj5BbHpoZWltZXImYXBvcztzIERpc2Vhc2UgQ29vcGVyYXRpdmUsIFN0dWR5PC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RnJvbSBXZWlsbCBD

b3JuZWxsIE1lZGljaW5lIChOLlIuUi4sIFAuUy4pLCBOZXcgWW9yaywgTlk7IFVuaXZlcnNpdHkg

b2YgQ2FsaWZvcm5pYSAoUi5HLlQuLCBSLkEuUi4sIEouQi5CLiksIFNhbiBEaWVnbzsgVW5pdmVy

c2l0eSBvZiBTb3V0aGVybiBDYWxpZm9ybmlhIChNLlMuUi4sIFIuUi4sIFAuUy5BLiksIExvcyBB

bmdlbGVzOyBZYWxlIFVuaXZlcnNpdHkgKEMuSC52LkQuKSwgTmV3IEhhdmVuLCBDVDsgTWF5byBD

bGluaWMgKEMuUi5KLiwgRC5TLksuKSwgUm9jaGVzdGVyLCBNTjsgTW91bnQgU2luYWkgU2Nob29s

IG9mIE1lZGljaW5lIChNLlMuKSwgTmV3IFlvcmssIE5ZOyBhbmQgQmF4YWx0YSAoRC5NLkcuLCBT

LkYuKSwgQmFubm9ja2J1cm4sIElMLiYjeEQ7RnJvbSBXZWlsbCBDb3JuZWxsIE1lZGljaW5lIChO

LlIuUi4sIFAuUy4pLCBOZXcgWW9yaywgTlk7IFVuaXZlcnNpdHkgb2YgQ2FsaWZvcm5pYSAoUi5H

LlQuLCBSLkEuUi4sIEouQi5CLiksIFNhbiBEaWVnbzsgVW5pdmVyc2l0eSBvZiBTb3V0aGVybiBD

YWxpZm9ybmlhIChNLlMuUi4sIFIuUi4sIFAuUy5BLiksIExvcyBBbmdlbGVzOyBZYWxlIFVuaXZl

cnNpdHkgKEMuSC52LkQuKSwgTmV3IEhhdmVuLCBDVDsgTWF5byBDbGluaWMgKEMuUi5KLiwgRC5T

LksuKSwgUm9jaGVzdGVyLCBNTjsgTW91bnQgU2luYWkgU2Nob29sIG9mIE1lZGljaW5lIChNLlMu

KSwgTmV3IFlvcmssIE5ZOyBhbmQgQmF4YWx0YSAoRC5NLkcuLCBTLkYuKSwgQmFubm9ja2J1cm4s

IElMLiBwYWlzZW5AdXNjLmVkdS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BIHBoYXNl

IDMgdHJpYWwgb2YgSVYgaW1tdW5vZ2xvYnVsaW4gZm9yIEFsemhlaW1lciBkaXNlYXNlPC90aXRs

ZT48c2Vjb25kYXJ5LXRpdGxlPk5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxw

ZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvbG9neTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+

PHBhZ2VzPjE3NjgtMTc3NTwvcGFnZXM+PHZvbHVtZT44ODwvdm9sdW1lPjxudW1iZXI+MTg8L251

bWJlcj48ZWRpdGlvbj4yMDE3LzA0LzA3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2Vk

PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFs

emhlaW1lciBEaXNlYXNlL2RpYWdub3N0aWMgaW1hZ2luZy8qZHJ1ZyB0aGVyYXB5L2dlbmV0aWNz

PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9ibG9vZDwva2V5d29yZD48

a2V5d29yZD5BcG9saXBvcHJvdGVpbiBFNC9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5CaW9t

YXJrZXJzL2Jsb29kPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL2RpYWdub3N0aWMgaW1hZ2luZy9k

cnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2FuYWRhPC9rZXl3b3JkPjxrZXl3b3JkPkNv

Z25pdGlvbi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+RG91YmxlLUJsaW5kIE1ldGhv

ZDwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3

b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGlucywgSW50cmF2ZW5vdXMvYWR2ZXJzZSBlZmZlY3Rz

Lyp0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29y

ZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5Ob290cm9waWMgQWdlbnRzL2FkdmVyc2Ug

ZWZmZWN0cy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPlBlcHRpZGUgRnJhZ21l

bnRzL2Jsb29kPC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBGYWlsdXJlPC9rZXl3b3JkPjxr

ZXl3b3JkPlVuaXRlZCBTdGF0ZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAx

NzwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1heSAyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGlzYm4+MTUyNi02MzJYIChFbGVjdHJvbmljKSYjeEQ7MDAyOC0zODc4IChMaW5raW5nKTwvaXNi

bj48YWNjZXNzaW9uLW51bT4yODM4MTUwNjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11

cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjgzODE1MDY8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNTQwOTg0NjwvY3VzdG9tMj48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTIxMi9XTkwuMDAwMDAwMDAwMDAwMzkwNDwvZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 88,89. Recently, EISAI published positive results with the antibody from BIOARCTIC, used in the clinical trial phase IIb for BAN2401, a protofibril selective amyloid beta antibody PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb2dvdmluc2t5PC9BdXRob3I+PFllYXI+MjAxNjwvWWVh

cj48UmVjTnVtPjM5MDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2Ny

aXB0Ij42Nyw3NDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM5MDk8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjEzOTY2MCI+MzkwOTwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TG9nb3ZpbnNreSwgVi48L2F1

dGhvcj48YXV0aG9yPlNhdGxpbiwgQS48L2F1dGhvcj48YXV0aG9yPkxhaSwgUi48L2F1dGhvcj48

YXV0aG9yPlN3YW5zb24sIEMuPC9hdXRob3I+PGF1dGhvcj5LYXBsb3csIEouPC9hdXRob3I+PGF1

dGhvcj5Pc3N3YWxkLCBHLjwvYXV0aG9yPjxhdXRob3I+QmFzdW4sIEguPC9hdXRob3I+PGF1dGhv

cj5MYW5uZmVsdCwgTC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk

cmVzcz5FaXNhaSwgSW5jLiwgMTAwIFRpY2UgQmx2ZCwgV29vZGNsaWZmIExha2UsIE5KLCAwNzY3

NywgVVNBLiYjeEQ7QmlvQXJjdGljIE5ldXJvc2NpZW5jZSBBQiwgV2FyZnZpbmdlcyB2YWcgMzUs

IDExMiA1MSwgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFs

dGgvR2VyaWF0cmljcywgVXBwc2FsYSBVbml2ZXJzaXR5LCBEYWcgSGFtbWFyc2tpb2xkcyB2YWcg

MTQgQiwgNzUxIDg1LCBVcHBzYWxhLCBTd2VkZW4uJiN4RDtCaW9BcmN0aWMgTmV1cm9zY2llbmNl

IEFCLCBXYXJmdmluZ2VzIHZhZyAzNSwgMTEyIDUxLCBTdG9ja2hvbG0sIFN3ZWRlbi4gTGFycy5M

YW5uZmVsdEBwdWJjYXJlLnV1LnNlLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoL0dl

cmlhdHJpY3MsIFVwcHNhbGEgVW5pdmVyc2l0eSwgRGFnIEhhbW1hcnNraW9sZHMgdmFnIDE0IEIs

IDc1MSA4NSwgVXBwc2FsYSwgU3dlZGVuLiBMYXJzLkxhbm5mZWx0QHB1YmNhcmUudXUuc2UuPC9h

dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+U2FmZXR5IGFuZCB0b2xlcmFiaWxpdHkgb2YgQkFO

MjQwMS0tYSBjbGluaWNhbCBzdHVkeSBpbiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2Ugd2l0aCBh

IHByb3RvZmlicmlsIHNlbGVjdGl2ZSBBYmV0YSBhbnRpYm9keTwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5BbHpoZWltZXJzIFJlcyBUaGVyPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlv

ZGljYWw+PGZ1bGwtdGl0bGU+QWx6aGVpbWVycyBSZXMgVGhlcjwvZnVsbC10aXRsZT48L3Blcmlv

ZGljYWw+PHBhZ2VzPjE0PC9wYWdlcz48dm9sdW1lPjg8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJl

cj48ZWRpdGlvbj4yMDE2LzA0LzA3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9r

ZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2Jsb29kLypkcnVnIHRoZXJhcHkvaW1t

dW5vbG9neTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvYmxvb2QvKmlt

bXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJvZGllcywgTW9ub2Nsb25hbCwgSHVtYW5p

emVkLyphZHZlcnNlIGVmZmVjdHMvcGhhcm1hY29raW5ldGljcy8qdGhlcmFwZXV0aWM8L2tleXdv

cmQ+PGtleXdvcmQ+dXNlPC9rZXl3b3JkPjxrZXl3b3JkPkJpb21hcmtlcnMvYmxvb2Q8L2tleXdv

cmQ+PGtleXdvcmQ+QnJhaW4vZHJ1ZyBlZmZlY3RzL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5Eb3NlLVJlc3BvbnNlIFJlbGF0aW9uc2hpcCwgRHJ1Zzwva2V5d29yZD48a2V5d29yZD5Eb3Vi

bGUtQmxpbmQgTWV0aG9kPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29y

ZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5QZXB0aWRl

IEZyYWdtZW50cy9ibG9vZDwva2V5d29yZD48a2V5d29yZD5BcmlhPC9rZXl3b3JkPjxrZXl3b3Jk

PkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkLWJldGE8

L2tleXdvcmQ+PGtleXdvcmQ+QWJldGE8L2tleXdvcmQ+PGtleXdvcmQ+QmFuMjQwMTwva2V5d29y

ZD48a2V5d29yZD5DbGluaWNhbCB0cmlhbDwva2V5d29yZD48a2V5d29yZD5JbW11bm90aGVyYXB5

PC9rZXl3b3JkPjxrZXl3b3JkPlByb3RvZmlicmlsPC9rZXl3b3JkPjxrZXl3b3JkPm1BYjE1ODwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+QXByIDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNzU4LTkxOTMgKEVsZWN0

cm9uaWMpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3MDQ4MTcwPC9hY2Nlc3Npb24tbnVtPjx1cmxz

PjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8y

NzA0ODE3MDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0ODIyMjk3PC9j

dXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTg2L3MxMzE5NS0wMTYtMDE4MS0y

PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5M

YW5uZmVsdDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJlY051bT4yMjIyPC9SZWNOdW0+PHJl

Y29yZD48cmVjLW51bWJlcj4yMjIyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3Rh

bXA9IjE1MzQ5Mjc3OTYiPjIyMjI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkxhbm5mZWx0LCBMLjwvYXV0aG9yPjxhdXRob3I+TW9sbGVyLCBDLjwvYXV0aG9yPjxhdXRo

b3I+QmFzdW4sIEguPC9hdXRob3I+PGF1dGhvcj5Pc3N3YWxkLCBHLjwvYXV0aG9yPjxhdXRob3I+

U2VobGluLCBELjwvYXV0aG9yPjxhdXRob3I+U2F0bGluLCBBLjwvYXV0aG9yPjxhdXRob3I+TG9n

b3ZpbnNreSwgVi48L2F1dGhvcj48YXV0aG9yPkdlbGxlcmZvcnMsIFAuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVh

bHRoL0dlcmlhdHJpY3MsIFVwcHNhbGEgVW5pdmVyc2l0eSwgRGFnIEhhbW1hcnNrb2xkcyB2YWcg

MTQgQiwgNzUxIDg1IFVwcHNhbGEsIFN3ZWRlbiA7IEJpb0FyY3RpYyBOZXVyb3NjaWVuY2UgQUIs

IFdhcmZ2aW5nZXMgdmFnIDM1LCAxMTIgNTEgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtCaW9BcmN0

aWMgTmV1cm9zY2llbmNlIEFCLCBXYXJmdmluZ2VzIHZhZyAzNSwgMTEyIDUxIFN0b2NraG9sbSwg

U3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoL0dlcmlhdHJpY3MsIFVwcHNh

bGEgVW5pdmVyc2l0eSwgRGFnIEhhbW1hcnNrb2xkcyB2YWcgMTQgQiwgNzUxIDg1IFVwcHNhbGEs

IFN3ZWRlbi4mI3hEO0Vpc2FpLCBJbmMsIDEwMCBUaWNlIEJvdWxldmFyZCwgV29vZGNsaWZmIExh

a2UsIE5KIDA3Njc3LCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UGVyc3BlY3Rp

dmVzIG9uIGZ1dHVyZSBBbHpoZWltZXIgdGhlcmFwaWVzOiBhbXlsb2lkLWJldGEgcHJvdG9maWJy

aWxzIC0gYSBuZXcgdGFyZ2V0IGZvciBpbW11bm90aGVyYXB5IHdpdGggQkFOMjQwMSBpbiBBbHpo

ZWltZXImYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWx6aGVpbWVycyBS

ZXMgVGhlcjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxl

PkFsemhlaW1lcnMgUmVzIFRoZXI8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xNjwv

cGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGVkaXRpb24+MjAxNC8w

Ny8xODwvZWRpdGlvbj48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48L2RhdGVzPjxpc2JuPjE3NTgt

OTE5MyAoUHJpbnQpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1MDMxNjMzPC9hY2Nlc3Npb24tbnVt

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8yNTAzMTYzMzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0MDU0

OTY3PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTg2L2FsenJ0MjQ2PC9l

bGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb2dvdmluc2t5PC9BdXRob3I+PFllYXI+MjAxNjwvWWVh

cj48UmVjTnVtPjM5MDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2Ny

aXB0Ij42Nyw3NDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM5MDk8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjEzOTY2MCI+MzkwOTwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TG9nb3ZpbnNreSwgVi48L2F1

dGhvcj48YXV0aG9yPlNhdGxpbiwgQS48L2F1dGhvcj48YXV0aG9yPkxhaSwgUi48L2F1dGhvcj48

YXV0aG9yPlN3YW5zb24sIEMuPC9hdXRob3I+PGF1dGhvcj5LYXBsb3csIEouPC9hdXRob3I+PGF1

dGhvcj5Pc3N3YWxkLCBHLjwvYXV0aG9yPjxhdXRob3I+QmFzdW4sIEguPC9hdXRob3I+PGF1dGhv

cj5MYW5uZmVsdCwgTC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk

cmVzcz5FaXNhaSwgSW5jLiwgMTAwIFRpY2UgQmx2ZCwgV29vZGNsaWZmIExha2UsIE5KLCAwNzY3

NywgVVNBLiYjeEQ7QmlvQXJjdGljIE5ldXJvc2NpZW5jZSBBQiwgV2FyZnZpbmdlcyB2YWcgMzUs

IDExMiA1MSwgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFs

dGgvR2VyaWF0cmljcywgVXBwc2FsYSBVbml2ZXJzaXR5LCBEYWcgSGFtbWFyc2tpb2xkcyB2YWcg

MTQgQiwgNzUxIDg1LCBVcHBzYWxhLCBTd2VkZW4uJiN4RDtCaW9BcmN0aWMgTmV1cm9zY2llbmNl

IEFCLCBXYXJmdmluZ2VzIHZhZyAzNSwgMTEyIDUxLCBTdG9ja2hvbG0sIFN3ZWRlbi4gTGFycy5M

YW5uZmVsdEBwdWJjYXJlLnV1LnNlLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoL0dl

cmlhdHJpY3MsIFVwcHNhbGEgVW5pdmVyc2l0eSwgRGFnIEhhbW1hcnNraW9sZHMgdmFnIDE0IEIs

IDc1MSA4NSwgVXBwc2FsYSwgU3dlZGVuLiBMYXJzLkxhbm5mZWx0QHB1YmNhcmUudXUuc2UuPC9h

dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+U2FmZXR5IGFuZCB0b2xlcmFiaWxpdHkgb2YgQkFO

MjQwMS0tYSBjbGluaWNhbCBzdHVkeSBpbiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2Ugd2l0aCBh

IHByb3RvZmlicmlsIHNlbGVjdGl2ZSBBYmV0YSBhbnRpYm9keTwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5BbHpoZWltZXJzIFJlcyBUaGVyPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlv

ZGljYWw+PGZ1bGwtdGl0bGU+QWx6aGVpbWVycyBSZXMgVGhlcjwvZnVsbC10aXRsZT48L3Blcmlv

ZGljYWw+PHBhZ2VzPjE0PC9wYWdlcz48dm9sdW1lPjg8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJl

cj48ZWRpdGlvbj4yMDE2LzA0LzA3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9r

ZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2Jsb29kLypkcnVnIHRoZXJhcHkvaW1t

dW5vbG9neTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvYmxvb2QvKmlt

bXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJvZGllcywgTW9ub2Nsb25hbCwgSHVtYW5p

emVkLyphZHZlcnNlIGVmZmVjdHMvcGhhcm1hY29raW5ldGljcy8qdGhlcmFwZXV0aWM8L2tleXdv

cmQ+PGtleXdvcmQ+dXNlPC9rZXl3b3JkPjxrZXl3b3JkPkJpb21hcmtlcnMvYmxvb2Q8L2tleXdv

cmQ+PGtleXdvcmQ+QnJhaW4vZHJ1ZyBlZmZlY3RzL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5Eb3NlLVJlc3BvbnNlIFJlbGF0aW9uc2hpcCwgRHJ1Zzwva2V5d29yZD48a2V5d29yZD5Eb3Vi

bGUtQmxpbmQgTWV0aG9kPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29y

ZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5QZXB0aWRl

IEZyYWdtZW50cy9ibG9vZDwva2V5d29yZD48a2V5d29yZD5BcmlhPC9rZXl3b3JkPjxrZXl3b3Jk

PkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkLWJldGE8

L2tleXdvcmQ+PGtleXdvcmQ+QWJldGE8L2tleXdvcmQ+PGtleXdvcmQ+QmFuMjQwMTwva2V5d29y

ZD48a2V5d29yZD5DbGluaWNhbCB0cmlhbDwva2V5d29yZD48a2V5d29yZD5JbW11bm90aGVyYXB5

PC9rZXl3b3JkPjxrZXl3b3JkPlByb3RvZmlicmlsPC9rZXl3b3JkPjxrZXl3b3JkPm1BYjE1ODwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+QXByIDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNzU4LTkxOTMgKEVsZWN0

cm9uaWMpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3MDQ4MTcwPC9hY2Nlc3Npb24tbnVtPjx1cmxz

PjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8y

NzA0ODE3MDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0ODIyMjk3PC9j

dXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTg2L3MxMzE5NS0wMTYtMDE4MS0y

PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5M

YW5uZmVsdDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJlY051bT4yMjIyPC9SZWNOdW0+PHJl

Y29yZD48cmVjLW51bWJlcj4yMjIyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3Rh

bXA9IjE1MzQ5Mjc3OTYiPjIyMjI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkxhbm5mZWx0LCBMLjwvYXV0aG9yPjxhdXRob3I+TW9sbGVyLCBDLjwvYXV0aG9yPjxhdXRo

b3I+QmFzdW4sIEguPC9hdXRob3I+PGF1dGhvcj5Pc3N3YWxkLCBHLjwvYXV0aG9yPjxhdXRob3I+

U2VobGluLCBELjwvYXV0aG9yPjxhdXRob3I+U2F0bGluLCBBLjwvYXV0aG9yPjxhdXRob3I+TG9n

b3ZpbnNreSwgVi48L2F1dGhvcj48YXV0aG9yPkdlbGxlcmZvcnMsIFAuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVh

bHRoL0dlcmlhdHJpY3MsIFVwcHNhbGEgVW5pdmVyc2l0eSwgRGFnIEhhbW1hcnNrb2xkcyB2YWcg

MTQgQiwgNzUxIDg1IFVwcHNhbGEsIFN3ZWRlbiA7IEJpb0FyY3RpYyBOZXVyb3NjaWVuY2UgQUIs

IFdhcmZ2aW5nZXMgdmFnIDM1LCAxMTIgNTEgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtCaW9BcmN0

aWMgTmV1cm9zY2llbmNlIEFCLCBXYXJmdmluZ2VzIHZhZyAzNSwgMTEyIDUxIFN0b2NraG9sbSwg

U3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoL0dlcmlhdHJpY3MsIFVwcHNh

bGEgVW5pdmVyc2l0eSwgRGFnIEhhbW1hcnNrb2xkcyB2YWcgMTQgQiwgNzUxIDg1IFVwcHNhbGEs

IFN3ZWRlbi4mI3hEO0Vpc2FpLCBJbmMsIDEwMCBUaWNlIEJvdWxldmFyZCwgV29vZGNsaWZmIExh

a2UsIE5KIDA3Njc3LCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UGVyc3BlY3Rp

dmVzIG9uIGZ1dHVyZSBBbHpoZWltZXIgdGhlcmFwaWVzOiBhbXlsb2lkLWJldGEgcHJvdG9maWJy

aWxzIC0gYSBuZXcgdGFyZ2V0IGZvciBpbW11bm90aGVyYXB5IHdpdGggQkFOMjQwMSBpbiBBbHpo

ZWltZXImYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWx6aGVpbWVycyBS

ZXMgVGhlcjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxl

PkFsemhlaW1lcnMgUmVzIFRoZXI8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xNjwv

cGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGVkaXRpb24+MjAxNC8w

Ny8xODwvZWRpdGlvbj48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48L2RhdGVzPjxpc2JuPjE3NTgt

OTE5MyAoUHJpbnQpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1MDMxNjMzPC9hY2Nlc3Npb24tbnVt

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8yNTAzMTYzMzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0MDU0

OTY3PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTg2L2FsenJ0MjQ2PC9l

bGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 67,74. The results for BAN2401 came after a trial at 18 months in early Alzheimer?s disease in a cohort of 856 patients. The analysis of the results showed slowing in clinical decline, which was dose dependent, together with the reduction of amyloid beta ADDIN EN.CITE <EndNote><Cite><Author>Eriksson</Author><Year>2018</Year><RecNum>4275</RecNum><DisplayText><style face="superscript">90</style></DisplayText><record><rec-number>4275</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1538331169">4275</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Christina Astrén Eriksson</author></authors></contributors><titles><title>BioArctic announces positive topline results of BAN2401 Phase 2b at 18 months in early Alzheimer’s Disease</title></titles><volume>2018</volume><number>July 6, 2018</number><dates><year>2018</year><pub-dates><date>July 6, 2018</date></pub-dates></dates><pub-location>BioArctic.se</pub-location><publisher>BioArctic</publisher><work-type>Web page</work-type><urls><related-urls><url>. Chaperones and mitochondria: new and old options for AD therapeuticsAnother approach to AD treatment is to inhibit protein aggregation using chaperone proteins. Evidence shows the intraneuronal amyloid is also important enough to affect the parenchymatous amyloid inside the brain PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWl0bzwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl

Y051bT4xMzk3PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDEsOTE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMzk3PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ1MDAzNDQiPjEzOTc8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNhaXRvLCBULjwvYXV0aG9yPjxhdXRo

b3I+TWF0c3ViYSwgWS48L2F1dGhvcj48YXV0aG9yPk1paGlyYSwgTi48L2F1dGhvcj48YXV0aG9y

PlRha2FubywgSi48L2F1dGhvcj48YXV0aG9yPk5pbHNzb24sIFAuPC9hdXRob3I+PGF1dGhvcj5J

dG9oYXJhLCBTLjwvYXV0aG9yPjxhdXRob3I+SXdhdGEsIE4uPC9hdXRob3I+PGF1dGhvcj5TYWlk

bywgVC4gQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz4x

XSBMYWJvcmF0b3J5IGZvciBQcm90ZW9seXRpYyBOZXVyb3NjaWVuY2UsIFJJS0VOIEJyYWluIFNj

aWVuY2UgSW5zdGl0dXRlLCBXYWtvLXNoaSwgU2FpdGFtYSwgSmFwYW4uIFsyXSBKYXBhbiBTY2ll

bmNlIGFuZCBUZWNobm9sb2d5IEFnZW5jeSwgU2FpdGFtYSwgSmFwYW4uJiN4RDtMYWJvcmF0b3J5

IGZvciBQcm90ZW9seXRpYyBOZXVyb3NjaWVuY2UsIFJJS0VOIEJyYWluIFNjaWVuY2UgSW5zdGl0

dXRlLCBXYWtvLXNoaSwgU2FpdGFtYSwgSmFwYW4uJiN4RDtMYWJvcmF0b3J5IGZvciBCZWhhdmlv

cmFsIEdlbmV0aWNzLCBSSUtFTiBCcmFpbiBTY2llbmNlIEluc3RpdHV0ZSwgV2Frby1zaGksIFNh

aXRhbWEsIEphcGFuLiYjeEQ7MV0gTGFib3JhdG9yeSBmb3IgUHJvdGVvbHl0aWMgTmV1cm9zY2ll

bmNlLCBSSUtFTiBCcmFpbiBTY2llbmNlIEluc3RpdHV0ZSwgV2Frby1zaGksIFNhaXRhbWEsIEph

cGFuLiBbMl0gRGVwYXJ0bWVudCBvZiBNb2xlY3VsYXIgTWVkaWNpbmFsIFNjaWVuY2VzLCBEaXZp

c2lvbiBvZiBCaW90ZWNobm9sb2d5LCBOYWdhc2FraSBVbml2ZXJzaXR5IEdyYWR1YXRlIFNjaG9v

bCBvZiBCaW9tZWRpY2FsIFNjaWVuY2VzLCBOYWdhc2FraSwgSmFwYW4uPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+U2luZ2xlIEFwcCBrbm9jay1pbiBtb3VzZSBtb2RlbHMgb2YgQWx6aGVp

bWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5hdCBOZXVyb3NjaTwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz42NjEtMzwvcGFnZXM+PHZvbHVtZT4xNzwv

dm9sdW1lPjxudW1iZXI+NTwvbnVtYmVyPjxlZGl0aW9uPjIwMTQvMDQvMTU8L2VkaXRpb24+PGtl

eXdvcmRzPjxrZXl3b3JkPkFnZSBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBE

aXNlYXNlLypnZW5ldGljcy9tZXRhYm9saXNtLypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZCBiZXRhLVByb3RlaW4gUHJlY3Vyc29yLypnZW5ldGljczwva2V5d29yZD48a2V5d29y

ZD5BbmFseXNpcyBvZiBWYXJpYW5jZTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3Jk

PjxrZXl3b3JkPipEaXNlYXNlIE1vZGVscywgQW5pbWFsPC9rZXl3b3JkPjxrZXl3b3JkPkVuenlt

ZS1MaW5rZWQgSW1tdW5vc29yYmVudCBBc3NheTwva2V5d29yZD48a2V5d29yZD4qR2VuZSBLbm9j

ay1JbiBUZWNobmlxdWVzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29y

ZD5NYXplIExlYXJuaW5nL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29y

ZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgVHJh

bnNnZW5pYzwva2V5d29yZD48a2V5d29yZD5NdXRhdGlvbi9nZW5ldGljczwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDE0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWF5PC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU0Ni0xNzI2IChFbGVjdHJvbmljKSYjeEQ7MTA5

Ny02MjU2IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNDcyODI2OTwvYWNjZXNzaW9u

LW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdv

di9wdWJtZWQvMjQ3MjgyNjk8L3VybD48dXJsPmh0dHBzOi8vd3d3Lm5hdHVyZS5jb20vYXJ0aWNs

ZXMvbm4uMzY5Ny5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjEwLjEwMzgvbm4uMzY5NzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNv

cmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Tmlsc3NvbjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+

PFJlY051bT4yNDgxPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4yNDgxPC9yZWMtbnVtYmVy

Pjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBm

d3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ5Mzk3MjAiPjI0ODE8L2tleT48L2ZvcmVp

Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv

bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk5pbHNzb24sIFAuPC9hdXRob3I+PGF1dGhvcj5M

b2dhbmF0aGFuLCBLLjwvYXV0aG9yPjxhdXRob3I+U2VraWd1Y2hpLCBNLjwvYXV0aG9yPjxhdXRo

b3I+TWF0c3ViYSwgWS48L2F1dGhvcj48YXV0aG9yPkh1aSwgSy48L2F1dGhvcj48YXV0aG9yPlRz

dWJ1a2ksIFMuPC9hdXRob3I+PGF1dGhvcj5UYW5ha2EsIE0uPC9hdXRob3I+PGF1dGhvcj5Jd2F0

YSwgTi48L2F1dGhvcj48YXV0aG9yPlNhaXRvLCBULjwvYXV0aG9yPjxhdXRob3I+U2FpZG8sIFQu

IEMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+TGFib3Jh

dG9yeSBmb3IgUHJvdGVvbHl0aWMgTmV1cm9zY2llbmNlLCBSSUtFTiBCcmFpbiBTY2llbmNlIElu

c3RpdHV0ZSwgMi0xIEhpcm9zYXdhLCBXYWtvLCBTYWl0YW1hIDM1MS0wMTk4LCBKYXBhbi4gRWxl

Y3Ryb25pYyBhZGRyZXNzOiBwZXItbmlsc3NvbkBicmFpbi5yaWtlbi5qcC48L2F1dGgtYWRkcmVz

cz48dGl0bGVzPjx0aXRsZT5BYmV0YSBzZWNyZXRpb24gYW5kIHBsYXF1ZSBmb3JtYXRpb24gZGVw

ZW5kIG9uIGF1dG9waGFneTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5DZWxsIFJlcDwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz42MS05PC9wYWdlcz48dm9sdW1lPjU8L3ZvbHVtZT48

bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4yMDEzLzEwLzA4PC9lZGl0aW9uPjxrZXl3b3Jkcz48

a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9tZXRhYm9saXNtL3BhdGhvbG9neS8qcGh5c2lvcGF0

aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy8qbWV0YWJvbGlz

bS8qc2VjcmV0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+

QXV0b3BoYWd5LypwaHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkRpc2Vhc2UgTW9kZWxzLCBB

bmltYWw8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vaGlzdG9jaGVtaXN0cnk8L2tleXdvcmQ+PGtl

eXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFuc2dlbmljPC9rZXl3b3JkPjxr

ZXl3b3JkPlBsYXF1ZSwgQW15bG9pZC8qbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PC9r

ZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPk9jdCAxNzwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjIyMTEtMTI0NyAoRWxlY3Ryb25pYyk8L2lz

Ym4+PGFjY2Vzc2lvbi1udW0+MjQwOTU3NDA8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQt

dXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI0MDk1NzQwPC91

cmw+PHVybD5odHRwczovL2FjLmVscy1jZG4uY29tL1MyMjExMTI0NzEzMDA1MDIwLzEtczIuMC1T

MjIxMTEyNDcxMzAwNTAyMC1tYWluLnBkZj9fdGlkPWNkZGVjMDBjLTA3NDMtNDI3OS05MzFhLTFj

NWJiYTMyNTE5NCZhbXA7YWNkbmF0PTE1MzYxNTM3MjBfZTBjMmZkYTBjNmI4ZThjNmE5MmY3YzRh

Y2YwODI2NGM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjEwLjEwMTYvai5jZWxyZXAuMjAxMy4wOC4wNDI8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWl0bzwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl

Y051bT4xMzk3PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDEsOTE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMzk3PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ1MDAzNDQiPjEzOTc8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNhaXRvLCBULjwvYXV0aG9yPjxhdXRo

b3I+TWF0c3ViYSwgWS48L2F1dGhvcj48YXV0aG9yPk1paGlyYSwgTi48L2F1dGhvcj48YXV0aG9y

PlRha2FubywgSi48L2F1dGhvcj48YXV0aG9yPk5pbHNzb24sIFAuPC9hdXRob3I+PGF1dGhvcj5J

dG9oYXJhLCBTLjwvYXV0aG9yPjxhdXRob3I+SXdhdGEsIE4uPC9hdXRob3I+PGF1dGhvcj5TYWlk

bywgVC4gQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz4x

XSBMYWJvcmF0b3J5IGZvciBQcm90ZW9seXRpYyBOZXVyb3NjaWVuY2UsIFJJS0VOIEJyYWluIFNj

aWVuY2UgSW5zdGl0dXRlLCBXYWtvLXNoaSwgU2FpdGFtYSwgSmFwYW4uIFsyXSBKYXBhbiBTY2ll

bmNlIGFuZCBUZWNobm9sb2d5IEFnZW5jeSwgU2FpdGFtYSwgSmFwYW4uJiN4RDtMYWJvcmF0b3J5

IGZvciBQcm90ZW9seXRpYyBOZXVyb3NjaWVuY2UsIFJJS0VOIEJyYWluIFNjaWVuY2UgSW5zdGl0

dXRlLCBXYWtvLXNoaSwgU2FpdGFtYSwgSmFwYW4uJiN4RDtMYWJvcmF0b3J5IGZvciBCZWhhdmlv

cmFsIEdlbmV0aWNzLCBSSUtFTiBCcmFpbiBTY2llbmNlIEluc3RpdHV0ZSwgV2Frby1zaGksIFNh

aXRhbWEsIEphcGFuLiYjeEQ7MV0gTGFib3JhdG9yeSBmb3IgUHJvdGVvbHl0aWMgTmV1cm9zY2ll

bmNlLCBSSUtFTiBCcmFpbiBTY2llbmNlIEluc3RpdHV0ZSwgV2Frby1zaGksIFNhaXRhbWEsIEph

cGFuLiBbMl0gRGVwYXJ0bWVudCBvZiBNb2xlY3VsYXIgTWVkaWNpbmFsIFNjaWVuY2VzLCBEaXZp

c2lvbiBvZiBCaW90ZWNobm9sb2d5LCBOYWdhc2FraSBVbml2ZXJzaXR5IEdyYWR1YXRlIFNjaG9v

bCBvZiBCaW9tZWRpY2FsIFNjaWVuY2VzLCBOYWdhc2FraSwgSmFwYW4uPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+U2luZ2xlIEFwcCBrbm9jay1pbiBtb3VzZSBtb2RlbHMgb2YgQWx6aGVp

bWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5hdCBOZXVyb3NjaTwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz42NjEtMzwvcGFnZXM+PHZvbHVtZT4xNzwv

dm9sdW1lPjxudW1iZXI+NTwvbnVtYmVyPjxlZGl0aW9uPjIwMTQvMDQvMTU8L2VkaXRpb24+PGtl

eXdvcmRzPjxrZXl3b3JkPkFnZSBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBE

aXNlYXNlLypnZW5ldGljcy9tZXRhYm9saXNtLypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZCBiZXRhLVByb3RlaW4gUHJlY3Vyc29yLypnZW5ldGljczwva2V5d29yZD48a2V5d29y

ZD5BbmFseXNpcyBvZiBWYXJpYW5jZTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3Jk

PjxrZXl3b3JkPipEaXNlYXNlIE1vZGVscywgQW5pbWFsPC9rZXl3b3JkPjxrZXl3b3JkPkVuenlt

ZS1MaW5rZWQgSW1tdW5vc29yYmVudCBBc3NheTwva2V5d29yZD48a2V5d29yZD4qR2VuZSBLbm9j

ay1JbiBUZWNobmlxdWVzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29y

ZD5NYXplIExlYXJuaW5nL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29y

ZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgVHJh

bnNnZW5pYzwva2V5d29yZD48a2V5d29yZD5NdXRhdGlvbi9nZW5ldGljczwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDE0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWF5PC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU0Ni0xNzI2IChFbGVjdHJvbmljKSYjeEQ7MTA5

Ny02MjU2IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNDcyODI2OTwvYWNjZXNzaW9u

LW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdv

di9wdWJtZWQvMjQ3MjgyNjk8L3VybD48dXJsPmh0dHBzOi8vd3d3Lm5hdHVyZS5jb20vYXJ0aWNs

ZXMvbm4uMzY5Ny5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjEwLjEwMzgvbm4uMzY5NzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNv

cmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Tmlsc3NvbjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+

PFJlY051bT4yNDgxPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4yNDgxPC9yZWMtbnVtYmVy

Pjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBm

d3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ5Mzk3MjAiPjI0ODE8L2tleT48L2ZvcmVp

Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv

bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk5pbHNzb24sIFAuPC9hdXRob3I+PGF1dGhvcj5M

b2dhbmF0aGFuLCBLLjwvYXV0aG9yPjxhdXRob3I+U2VraWd1Y2hpLCBNLjwvYXV0aG9yPjxhdXRo

b3I+TWF0c3ViYSwgWS48L2F1dGhvcj48YXV0aG9yPkh1aSwgSy48L2F1dGhvcj48YXV0aG9yPlRz

dWJ1a2ksIFMuPC9hdXRob3I+PGF1dGhvcj5UYW5ha2EsIE0uPC9hdXRob3I+PGF1dGhvcj5Jd2F0

YSwgTi48L2F1dGhvcj48YXV0aG9yPlNhaXRvLCBULjwvYXV0aG9yPjxhdXRob3I+U2FpZG8sIFQu

IEMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+TGFib3Jh

dG9yeSBmb3IgUHJvdGVvbHl0aWMgTmV1cm9zY2llbmNlLCBSSUtFTiBCcmFpbiBTY2llbmNlIElu

c3RpdHV0ZSwgMi0xIEhpcm9zYXdhLCBXYWtvLCBTYWl0YW1hIDM1MS0wMTk4LCBKYXBhbi4gRWxl

Y3Ryb25pYyBhZGRyZXNzOiBwZXItbmlsc3NvbkBicmFpbi5yaWtlbi5qcC48L2F1dGgtYWRkcmVz

cz48dGl0bGVzPjx0aXRsZT5BYmV0YSBzZWNyZXRpb24gYW5kIHBsYXF1ZSBmb3JtYXRpb24gZGVw

ZW5kIG9uIGF1dG9waGFneTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5DZWxsIFJlcDwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz42MS05PC9wYWdlcz48dm9sdW1lPjU8L3ZvbHVtZT48

bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4yMDEzLzEwLzA4PC9lZGl0aW9uPjxrZXl3b3Jkcz48

a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9tZXRhYm9saXNtL3BhdGhvbG9neS8qcGh5c2lvcGF0

aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy8qbWV0YWJvbGlz

bS8qc2VjcmV0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+

QXV0b3BoYWd5LypwaHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkRpc2Vhc2UgTW9kZWxzLCBB

bmltYWw8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vaGlzdG9jaGVtaXN0cnk8L2tleXdvcmQ+PGtl

eXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFuc2dlbmljPC9rZXl3b3JkPjxr

ZXl3b3JkPlBsYXF1ZSwgQW15bG9pZC8qbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PC9r

ZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPk9jdCAxNzwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjIyMTEtMTI0NyAoRWxlY3Ryb25pYyk8L2lz

Ym4+PGFjY2Vzc2lvbi1udW0+MjQwOTU3NDA8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQt

dXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI0MDk1NzQwPC91

cmw+PHVybD5odHRwczovL2FjLmVscy1jZG4uY29tL1MyMjExMTI0NzEzMDA1MDIwLzEtczIuMC1T

MjIxMTEyNDcxMzAwNTAyMC1tYWluLnBkZj9fdGlkPWNkZGVjMDBjLTA3NDMtNDI3OS05MzFhLTFj

NWJiYTMyNTE5NCZhbXA7YWNkbmF0PTE1MzYxNTM3MjBfZTBjMmZkYTBjNmI4ZThjNmE5MmY3YzRh

Y2YwODI2NGM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjEwLjEwMTYvai5jZWxyZXAuMjAxMy4wOC4wNDI8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 41,91. Chaperones transport amyloid into the mitochondria, inducing neurotoxicity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXNwZXJzZW48L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFy

PjxSZWNOdW0+MjQ4MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjkyPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjQ4MjwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0OTY2MDQ1Ij4yNDgyPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DYXNwZXJzZW4sIEMuPC9hdXRob3I+

PGF1dGhvcj5XYW5nLCBOLjwvYXV0aG9yPjxhdXRob3I+WWFvLCBKLjwvYXV0aG9yPjxhdXRob3I+

U29zdW5vdiwgQS48L2F1dGhvcj48YXV0aG9yPkNoZW4sIFguPC9hdXRob3I+PGF1dGhvcj5MdXN0

YmFkZXIsIEouIFcuPC9hdXRob3I+PGF1dGhvcj5YdSwgSC4gVy48L2F1dGhvcj48YXV0aG9yPlN0

ZXJuLCBELjwvYXV0aG9yPjxhdXRob3I+TWNLaGFubiwgRy48L2F1dGhvcj48YXV0aG9yPllhbiwg

Uy4gRC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBh

cnRtZW50IG9mIFN1cmdlcnksIENvbGxlZ2Ugb2YgUGh5c2ljaWFucyAmYW1wOyBTdXJnZW9ucyBv

ZiBDb2x1bWJpYSBVbml2ZXJzaXR5LCBOZXcgWW9yaywgTmV3IFlvcmsgMTAwMzIsIFVTQS48L2F1

dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5NaXRvY2hvbmRyaWFsIEFiZXRhOiBhIHBvdGVudGlh

bCBmb2NhbCBwb2ludCBmb3IgbmV1cm9uYWwgbWV0YWJvbGljIGR5c2Z1bmN0aW9uIGluIEFsemhl

aW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5GQVNFQiBKPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjIwNDAtMTwvcGFnZXM+PHZvbHVtZT4xOTwvdm9s

dW1lPjxudW1iZXI+MTQ8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vh

c2UvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzLypj

aGVtaXN0cnkvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5

d29yZD5CcmFpbi91bHRyYXN0cnVjdHVyZTwva2V5d29yZD48a2V5d29yZD5CcmVmZWxkaW4gQS9w

aGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgQ29ydGV4L3BhdGhvbG9neTwv

a2V5d29yZD48a2V5d29yZD5DeXRvc29sL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+RWxl

Y3Ryb24gVHJhbnNwb3J0IENoYWluIENvbXBsZXggUHJvdGVpbnMvY2hlbWlzdHJ5PC9rZXl3b3Jk

PjxrZXl3b3JkPkVuZXJneSBNZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkVuenltZS1MaW5r

ZWQgSW1tdW5vc29yYmVudCBBc3NheTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+

PGtleXdvcmQ+SW1tdW5vYmxvdHRpbmc8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48

a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+Kk1pY2UsIFRyYW5z

Z2VuaWM8L2tleXdvcmQ+PGtleXdvcmQ+TWljcm9zY29weSwgQ29uZm9jYWw8L2tleXdvcmQ+PGtl

eXdvcmQ+TWljcm9zY29weSwgSW1tdW5vZWxlY3Ryb248L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2No

b25kcmlhL21ldGFib2xpc20vKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5Nb2RlbHMsIEJp

b2xvZ2ljYWw8L2tleXdvcmQ+PGtleXdvcmQ+TXV0YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+TmV1

cm9ucy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5PeGlkYXRpdmUgU3RyZXNzPC9rZXl3

b3JkPjxrZXl3b3JkPk94eWdlbiBDb25zdW1wdGlvbjwva2V5d29yZD48a2V5d29yZD5QZXB0aWRl

IEZyYWdtZW50cy9jaGVtaXN0cnkvKmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPlBlcHRpZGUg

SHlkcm9sYXNlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlBsYXF1ZSwgQW15bG9pZC9w

YXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVpbiBTeW50aGVzaXMgSW5oaWJpdG9ycy9w

aGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+VGltZSBGYWN0b3JzPC9rZXl3b3JkPjwva2V5

d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5EZWM8L2RhdGU+

PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTMwLTY4NjAgKEVsZWN0cm9uaWMpJiN4RDswODky

LTY2MzggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjE2MjEwMzk2PC9hY2Nlc3Npb24t

bnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3Yv

cHVibWVkLzE2MjEwMzk2PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4xMDk2L2ZqLjA1LTM3MzVmamU8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXNwZXJzZW48L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFy

PjxSZWNOdW0+MjQ4MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjkyPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjQ4MjwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0OTY2MDQ1Ij4yNDgyPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DYXNwZXJzZW4sIEMuPC9hdXRob3I+

PGF1dGhvcj5XYW5nLCBOLjwvYXV0aG9yPjxhdXRob3I+WWFvLCBKLjwvYXV0aG9yPjxhdXRob3I+

U29zdW5vdiwgQS48L2F1dGhvcj48YXV0aG9yPkNoZW4sIFguPC9hdXRob3I+PGF1dGhvcj5MdXN0

YmFkZXIsIEouIFcuPC9hdXRob3I+PGF1dGhvcj5YdSwgSC4gVy48L2F1dGhvcj48YXV0aG9yPlN0

ZXJuLCBELjwvYXV0aG9yPjxhdXRob3I+TWNLaGFubiwgRy48L2F1dGhvcj48YXV0aG9yPllhbiwg

Uy4gRC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBh

cnRtZW50IG9mIFN1cmdlcnksIENvbGxlZ2Ugb2YgUGh5c2ljaWFucyAmYW1wOyBTdXJnZW9ucyBv

ZiBDb2x1bWJpYSBVbml2ZXJzaXR5LCBOZXcgWW9yaywgTmV3IFlvcmsgMTAwMzIsIFVTQS48L2F1

dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5NaXRvY2hvbmRyaWFsIEFiZXRhOiBhIHBvdGVudGlh

bCBmb2NhbCBwb2ludCBmb3IgbmV1cm9uYWwgbWV0YWJvbGljIGR5c2Z1bmN0aW9uIGluIEFsemhl

aW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5GQVNFQiBKPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjIwNDAtMTwvcGFnZXM+PHZvbHVtZT4xOTwvdm9s

dW1lPjxudW1iZXI+MTQ8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vh

c2UvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzLypj

aGVtaXN0cnkvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5

d29yZD5CcmFpbi91bHRyYXN0cnVjdHVyZTwva2V5d29yZD48a2V5d29yZD5CcmVmZWxkaW4gQS9w

aGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgQ29ydGV4L3BhdGhvbG9neTwv

a2V5d29yZD48a2V5d29yZD5DeXRvc29sL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+RWxl

Y3Ryb24gVHJhbnNwb3J0IENoYWluIENvbXBsZXggUHJvdGVpbnMvY2hlbWlzdHJ5PC9rZXl3b3Jk

PjxrZXl3b3JkPkVuZXJneSBNZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkVuenltZS1MaW5r

ZWQgSW1tdW5vc29yYmVudCBBc3NheTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+

PGtleXdvcmQ+SW1tdW5vYmxvdHRpbmc8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48

a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+Kk1pY2UsIFRyYW5z

Z2VuaWM8L2tleXdvcmQ+PGtleXdvcmQ+TWljcm9zY29weSwgQ29uZm9jYWw8L2tleXdvcmQ+PGtl

eXdvcmQ+TWljcm9zY29weSwgSW1tdW5vZWxlY3Ryb248L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2No

b25kcmlhL21ldGFib2xpc20vKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5Nb2RlbHMsIEJp

b2xvZ2ljYWw8L2tleXdvcmQ+PGtleXdvcmQ+TXV0YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+TmV1

cm9ucy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5PeGlkYXRpdmUgU3RyZXNzPC9rZXl3

b3JkPjxrZXl3b3JkPk94eWdlbiBDb25zdW1wdGlvbjwva2V5d29yZD48a2V5d29yZD5QZXB0aWRl

IEZyYWdtZW50cy9jaGVtaXN0cnkvKmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPlBlcHRpZGUg

SHlkcm9sYXNlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlBsYXF1ZSwgQW15bG9pZC9w

YXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVpbiBTeW50aGVzaXMgSW5oaWJpdG9ycy9w

aGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+VGltZSBGYWN0b3JzPC9rZXl3b3JkPjwva2V5

d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5EZWM8L2RhdGU+

PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTMwLTY4NjAgKEVsZWN0cm9uaWMpJiN4RDswODky

LTY2MzggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjE2MjEwMzk2PC9hY2Nlc3Npb24t

bnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3Yv

cHVibWVkLzE2MjEwMzk2PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4xMDk2L2ZqLjA1LTM3MzVmamU8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 92 and if we could inhibit that transport, it would be possible to preserve mitochondrial function and save the synapses in these nerve cells. On the other hand, chaperones can also help increase the solubility of Aβ. BRICHOS is a conserved domain in proteins with proposed chaperone activity and it has been related to amyloidosis and dementia in the British and Danish familial cases ADDIN EN.CITE <EndNote><Cite><Author>Sanchez-Pulido</Author><Year>2002</Year><RecNum>2426</RecNum><DisplayText><style face="superscript">93</style></DisplayText><record><rec-number>2426</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1534931268">2426</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sanchez-Pulido, L.</author><author>Devos, D.</author><author>Valencia, A.</author></authors></contributors><auth-address>Protein Design Group, Centro Nacional de Biotecnologia (CNB-CSIC), Cantoblanco E-28049, Madrid, Spain.</auth-address><titles><title>BRICHOS: a conserved domain in proteins associated with dementia, respiratory distress and cancer</title><secondary-title>Trends Biochem Sci</secondary-title></titles><pages>329-32</pages><volume>27</volume><number>7</number><edition>2002/07/13</edition><keywords><keyword>Amino Acid Motifs</keyword><keyword>Amino Acid Sequence</keyword><keyword>Animals</keyword><keyword>Dementia/*genetics/metabolism</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Intercellular Signaling Peptides and Proteins/chemistry/genetics/metabolism</keyword><keyword>*Membrane Proteins</keyword><keyword>Molecular Sequence Data</keyword><keyword>Neoplasm Proteins/chemistry/genetics/metabolism</keyword><keyword>Neoplasms/*genetics/metabolism</keyword><keyword>*Protein Structure, Tertiary</keyword><keyword>Pulmonary Surfactants/chemistry/metabolism</keyword><keyword>Respiratory Distress Syndrome, Newborn/*genetics/metabolism</keyword><keyword>Sequence Alignment</keyword></keywords><dates><year>2002</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0968-0004 (Print)&#xD;0968-0004 (Linking)</isbn><accession-num>12114016</accession-num><urls><related-urls><url>. Expression of BRICHOS in the brain prevents toxicity in Drosophila Aβ models PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZXJtYW5zc29uPC9BdXRob3I+PFllYXI+MjAxNDwvWWVh

cj48UmVjTnVtPjI0Nzk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2Ny

aXB0Ij45NDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI0Nzk8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDkzOTIzMiI+MjQ3OTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SGVybWFuc3NvbiwgRS48L2F1dGhv

cj48YXV0aG9yPlNjaHVsdHosIFMuPC9hdXRob3I+PGF1dGhvcj5Dcm93dGhlciwgRC48L2F1dGhv

cj48YXV0aG9yPkxpbnNlLCBTLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48

YXV0aG9yPldlc3Rlcm1hcmssIEcuPC9hdXRob3I+PGF1dGhvcj5Kb2hhbnNzb24sIEouPC9hdXRo

b3I+PGF1dGhvcj5QcmVzdG8sIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxh

dXRoLWFkZHJlc3M+S0kgQWx6aGVpbWVyIERpc2Vhc2UgUmVzZWFyY2ggQ2VudHJlLCBOVlMgRGVw

YXJ0bWVudCwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBOb3Z1bSwgNXRoIEZsb29yLCAxNDEgODYg

U3RvY2tob2xtLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIEJpb2NoZW1pc3RyeSwgSW5zdGl0

dXRlIGZvciBDYW5jZXIgUmVzZWFyY2gsIE9zbG8gVW5pdmVyc2l0eSBIb3NwaXRhbCAtIFRoZSBO

b3J3ZWdpYW4gUmFkaXVtIEhvc3BpdGFsLCAwMzc5IE9zbG8sIE5vcndheS4mI3hEO0RlcGFydG1l

bnQgb2YgR2VuZXRpY3MsIFVuaXZlcnNpdHkgb2YgQ2FtYnJpZGdlLCBEb3duaW5nIFN0cmVldCwg

Q2FtYnJpZGdlLCBDQjIgM0VILCBVSy4mI3hEO0RlcGFydG1lbnQgb2YgQmlvY2hlbWlzdHJ5IGFu

ZCBTdHJ1Y3R1cmFsIEJpb2xvZ3ksIEx1bmQgVW5pdmVyc2l0eSwgUE8gQm94IDEyNCwgMjIxIDAw

IEx1bmQsIFN3ZWRlbi4mI3hEO0RlcGFydG1lbnQgb2YgTWVkaWNhbCBDZWxsIEJpb2xvZ3ksIFVw

cHNhbGEgVW5pdmVyc2l0eSwgNzUxIDIzIFVwcHNhbGEsIFN3ZWRlbi4mI3hEO0tJIEFsemhlaW1l

ciBEaXNlYXNlIFJlc2VhcmNoIENlbnRyZSwgTlZTIERlcGFydG1lbnQsIEthcm9saW5za2EgSW5z

dGl0dXRldCwgTm92dW0sIDV0aCBGbG9vciwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuLiBEZXBh

cnRtZW50IG9mIEFuYXRvbXksIFBoeXNpb2xvZ3kgYW5kIEJpb2NoZW1pc3RyeSwgU3dlZGlzaCBV

bml2ZXJzaXR5IG9mIEFncmljdWx0dXJhbCBTY2llbmNlcywgVGhlIEJpb21lZGljYWwgQ2VudHJl

LCA3NTEgMjMgVXBwc2FsYSwgU3dlZGVuLiBJbnN0aXR1dGUgb2YgTWF0aGVtYXRpY3MgYW5kIE5h

dHVyYWwgU2NpZW5jZXMsIFRhbGxpbm4gVW5pdmVyc2l0eSwgTmFydmEgbW50IDI1LCAxMDEgMjAg

VGFsbGlubiwgRXN0b25pYS4gamFubmUuam9oYW5zc29uQGtpLnNlIGplbm55LnByZXN0b0BraS5z

ZS4mI3hEO0tJIEFsemhlaW1lciBEaXNlYXNlIFJlc2VhcmNoIENlbnRyZSwgTlZTIERlcGFydG1l

bnQsIEthcm9saW5za2EgSW5zdGl0dXRldCwgTm92dW0sIDV0aCBGbG9vciwgMTQxIDg2IFN0b2Nr

aG9sbSwgU3dlZGVuLiBqYW5uZS5qb2hhbnNzb25Aa2kuc2UgamVubnkucHJlc3RvQGtpLnNlLjwv

YXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSBjaGFwZXJvbmUgZG9tYWluIEJSSUNIT1Mg

cHJldmVudHMgQ05TIHRveGljaXR5IG9mIGFteWxvaWQtYmV0YSBwZXB0aWRlIGluIERyb3NvcGhp

bGEgbWVsYW5vZ2FzdGVyPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkRpcyBNb2RlbCBNZWNoPC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjY1OS02NTwvcGFnZXM+PHZvbHVtZT43PC92

b2x1bWU+PG51bWJlcj42PC9udW1iZXI+PGVkaXRpb24+MjAxNC8wNC8wMTwvZWRpdGlvbj48a2V5

d29yZHM+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL21ldGFib2xpc20vKnRveGljaXR5

PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFscywgR2Vu

ZXRpY2FsbHkgTW9kaWZpZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5DZW50cmFsIE5lcnZvdXMgU3lzdGVtLypkcnVnIGVmZmVjdHM8L2tleXdv

cmQ+PGtleXdvcmQ+RHJvc29waGlsYSBtZWxhbm9nYXN0ZXIvKm1ldGFib2xpc20vcGh5c2lvbG9n

eTwva2V5d29yZD48a2V5d29yZD5Nb2xlY3VsYXIgQ2hhcGVyb25lcy8qbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5Nb3RvciBBY3Rpdml0eTwva2V5d29yZD48a2V5d29yZD5QZXB0aWRlIEZy

YWdtZW50cy9tZXRhYm9saXNtLyp0b3hpY2l0eTwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIm

YXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZDwva2V5d29yZD48a2V5d29y

ZD5DaGFwZXJvbmU8L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVpbiBtaXNmb2xkaW5nPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdW48

L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNzU0LTg0MTEgKEVsZWN0cm9uaWMpJiN4

RDsxNzU0LTg0MDMgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI0NjgyNzgzPC9hY2Nl

c3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5u

aWguZ292L3B1Ym1lZC8yNDY4Mjc4MzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9t

Mj5QTUM0MDM2NDczPC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMjQyL2Rt

bS4wMTQ3ODc8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5v

dGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZXJtYW5zc29uPC9BdXRob3I+PFllYXI+MjAxNDwvWWVh

cj48UmVjTnVtPjI0Nzk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2Ny

aXB0Ij45NDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI0Nzk8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDkzOTIzMiI+MjQ3OTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SGVybWFuc3NvbiwgRS48L2F1dGhv

cj48YXV0aG9yPlNjaHVsdHosIFMuPC9hdXRob3I+PGF1dGhvcj5Dcm93dGhlciwgRC48L2F1dGhv

cj48YXV0aG9yPkxpbnNlLCBTLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48

YXV0aG9yPldlc3Rlcm1hcmssIEcuPC9hdXRob3I+PGF1dGhvcj5Kb2hhbnNzb24sIEouPC9hdXRo

b3I+PGF1dGhvcj5QcmVzdG8sIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxh

dXRoLWFkZHJlc3M+S0kgQWx6aGVpbWVyIERpc2Vhc2UgUmVzZWFyY2ggQ2VudHJlLCBOVlMgRGVw

YXJ0bWVudCwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBOb3Z1bSwgNXRoIEZsb29yLCAxNDEgODYg

U3RvY2tob2xtLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIEJpb2NoZW1pc3RyeSwgSW5zdGl0

dXRlIGZvciBDYW5jZXIgUmVzZWFyY2gsIE9zbG8gVW5pdmVyc2l0eSBIb3NwaXRhbCAtIFRoZSBO

b3J3ZWdpYW4gUmFkaXVtIEhvc3BpdGFsLCAwMzc5IE9zbG8sIE5vcndheS4mI3hEO0RlcGFydG1l

bnQgb2YgR2VuZXRpY3MsIFVuaXZlcnNpdHkgb2YgQ2FtYnJpZGdlLCBEb3duaW5nIFN0cmVldCwg

Q2FtYnJpZGdlLCBDQjIgM0VILCBVSy4mI3hEO0RlcGFydG1lbnQgb2YgQmlvY2hlbWlzdHJ5IGFu

ZCBTdHJ1Y3R1cmFsIEJpb2xvZ3ksIEx1bmQgVW5pdmVyc2l0eSwgUE8gQm94IDEyNCwgMjIxIDAw

IEx1bmQsIFN3ZWRlbi4mI3hEO0RlcGFydG1lbnQgb2YgTWVkaWNhbCBDZWxsIEJpb2xvZ3ksIFVw

cHNhbGEgVW5pdmVyc2l0eSwgNzUxIDIzIFVwcHNhbGEsIFN3ZWRlbi4mI3hEO0tJIEFsemhlaW1l

ciBEaXNlYXNlIFJlc2VhcmNoIENlbnRyZSwgTlZTIERlcGFydG1lbnQsIEthcm9saW5za2EgSW5z

dGl0dXRldCwgTm92dW0sIDV0aCBGbG9vciwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuLiBEZXBh

cnRtZW50IG9mIEFuYXRvbXksIFBoeXNpb2xvZ3kgYW5kIEJpb2NoZW1pc3RyeSwgU3dlZGlzaCBV

bml2ZXJzaXR5IG9mIEFncmljdWx0dXJhbCBTY2llbmNlcywgVGhlIEJpb21lZGljYWwgQ2VudHJl

LCA3NTEgMjMgVXBwc2FsYSwgU3dlZGVuLiBJbnN0aXR1dGUgb2YgTWF0aGVtYXRpY3MgYW5kIE5h

dHVyYWwgU2NpZW5jZXMsIFRhbGxpbm4gVW5pdmVyc2l0eSwgTmFydmEgbW50IDI1LCAxMDEgMjAg

VGFsbGlubiwgRXN0b25pYS4gamFubmUuam9oYW5zc29uQGtpLnNlIGplbm55LnByZXN0b0BraS5z

ZS4mI3hEO0tJIEFsemhlaW1lciBEaXNlYXNlIFJlc2VhcmNoIENlbnRyZSwgTlZTIERlcGFydG1l

bnQsIEthcm9saW5za2EgSW5zdGl0dXRldCwgTm92dW0sIDV0aCBGbG9vciwgMTQxIDg2IFN0b2Nr

aG9sbSwgU3dlZGVuLiBqYW5uZS5qb2hhbnNzb25Aa2kuc2UgamVubnkucHJlc3RvQGtpLnNlLjwv

YXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSBjaGFwZXJvbmUgZG9tYWluIEJSSUNIT1Mg

cHJldmVudHMgQ05TIHRveGljaXR5IG9mIGFteWxvaWQtYmV0YSBwZXB0aWRlIGluIERyb3NvcGhp

bGEgbWVsYW5vZ2FzdGVyPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkRpcyBNb2RlbCBNZWNoPC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjY1OS02NTwvcGFnZXM+PHZvbHVtZT43PC92

b2x1bWU+PG51bWJlcj42PC9udW1iZXI+PGVkaXRpb24+MjAxNC8wNC8wMTwvZWRpdGlvbj48a2V5

d29yZHM+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL21ldGFib2xpc20vKnRveGljaXR5

PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFscywgR2Vu

ZXRpY2FsbHkgTW9kaWZpZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5DZW50cmFsIE5lcnZvdXMgU3lzdGVtLypkcnVnIGVmZmVjdHM8L2tleXdv

cmQ+PGtleXdvcmQ+RHJvc29waGlsYSBtZWxhbm9nYXN0ZXIvKm1ldGFib2xpc20vcGh5c2lvbG9n

eTwva2V5d29yZD48a2V5d29yZD5Nb2xlY3VsYXIgQ2hhcGVyb25lcy8qbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5Nb3RvciBBY3Rpdml0eTwva2V5d29yZD48a2V5d29yZD5QZXB0aWRlIEZy

YWdtZW50cy9tZXRhYm9saXNtLyp0b3hpY2l0eTwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIm

YXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZDwva2V5d29yZD48a2V5d29y

ZD5DaGFwZXJvbmU8L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVpbiBtaXNmb2xkaW5nPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdW48

L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNzU0LTg0MTEgKEVsZWN0cm9uaWMpJiN4

RDsxNzU0LTg0MDMgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI0NjgyNzgzPC9hY2Nl

c3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5u

aWguZ292L3B1Ym1lZC8yNDY4Mjc4MzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9t

Mj5QTUM0MDM2NDczPC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMjQyL2Rt

bS4wMTQ3ODc8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5v

dGU+

ADDIN EN.CITE.DATA 94 and in APP mice PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaW08L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO

dW0+MjQ4MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjk1

PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjQ4MDwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhw

Znd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0OTM5NDc4Ij4yNDgwPC9rZXk+PC9mb3Jl

aWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxj

b250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LaW0sIEouPC9hdXRob3I+PGF1dGhvcj5DaGFr

cmFiYXJ0eSwgUC48L2F1dGhvcj48YXV0aG9yPkhhbm5hLCBBLjwvYXV0aG9yPjxhdXRob3I+TWFy

Y2gsIEEuPC9hdXRob3I+PGF1dGhvcj5EaWNrc29uLCBELiBXLjwvYXV0aG9yPjxhdXRob3I+Qm9y

Y2hlbHQsIEQuIFIuPC9hdXRob3I+PGF1dGhvcj5Hb2xkZSwgVC48L2F1dGhvcj48YXV0aG9yPkph

bnVzLCBDLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRl

cGFydG1lbnQgb2YgTmV1cm9zY2llbmNlIGFuZCBDZW50ZXIgZm9yIFRyYW5zbGF0aW9uYWwgUmVz

ZWFyY2ggaW4gTmV1cm9kZWdlbmVyYXRpdmUgRGlzZWFzZSwgVW5pdmVyc2l0eSBvZiBGbG9yaWRh

LCAxMjc1IENlbnRlciBEcml2ZSwgR2FpbmVzdmlsbGUsIEZMIDMyNjEwLCBVU0EuPC9hdXRoLWFk

ZHJlc3M+PHRpdGxlcz48dGl0bGU+Tm9ybWFsIGNvZ25pdGlvbiBpbiB0cmFuc2dlbmljIEJSSTIt

QWJldGEgbWljZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Nb2wgTmV1cm9kZWdlbmVyPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TW9sIE5ldXJvZGVn

ZW5lcjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjE1PC9wYWdlcz48dm9sdW1lPjg8

L3ZvbHVtZT48ZWRpdGlvbj4yMDEzLzA1LzE1PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5B

bHpoZWltZXIgRGlzZWFzZS9tZXRhYm9saXNtLypwYXRob2xvZ3kvcHN5Y2hvbG9neTwva2V5d29y

ZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CbG90dGluZywgV2VzdGVybjwva2V5d29y

ZD48a2V5d29yZD5CcmFpbi8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPipDb2duaXRpb248

L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFuaW1hbDwva2V5d29yZD48a2V5d29y

ZD5Fbnp5bWUtTGlua2VkIEltbXVub3NvcmJlbnQgQXNzYXk8L2tleXdvcmQ+PGtleXdvcmQ+RmVt

YWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9oaXN0

b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbWJy

YW5lIFByb3RlaW5zL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48

a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgVHJhbnNn

ZW5pYzwva2V5d29yZD48a2V5d29yZD5QZXB0aWRlIEZyYWdtZW50cy8qbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5SZWNvbWJpbmFudCBGdXNpb24gUHJvdGVpbnMvbWV0YWJvbGlzbTwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

TWF5IDEyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTc1MC0xMzI2IChFbGVjdHJv

bmljKSYjeEQ7MTc1MC0xMzI2IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzY2MzMy

MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNi

aS5ubG0ubmloLmdvdi9wdWJtZWQvMjM2NjMzMjA8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGN1c3RvbTI+UE1DMzY1ODk0NDwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu

MTE4Ni8xNzUwLTEzMjYtOC0xNTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9D

aXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaW08L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO

dW0+MjQ4MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjk1

PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjQ4MDwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhw

Znd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0OTM5NDc4Ij4yNDgwPC9rZXk+PC9mb3Jl

aWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxj

b250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LaW0sIEouPC9hdXRob3I+PGF1dGhvcj5DaGFr

cmFiYXJ0eSwgUC48L2F1dGhvcj48YXV0aG9yPkhhbm5hLCBBLjwvYXV0aG9yPjxhdXRob3I+TWFy

Y2gsIEEuPC9hdXRob3I+PGF1dGhvcj5EaWNrc29uLCBELiBXLjwvYXV0aG9yPjxhdXRob3I+Qm9y

Y2hlbHQsIEQuIFIuPC9hdXRob3I+PGF1dGhvcj5Hb2xkZSwgVC48L2F1dGhvcj48YXV0aG9yPkph

bnVzLCBDLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRl

cGFydG1lbnQgb2YgTmV1cm9zY2llbmNlIGFuZCBDZW50ZXIgZm9yIFRyYW5zbGF0aW9uYWwgUmVz

ZWFyY2ggaW4gTmV1cm9kZWdlbmVyYXRpdmUgRGlzZWFzZSwgVW5pdmVyc2l0eSBvZiBGbG9yaWRh

LCAxMjc1IENlbnRlciBEcml2ZSwgR2FpbmVzdmlsbGUsIEZMIDMyNjEwLCBVU0EuPC9hdXRoLWFk

ZHJlc3M+PHRpdGxlcz48dGl0bGU+Tm9ybWFsIGNvZ25pdGlvbiBpbiB0cmFuc2dlbmljIEJSSTIt

QWJldGEgbWljZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Nb2wgTmV1cm9kZWdlbmVyPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TW9sIE5ldXJvZGVn

ZW5lcjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjE1PC9wYWdlcz48dm9sdW1lPjg8

L3ZvbHVtZT48ZWRpdGlvbj4yMDEzLzA1LzE1PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5B

bHpoZWltZXIgRGlzZWFzZS9tZXRhYm9saXNtLypwYXRob2xvZ3kvcHN5Y2hvbG9neTwva2V5d29y

ZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CbG90dGluZywgV2VzdGVybjwva2V5d29y

ZD48a2V5d29yZD5CcmFpbi8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPipDb2duaXRpb248

L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFuaW1hbDwva2V5d29yZD48a2V5d29y

ZD5Fbnp5bWUtTGlua2VkIEltbXVub3NvcmJlbnQgQXNzYXk8L2tleXdvcmQ+PGtleXdvcmQ+RmVt

YWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9oaXN0

b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbWJy

YW5lIFByb3RlaW5zL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48

a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgVHJhbnNn

ZW5pYzwva2V5d29yZD48a2V5d29yZD5QZXB0aWRlIEZyYWdtZW50cy8qbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5SZWNvbWJpbmFudCBGdXNpb24gUHJvdGVpbnMvbWV0YWJvbGlzbTwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

TWF5IDEyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTc1MC0xMzI2IChFbGVjdHJv

bmljKSYjeEQ7MTc1MC0xMzI2IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzY2MzMy

MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNi

aS5ubG0ubmloLmdvdi9wdWJtZWQvMjM2NjMzMjA8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGN1c3RvbTI+UE1DMzY1ODk0NDwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu

MTE4Ni8xNzUwLTEzMjYtOC0xNTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9D

aXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 95. In prematurely born children with a collapse of the lungs, BRICHOS is used as lung surfactant and applied in form of aerosol PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxsYW5kZXI8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFy

PjxSZWNOdW0+MjQxMzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjk2LDk3PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjQxMzwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0OTMxMjY2Ij4yNDEzPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XaWxsYW5kZXIsIEguPC9hdXRo

b3I+PGF1dGhvcj5Bc2thcmllaCwgRy48L2F1dGhvcj48YXV0aG9yPkxhbmRyZWgsIE0uPC9hdXRo

b3I+PGF1dGhvcj5XZXN0ZXJtYXJrLCBQLjwvYXV0aG9yPjxhdXRob3I+Tm9yZGxpbmcsIEsuPC9h

dXRob3I+PGF1dGhvcj5LZXJhbmVuLCBILjwvYXV0aG9yPjxhdXRob3I+SGVybWFuc3NvbiwgRS48

L2F1dGhvcj48YXV0aG9yPkhhbXZhcywgQS48L2F1dGhvcj48YXV0aG9yPk5vZ2VlLCBMLiBNLjwv

YXV0aG9yPjxhdXRob3I+QmVyZ21hbiwgVC48L2F1dGhvcj48YXV0aG9yPlNhZW56LCBBLjwvYXV0

aG9yPjxhdXRob3I+Q2FzYWxzLCBDLjwvYXV0aG9yPjxhdXRob3I+QXF2aXN0ZywgSi48L2F1dGhv

cj48YXV0aG9yPkpvcm52YWxsLCBILjwvYXV0aG9yPjxhdXRob3I+QmVyZ2x1bmQsIEguPC9hdXRo

b3I+PGF1dGhvcj5QcmVzdG8sIEouPC9hdXRob3I+PGF1dGhvcj5LbmlnaHQsIFMuIEQuPC9hdXRo

b3I+PGF1dGhvcj5Kb2hhbnNzb24sIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

PjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBBbmF0b215LCBQaHlzaW9sb2d5LCBhbmQgQmlv

Y2hlbWlzdHJ5LCBTd2VkaXNoIFVuaXZlcnNpdHkgb2YgQWdyaWN1bHR1cmFsIFNjaWVuY2VzLCBT

LTc1MSAyNCBVcHBzYWxhLCBTd2VkZW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+SGln

aC1yZXNvbHV0aW9uIHN0cnVjdHVyZSBvZiBhIEJSSUNIT1MgZG9tYWluIGFuZCBpdHMgaW1wbGlj

YXRpb25zIGZvciBhbnRpLWFteWxvaWQgY2hhcGVyb25lIGFjdGl2aXR5IG9uIGx1bmcgc3VyZmFj

dGFudCBwcm90ZWluIEM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2Np

IFUgUyBBPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+

UHJvYyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+

MjMyNS05PC9wYWdlcz48dm9sdW1lPjEwOTwvdm9sdW1lPjxudW1iZXI+NzwvbnVtYmVyPjxlZGl0

aW9uPjIwMTIvMDIvMDc8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFtaW5vIEFjaWQgU2Vx

dWVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZC8qYW50YWdvbmlzdHMgJmFtcDsgaW5oaWJp

dG9yczwva2V5d29yZD48a2V5d29yZD5DcnlzdGFsbG9ncmFwaHksIFgtUmF5PC9rZXl3b3JkPjxr

ZXl3b3JkPkx1bmcvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TW9kZWxzLCBNb2xlY3Vs

YXI8L2tleXdvcmQ+PGtleXdvcmQ+TW9sZWN1bGFyIENoYXBlcm9uZXMvY2hlbWlzdHJ5LyptZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1vbGVjdWxhciBTZXF1ZW5jZSBEYXRhPC9rZXl3b3Jk

PjxrZXl3b3JkPlByb3RlaW4gQ29uZm9ybWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlB1bG1vbmFy

eSBTdXJmYWN0YW50LUFzc29jaWF0ZWQgUHJvdGVpbiBDL2NoZW1pc3RyeS8qbWV0YWJvbGlzbTwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEyPC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+RmViIDE0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA5MS02NDkwIChFbGVj

dHJvbmljKSYjeEQ7MDAyNy04NDI0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMjMw

ODM3NTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjIzMDgzNzU8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGN1c3RvbTI+UE1DMzI4OTMxNDwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

MTAuMTA3My9wbmFzLjExMTQ3NDAxMDk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3Jk

PjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPldhbHRoZXI8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS

ZWNOdW0+MjQyNzwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MjQyNzwvcmVjLW51bWJlcj48

Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4

OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0OTMyMzY1Ij4yNDI3PC9rZXk+PC9mb3JlaWdu

LWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250

cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XYWx0aGVyLCBGLiBKLjwvYXV0aG9yPjxhdXRob3I+

SGVybmFuZGV6LUp1dmllbCwgSi4gTS48L2F1dGhvcj48YXV0aG9yPldhcmluZywgQS4gSi48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9m

IFBlZGlhdHJpY3MsIERpdmlzaW9uIG9mIE1lZGljYWwgR2VuZXRpY3MsIExvcyBBbmdlbGVzIEJp

b21lZGljYWwgUmVzZWFyY2ggSW5zdGl0dXRlLCBIYXJib3ItVUNMQSBNZWRpY2FsIENlbnRlciAs

IFRvcnJhbmNlLCBDQSAsIFVTQSA7IERlcGFydG1lbnQgb2YgUGVkaWF0cmljcywgRGF2aWQgR2Vm

ZmVuIFNjaG9vbCBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBDYWxpZm9ybmlhLCBMQSAsIFVT

QS4mI3hEO0RlcGFydG1lbnQgb2YgUGVkaWF0cmljcywgRGl2aXNpb24gb2YgTWVkaWNhbCBHZW5l

dGljcywgTG9zIEFuZ2VsZXMgQmlvbWVkaWNhbCBSZXNlYXJjaCBJbnN0aXR1dGUsIEhhcmJvci1V

Q0xBIE1lZGljYWwgQ2VudGVyICwgVG9ycmFuY2UsIENBICwgVVNBLiYjeEQ7RGVwYXJ0bWVudCBv

ZiBQZWRpYXRyaWNzLCBEYXZpZCBHZWZmZW4gU2Nob29sIG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5

IG9mIENhbGlmb3JuaWEsIExBICwgVVNBIDsgRGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgRGl2aXNp

b24gb2YgTW9sZWN1bGFyIE1lZGljaW5lLCBMb3MgQW5nZWxlcyBCaW9tZWRpY2FsIFJlc2VhcmNo

IEluc3RpdHV0ZSwgSGFyYm9yLVVDTEEgTWVkaWNhbCBDZW50ZXIsIEhhcmJvci1VQ0xBIE1lZGlj

YWwgQ2VudGVyICwgVG9ycmFuY2UsIENBICwgVVNBIDsgRGVwYXJ0bWVudCBvZiBNZWRpY2luZSwg

RGF2aWQgR2VmZmVuIFNjaG9vbCBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBDYWxpZm9ybmlh

LCBMQSAsIFVTQSA7IERlcGFydG1lbnQgb2YgUGh5c2lvbG9neSAmYW1wOyBCaW9waHlzaWNzLCBT

Y2hvb2wgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQ2FsaWZvcm5pYSAsIElydmluZSwgQ0Eg

LCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QWVyb3NvbCBkZWxpdmVyeSBvZiBz

eW50aGV0aWMgbHVuZyBzdXJmYWN0YW50PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlBlZXJKPC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPmU0MDM8L3BhZ2VzPjx2b2x1bWU+Mjwvdm9s

dW1lPjxlZGl0aW9uPjIwMTQvMDYvMTI8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFlcm9z

b2wgZGVsaXZlcnk8L2tleXdvcmQ+PGtleXdvcmQ+Q2FwdGl2ZSBidWJibGUgc3VyZmFjdG9tZXRy

eTwva2V5d29yZD48a2V5d29yZD5MdW5nIGZ1bmN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk1lY2hh

bmljYWwgdmVudGlsYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+TmFzYWwgY29udGludW91cyBwb3Np

dGl2ZSBhaXJ3YXkgcHJlc3N1cmU8L2tleXdvcmQ+PGtleXdvcmQ+U3VyZmFjdGFudCBwcm90ZWlu

IEI8L2tleXdvcmQ+PGtleXdvcmQ+U3VyZmFjdGFudCBwcm90ZWluIEM8L2tleXdvcmQ+PGtleXdv

cmQ+U3VyZmFjdGFudC1kZWZpY2llbnQgcmFiYml0czwva2V5d29yZD48a2V5d29yZD5TeW50aGV0

aWMgbHVuZyBzdXJmYWN0YW50PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8

L3llYXI+PC9kYXRlcz48aXNibj4yMTY3LTgzNTkgKFByaW50KSYjeEQ7MjE2Ny04MzU5IChMaW5r

aW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNDkxODAzMDwvYWNjZXNzaW9uLW51bT48dXJscz48

cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjQ5

MTgwMzA8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNDA0NTMzMjwvY3Vz

dG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuNzcxNy9wZWVyai40MDM8L2VsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxsYW5kZXI8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFy

PjxSZWNOdW0+MjQxMzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjk2LDk3PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjQxMzwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0OTMxMjY2Ij4yNDEzPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XaWxsYW5kZXIsIEguPC9hdXRo

b3I+PGF1dGhvcj5Bc2thcmllaCwgRy48L2F1dGhvcj48YXV0aG9yPkxhbmRyZWgsIE0uPC9hdXRo

b3I+PGF1dGhvcj5XZXN0ZXJtYXJrLCBQLjwvYXV0aG9yPjxhdXRob3I+Tm9yZGxpbmcsIEsuPC9h

dXRob3I+PGF1dGhvcj5LZXJhbmVuLCBILjwvYXV0aG9yPjxhdXRob3I+SGVybWFuc3NvbiwgRS48

L2F1dGhvcj48YXV0aG9yPkhhbXZhcywgQS48L2F1dGhvcj48YXV0aG9yPk5vZ2VlLCBMLiBNLjwv

YXV0aG9yPjxhdXRob3I+QmVyZ21hbiwgVC48L2F1dGhvcj48YXV0aG9yPlNhZW56LCBBLjwvYXV0

aG9yPjxhdXRob3I+Q2FzYWxzLCBDLjwvYXV0aG9yPjxhdXRob3I+QXF2aXN0ZywgSi48L2F1dGhv

cj48YXV0aG9yPkpvcm52YWxsLCBILjwvYXV0aG9yPjxhdXRob3I+QmVyZ2x1bmQsIEguPC9hdXRo

b3I+PGF1dGhvcj5QcmVzdG8sIEouPC9hdXRob3I+PGF1dGhvcj5LbmlnaHQsIFMuIEQuPC9hdXRo

b3I+PGF1dGhvcj5Kb2hhbnNzb24sIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

PjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBBbmF0b215LCBQaHlzaW9sb2d5LCBhbmQgQmlv

Y2hlbWlzdHJ5LCBTd2VkaXNoIFVuaXZlcnNpdHkgb2YgQWdyaWN1bHR1cmFsIFNjaWVuY2VzLCBT

LTc1MSAyNCBVcHBzYWxhLCBTd2VkZW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+SGln

aC1yZXNvbHV0aW9uIHN0cnVjdHVyZSBvZiBhIEJSSUNIT1MgZG9tYWluIGFuZCBpdHMgaW1wbGlj

YXRpb25zIGZvciBhbnRpLWFteWxvaWQgY2hhcGVyb25lIGFjdGl2aXR5IG9uIGx1bmcgc3VyZmFj

dGFudCBwcm90ZWluIEM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2Np

IFUgUyBBPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+

UHJvYyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+

MjMyNS05PC9wYWdlcz48dm9sdW1lPjEwOTwvdm9sdW1lPjxudW1iZXI+NzwvbnVtYmVyPjxlZGl0

aW9uPjIwMTIvMDIvMDc8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFtaW5vIEFjaWQgU2Vx

dWVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZC8qYW50YWdvbmlzdHMgJmFtcDsgaW5oaWJp

dG9yczwva2V5d29yZD48a2V5d29yZD5DcnlzdGFsbG9ncmFwaHksIFgtUmF5PC9rZXl3b3JkPjxr

ZXl3b3JkPkx1bmcvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TW9kZWxzLCBNb2xlY3Vs

YXI8L2tleXdvcmQ+PGtleXdvcmQ+TW9sZWN1bGFyIENoYXBlcm9uZXMvY2hlbWlzdHJ5LyptZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1vbGVjdWxhciBTZXF1ZW5jZSBEYXRhPC9rZXl3b3Jk

PjxrZXl3b3JkPlByb3RlaW4gQ29uZm9ybWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlB1bG1vbmFy

eSBTdXJmYWN0YW50LUFzc29jaWF0ZWQgUHJvdGVpbiBDL2NoZW1pc3RyeS8qbWV0YWJvbGlzbTwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEyPC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+RmViIDE0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA5MS02NDkwIChFbGVj

dHJvbmljKSYjeEQ7MDAyNy04NDI0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMjMw

ODM3NTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjIzMDgzNzU8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGN1c3RvbTI+UE1DMzI4OTMxNDwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

MTAuMTA3My9wbmFzLjExMTQ3NDAxMDk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3Jk

PjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPldhbHRoZXI8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS

ZWNOdW0+MjQyNzwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MjQyNzwvcmVjLW51bWJlcj48

Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4

OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0OTMyMzY1Ij4yNDI3PC9rZXk+PC9mb3JlaWdu

LWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250

cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XYWx0aGVyLCBGLiBKLjwvYXV0aG9yPjxhdXRob3I+

SGVybmFuZGV6LUp1dmllbCwgSi4gTS48L2F1dGhvcj48YXV0aG9yPldhcmluZywgQS4gSi48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9m

IFBlZGlhdHJpY3MsIERpdmlzaW9uIG9mIE1lZGljYWwgR2VuZXRpY3MsIExvcyBBbmdlbGVzIEJp

b21lZGljYWwgUmVzZWFyY2ggSW5zdGl0dXRlLCBIYXJib3ItVUNMQSBNZWRpY2FsIENlbnRlciAs

IFRvcnJhbmNlLCBDQSAsIFVTQSA7IERlcGFydG1lbnQgb2YgUGVkaWF0cmljcywgRGF2aWQgR2Vm

ZmVuIFNjaG9vbCBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBDYWxpZm9ybmlhLCBMQSAsIFVT

QS4mI3hEO0RlcGFydG1lbnQgb2YgUGVkaWF0cmljcywgRGl2aXNpb24gb2YgTWVkaWNhbCBHZW5l

dGljcywgTG9zIEFuZ2VsZXMgQmlvbWVkaWNhbCBSZXNlYXJjaCBJbnN0aXR1dGUsIEhhcmJvci1V

Q0xBIE1lZGljYWwgQ2VudGVyICwgVG9ycmFuY2UsIENBICwgVVNBLiYjeEQ7RGVwYXJ0bWVudCBv

ZiBQZWRpYXRyaWNzLCBEYXZpZCBHZWZmZW4gU2Nob29sIG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5

IG9mIENhbGlmb3JuaWEsIExBICwgVVNBIDsgRGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgRGl2aXNp

b24gb2YgTW9sZWN1bGFyIE1lZGljaW5lLCBMb3MgQW5nZWxlcyBCaW9tZWRpY2FsIFJlc2VhcmNo

IEluc3RpdHV0ZSwgSGFyYm9yLVVDTEEgTWVkaWNhbCBDZW50ZXIsIEhhcmJvci1VQ0xBIE1lZGlj

YWwgQ2VudGVyICwgVG9ycmFuY2UsIENBICwgVVNBIDsgRGVwYXJ0bWVudCBvZiBNZWRpY2luZSwg

RGF2aWQgR2VmZmVuIFNjaG9vbCBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBDYWxpZm9ybmlh

LCBMQSAsIFVTQSA7IERlcGFydG1lbnQgb2YgUGh5c2lvbG9neSAmYW1wOyBCaW9waHlzaWNzLCBT

Y2hvb2wgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQ2FsaWZvcm5pYSAsIElydmluZSwgQ0Eg

LCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QWVyb3NvbCBkZWxpdmVyeSBvZiBz

eW50aGV0aWMgbHVuZyBzdXJmYWN0YW50PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlBlZXJKPC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPmU0MDM8L3BhZ2VzPjx2b2x1bWU+Mjwvdm9s

dW1lPjxlZGl0aW9uPjIwMTQvMDYvMTI8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFlcm9z

b2wgZGVsaXZlcnk8L2tleXdvcmQ+PGtleXdvcmQ+Q2FwdGl2ZSBidWJibGUgc3VyZmFjdG9tZXRy

eTwva2V5d29yZD48a2V5d29yZD5MdW5nIGZ1bmN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk1lY2hh

bmljYWwgdmVudGlsYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+TmFzYWwgY29udGludW91cyBwb3Np

dGl2ZSBhaXJ3YXkgcHJlc3N1cmU8L2tleXdvcmQ+PGtleXdvcmQ+U3VyZmFjdGFudCBwcm90ZWlu

IEI8L2tleXdvcmQ+PGtleXdvcmQ+U3VyZmFjdGFudCBwcm90ZWluIEM8L2tleXdvcmQ+PGtleXdv

cmQ+U3VyZmFjdGFudC1kZWZpY2llbnQgcmFiYml0czwva2V5d29yZD48a2V5d29yZD5TeW50aGV0

aWMgbHVuZyBzdXJmYWN0YW50PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8

L3llYXI+PC9kYXRlcz48aXNibj4yMTY3LTgzNTkgKFByaW50KSYjeEQ7MjE2Ny04MzU5IChMaW5r

aW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNDkxODAzMDwvYWNjZXNzaW9uLW51bT48dXJscz48

cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjQ5

MTgwMzA8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNDA0NTMzMjwvY3Vz

dG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuNzcxNy9wZWVyai40MDM8L2VsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 96,97. We have difficulties in preclinical models, as the peptides forming the chaperones do not cross the blood-brain barrier. A promising solution to solve this problem is the focused ultrasound therapy, which employs controlled high-frequency ultrasound pulses to shortly disrupt the BBB and allow passage of bigger molecules into the brain PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWluZW5nYTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+

PFJlY051bT4zMjE5PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+OTg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zMjE5PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU0NjA0MjYiPjMyMTk8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkxlaW5lbmdhLCBHLjwvYXV0aG9yPjxh

dXRob3I+R290eiwgSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk

cmVzcz5DbGVtIEpvbmVzIENlbnRyZSBmb3IgQWdlaW5nIERlbWVudGlhIFJlc2VhcmNoLCBRdWVl

bnNsYW5kIEJyYWluIEluc3RpdHV0ZSwgVGhlIFVuaXZlcnNpdHkgb2YgUXVlZW5zbGFuZCwgU3Qg

THVjaWEgQ2FtcHVzLCBCcmlzYmFuZSwgUXVlZW5zbGFuZCA0MDcyLCBBdXN0cmFsaWEuJiN4RDtD

bGVtIEpvbmVzIENlbnRyZSBmb3IgQWdlaW5nIERlbWVudGlhIFJlc2VhcmNoLCBRdWVlbnNsYW5k

IEJyYWluIEluc3RpdHV0ZSwgVGhlIFVuaXZlcnNpdHkgb2YgUXVlZW5zbGFuZCwgU3QgTHVjaWEg

Q2FtcHVzLCBCcmlzYmFuZSwgUXVlZW5zbGFuZCA0MDcyLCBBdXN0cmFsaWEuIGouZ29ldHpAdXEu

ZWR1LmF1LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlNjYW5uaW5nIHVsdHJhc291bmQg

cmVtb3ZlcyBhbXlsb2lkLWJldGEgYW5kIHJlc3RvcmVzIG1lbW9yeSBpbiBhbiBBbHpoZWltZXIm

YXBvcztzIGRpc2Vhc2UgbW91c2UgbW9kZWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+U2NpIFRy

YW5zbCBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRs

ZT5TY2kgVHJhbnNsIE1lZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjI3OHJhMzM8

L3BhZ2VzPjx2b2x1bWU+Nzwvdm9sdW1lPjxudW1iZXI+Mjc4PC9udW1iZXI+PGVkaXRpb24+MjAx

NS8wMy8xMzwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWxidW1pbnMvbWV0YWJvbGlzbTwv

a2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qZGlhZ25vc3RpYyBpbWFnaW5nL21l

dGFib2xpc20vKnRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVz

LyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+

Qmxvb2QtQnJhaW4gQmFycmllci9wYXRob2xvZ3kvcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPkNlbGwgQ291bnQ8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFuaW1h

bDwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW5mbGFtbWF0aW9u

L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5MeXNvc29tZXMvbWV0YWJvbGlzbTwva2V5d29y

ZD48a2V5d29yZD5NZW1vcnkvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgSW5i

cmVkIEM1N0JMPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIFRyYW5zZ2VuaWM8L2tleXdvcmQ+PGtl

eXdvcmQ+TWljcm9nbGlhL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UGhhZ29jeXRvc2lz

PC9rZXl3b3JkPjxrZXl3b3JkPlBsYXF1ZSwgQW15bG9pZC9kaWFnbm9zdGljIGltYWdpbmcvbWV0

YWJvbGlzbS9wYXRob2xvZ3kvcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPipVbHRy

YXNvbmljczwva2V5d29yZD48a2V5d29yZD5VbHRyYXNvbm9ncmFwaHk8L2tleXdvcmQ+PC9rZXl3

b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1hciAxMTwvZGF0

ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE5NDYtNjI0MiAoRWxlY3Ryb25pYykmI3hEOzE5

NDYtNjIzNCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjU3NjE4ODk8L2FjY2Vzc2lv

bi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5n

b3YvcHVibWVkLzI1NzYxODg5PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmlj

LXJlc291cmNlLW51bT4xMC4xMTI2L3NjaXRyYW5zbG1lZC5hYWEyNTEyPC9lbGVjdHJvbmljLXJl

c291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWluZW5nYTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+

PFJlY051bT4zMjE5PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+OTg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zMjE5PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU0NjA0MjYiPjMyMTk8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkxlaW5lbmdhLCBHLjwvYXV0aG9yPjxh

dXRob3I+R290eiwgSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk

cmVzcz5DbGVtIEpvbmVzIENlbnRyZSBmb3IgQWdlaW5nIERlbWVudGlhIFJlc2VhcmNoLCBRdWVl

bnNsYW5kIEJyYWluIEluc3RpdHV0ZSwgVGhlIFVuaXZlcnNpdHkgb2YgUXVlZW5zbGFuZCwgU3Qg

THVjaWEgQ2FtcHVzLCBCcmlzYmFuZSwgUXVlZW5zbGFuZCA0MDcyLCBBdXN0cmFsaWEuJiN4RDtD

bGVtIEpvbmVzIENlbnRyZSBmb3IgQWdlaW5nIERlbWVudGlhIFJlc2VhcmNoLCBRdWVlbnNsYW5k

IEJyYWluIEluc3RpdHV0ZSwgVGhlIFVuaXZlcnNpdHkgb2YgUXVlZW5zbGFuZCwgU3QgTHVjaWEg

Q2FtcHVzLCBCcmlzYmFuZSwgUXVlZW5zbGFuZCA0MDcyLCBBdXN0cmFsaWEuIGouZ29ldHpAdXEu

ZWR1LmF1LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlNjYW5uaW5nIHVsdHJhc291bmQg

cmVtb3ZlcyBhbXlsb2lkLWJldGEgYW5kIHJlc3RvcmVzIG1lbW9yeSBpbiBhbiBBbHpoZWltZXIm

YXBvcztzIGRpc2Vhc2UgbW91c2UgbW9kZWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+U2NpIFRy

YW5zbCBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRs

ZT5TY2kgVHJhbnNsIE1lZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjI3OHJhMzM8

L3BhZ2VzPjx2b2x1bWU+Nzwvdm9sdW1lPjxudW1iZXI+Mjc4PC9udW1iZXI+PGVkaXRpb24+MjAx

NS8wMy8xMzwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWxidW1pbnMvbWV0YWJvbGlzbTwv

a2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qZGlhZ25vc3RpYyBpbWFnaW5nL21l

dGFib2xpc20vKnRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVz

LyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+

Qmxvb2QtQnJhaW4gQmFycmllci9wYXRob2xvZ3kvcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPkNlbGwgQ291bnQ8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFuaW1h

bDwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW5mbGFtbWF0aW9u

L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5MeXNvc29tZXMvbWV0YWJvbGlzbTwva2V5d29y

ZD48a2V5d29yZD5NZW1vcnkvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgSW5i

cmVkIEM1N0JMPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIFRyYW5zZ2VuaWM8L2tleXdvcmQ+PGtl

eXdvcmQ+TWljcm9nbGlhL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UGhhZ29jeXRvc2lz

PC9rZXl3b3JkPjxrZXl3b3JkPlBsYXF1ZSwgQW15bG9pZC9kaWFnbm9zdGljIGltYWdpbmcvbWV0

YWJvbGlzbS9wYXRob2xvZ3kvcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPipVbHRy

YXNvbmljczwva2V5d29yZD48a2V5d29yZD5VbHRyYXNvbm9ncmFwaHk8L2tleXdvcmQ+PC9rZXl3

b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1hciAxMTwvZGF0

ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE5NDYtNjI0MiAoRWxlY3Ryb25pYykmI3hEOzE5

NDYtNjIzNCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjU3NjE4ODk8L2FjY2Vzc2lv

bi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5n

b3YvcHVibWVkLzI1NzYxODg5PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmlj

LXJlc291cmNlLW51bT4xMC4xMTI2L3NjaXRyYW5zbG1lZC5hYWEyNTEyPC9lbGVjdHJvbmljLXJl

c291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 98. Other approaches make use of native BBB transporters such as transferrin-1, which can actively pass molecules from the plasma into the brain PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmF5PC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj

TnVtPjMyMzI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij45

OSwxMDA8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zMjMyPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU0NjA4OTMiPjMyMzI8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJyYXksIE4uPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkJpb2xvZ2ljczogVHJhbnNmZXJyaW4m

YXBvczsgYmlzcGVjaWZpYyBhbnRpYm9kaWVzIGFjcm9zcyB0aGUgYmxvb2QtYnJhaW4gYmFycmll

cjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OYXQgUmV2IERydWcgRGlzY292PC9zZWNvbmRhcnkt

dGl0bGU+PC90aXRsZXM+PHBhZ2VzPjE0LTU8L3BhZ2VzPjx2b2x1bWU+MTQ8L3ZvbHVtZT48bnVt

YmVyPjE8L251bWJlcj48ZWRpdGlvbj4yMDE0LzEyLzE3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5

d29yZD5BbXlsb2lkIFByZWN1cnNvciBQcm90ZWluIFNlY3JldGFzZXMvKmltbXVub2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BbnRpYm9kaWVzLCBCaXNw

ZWNpZmljLypwaGFybWFjb2tpbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkFudGlnZW5zLCBDRC8q

aW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5Bc3BhcnRpYyBBY2lkIEVuZG9wZXB0aWRhc2Vz

LyppbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJsb29kLUJyYWluIEJhcnJpZXIvKm1ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+KkNhcGlsbGFyeSBQZXJtZWFiaWxpdHk8L2tleXdvcmQ+

PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPlJlY2VwdG9ycywgVHJhbnNmZXJyaW4v

KmltbXVub2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNTwveWVhcj48

cHViLWRhdGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0NzQt

MTc4NCAoRWxlY3Ryb25pYykmI3hEOzE0NzQtMTc3NiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lv

bi1udW0+MjU1MDMzMzU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0

dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI1NTAzMzM1PC91cmw+PC9yZWxhdGVk

LXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDM4L25yZDQ1MjI8L2Vs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkZyaWRl

bjwvQXV0aG9yPjxZZWFyPjE5OTE8L1llYXI+PFJlY051bT4zMjYzPC9SZWNOdW0+PHJlY29yZD48

cmVjLW51bWJlcj4zMjYzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk

Yi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1

MzU0NjA4OTkiPjMyNjM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h

bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkZy

aWRlbiwgUC4gTS48L2F1dGhvcj48YXV0aG9yPldhbHVzLCBMLiBSLjwvYXV0aG9yPjxhdXRob3I+

TXVzc28sIEcuIEYuPC9hdXRob3I+PGF1dGhvcj5UYXlsb3IsIE0uIEEuPC9hdXRob3I+PGF1dGhv

cj5NYWxmcm95LCBCLjwvYXV0aG9yPjxhdXRob3I+U3Rhcnp5aywgUi4gTS48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5BbGtlcm1lcywgSW5jLiwgQ2FtYnJp

ZGdlLCBNQSAwMjEzOS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BbnRpLXRyYW5zZmVy

cmluIHJlY2VwdG9yIGFudGlib2R5IGFuZCBhbnRpYm9keS1kcnVnIGNvbmp1Z2F0ZXMgY3Jvc3Mg

dGhlIGJsb29kLWJyYWluIGJhcnJpZXI8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UHJvYyBOYXRs

IEFjYWQgU2NpIFUgUyBBPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1

bGwtdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNh

bD48cGFnZXM+NDc3MS01PC9wYWdlcz48dm9sdW1lPjg4PC92b2x1bWU+PG51bWJlcj4xMTwvbnVt

YmVyPjxlZGl0aW9uPjE5OTEvMDYvMDE8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1h

bHM8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJvZGllcywgTW9ub2Nsb25hbC9hZG1pbmlzdHJhdGlv

biAmYW1wOyBkb3NhZ2U8L2tleXdvcmQ+PGtleXdvcmQ+QXV0b3JhZGlvZ3JhcGh5PC9rZXl3b3Jk

PjxrZXl3b3JkPipCbG9vZC1CcmFpbiBCYXJyaWVyPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL2Js

b29kIHN1cHBseS9jeXRvbG9neTwva2V5d29yZD48a2V5d29yZD5DYXBpbGxhcmllcy9jeXRvbG9n

eTwva2V5d29yZD48a2V5d29yZD5EcnVnIENhcnJpZXJzPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFs

ZTwva2V5d29yZD48a2V5d29yZD5JbW11bm9oaXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29y

ZD5JbW11bm90b3hpbnMvKmFkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZTwva2V5d29yZD48a2V5

d29yZD5LaW5ldGljczwva2V5d29yZD48a2V5d29yZD5NZXRob3RyZXhhdGUvKmFkbWluaXN0cmF0

aW9uICZhbXA7IGRvc2FnZTwva2V5d29yZD48a2V5d29yZD5SYXRzPC9rZXl3b3JkPjxrZXl3b3Jk

PlJhdHMsIEluYnJlZCBTdHJhaW5zPC9rZXl3b3JkPjxrZXl3b3JkPlJlY2VwdG9ycywgVHJhbnNm

ZXJyaW4vKmltbXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+VHJpdGl1bTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4xOTkxPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVuIDE8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDI3LTg0MjQgKFByaW50KSYjeEQ7MDAyNy04

NDI0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMDUyNTU3PC9hY2Nlc3Npb24tbnVt

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8yMDUyNTU3PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzUxNzQ4

PC9jdXN0b20yPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmF5PC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj

TnVtPjMyMzI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij45

OSwxMDA8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zMjMyPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU0NjA4OTMiPjMyMzI8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJyYXksIE4uPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkJpb2xvZ2ljczogVHJhbnNmZXJyaW4m

YXBvczsgYmlzcGVjaWZpYyBhbnRpYm9kaWVzIGFjcm9zcyB0aGUgYmxvb2QtYnJhaW4gYmFycmll

cjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OYXQgUmV2IERydWcgRGlzY292PC9zZWNvbmRhcnkt

dGl0bGU+PC90aXRsZXM+PHBhZ2VzPjE0LTU8L3BhZ2VzPjx2b2x1bWU+MTQ8L3ZvbHVtZT48bnVt

YmVyPjE8L251bWJlcj48ZWRpdGlvbj4yMDE0LzEyLzE3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5

d29yZD5BbXlsb2lkIFByZWN1cnNvciBQcm90ZWluIFNlY3JldGFzZXMvKmltbXVub2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BbnRpYm9kaWVzLCBCaXNw

ZWNpZmljLypwaGFybWFjb2tpbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkFudGlnZW5zLCBDRC8q

aW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5Bc3BhcnRpYyBBY2lkIEVuZG9wZXB0aWRhc2Vz

LyppbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJsb29kLUJyYWluIEJhcnJpZXIvKm1ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+KkNhcGlsbGFyeSBQZXJtZWFiaWxpdHk8L2tleXdvcmQ+

PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPlJlY2VwdG9ycywgVHJhbnNmZXJyaW4v

KmltbXVub2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNTwveWVhcj48

cHViLWRhdGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0NzQt

MTc4NCAoRWxlY3Ryb25pYykmI3hEOzE0NzQtMTc3NiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lv

bi1udW0+MjU1MDMzMzU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0

dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI1NTAzMzM1PC91cmw+PC9yZWxhdGVk

LXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDM4L25yZDQ1MjI8L2Vs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkZyaWRl

bjwvQXV0aG9yPjxZZWFyPjE5OTE8L1llYXI+PFJlY051bT4zMjYzPC9SZWNOdW0+PHJlY29yZD48

cmVjLW51bWJlcj4zMjYzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk

Yi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1

MzU0NjA4OTkiPjMyNjM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h

bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkZy

aWRlbiwgUC4gTS48L2F1dGhvcj48YXV0aG9yPldhbHVzLCBMLiBSLjwvYXV0aG9yPjxhdXRob3I+

TXVzc28sIEcuIEYuPC9hdXRob3I+PGF1dGhvcj5UYXlsb3IsIE0uIEEuPC9hdXRob3I+PGF1dGhv

cj5NYWxmcm95LCBCLjwvYXV0aG9yPjxhdXRob3I+U3Rhcnp5aywgUi4gTS48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5BbGtlcm1lcywgSW5jLiwgQ2FtYnJp

ZGdlLCBNQSAwMjEzOS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BbnRpLXRyYW5zZmVy

cmluIHJlY2VwdG9yIGFudGlib2R5IGFuZCBhbnRpYm9keS1kcnVnIGNvbmp1Z2F0ZXMgY3Jvc3Mg

dGhlIGJsb29kLWJyYWluIGJhcnJpZXI8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UHJvYyBOYXRs

IEFjYWQgU2NpIFUgUyBBPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1

bGwtdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNh

bD48cGFnZXM+NDc3MS01PC9wYWdlcz48dm9sdW1lPjg4PC92b2x1bWU+PG51bWJlcj4xMTwvbnVt

YmVyPjxlZGl0aW9uPjE5OTEvMDYvMDE8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1h

bHM8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJvZGllcywgTW9ub2Nsb25hbC9hZG1pbmlzdHJhdGlv

biAmYW1wOyBkb3NhZ2U8L2tleXdvcmQ+PGtleXdvcmQ+QXV0b3JhZGlvZ3JhcGh5PC9rZXl3b3Jk

PjxrZXl3b3JkPipCbG9vZC1CcmFpbiBCYXJyaWVyPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL2Js

b29kIHN1cHBseS9jeXRvbG9neTwva2V5d29yZD48a2V5d29yZD5DYXBpbGxhcmllcy9jeXRvbG9n

eTwva2V5d29yZD48a2V5d29yZD5EcnVnIENhcnJpZXJzPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFs

ZTwva2V5d29yZD48a2V5d29yZD5JbW11bm9oaXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29y

ZD5JbW11bm90b3hpbnMvKmFkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZTwva2V5d29yZD48a2V5

d29yZD5LaW5ldGljczwva2V5d29yZD48a2V5d29yZD5NZXRob3RyZXhhdGUvKmFkbWluaXN0cmF0

aW9uICZhbXA7IGRvc2FnZTwva2V5d29yZD48a2V5d29yZD5SYXRzPC9rZXl3b3JkPjxrZXl3b3Jk

PlJhdHMsIEluYnJlZCBTdHJhaW5zPC9rZXl3b3JkPjxrZXl3b3JkPlJlY2VwdG9ycywgVHJhbnNm

ZXJyaW4vKmltbXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+VHJpdGl1bTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4xOTkxPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVuIDE8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDI3LTg0MjQgKFByaW50KSYjeEQ7MDAyNy04

NDI0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMDUyNTU3PC9hY2Nlc3Npb24tbnVt

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8yMDUyNTU3PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzUxNzQ4

PC9jdXN0b20yPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 99,100. Considerable research in AD is focusing on synaptic function, where mitochondria might underlie one of the molecular pathways for neurodegeneration. Dimebon is a small molecule approved for human use as an antihistamine PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Pa3VuPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48UmVj

TnVtPjI0Njk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4x

MDE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yNDY5PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ5MzI4ODYiPjI0Njk8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk9rdW4sIEkuPC9hdXRob3I+PGF1dGhvcj5U

a2FjaGVua28sIFMuIEUuPC9hdXRob3I+PGF1dGhvcj5LaHZhdCwgQS48L2F1dGhvcj48YXV0aG9y

Pk1pdGtpbiwgTy48L2F1dGhvcj48YXV0aG9yPkthemV5LCBWLjwvYXV0aG9yPjxhdXRob3I+SXZh

Y2h0Y2hlbmtvLCBBLiBWLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1h

ZGRyZXNzPkF2aW5ldXJvIFBoYXJtYWNldXRpY2xhcyBJbmMuLCBTYW4gRGllZ28sIENBIDkyMTIx

LCBVU0EuIG9rdW5AY2hlbWRpdi5jb208L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Gcm9t

IGFudGktYWxsZXJnaWMgdG8gYW50aS1BbHpoZWltZXImYXBvcztzOiBNb2xlY3VsYXIgcGhhcm1h

Y29sb2d5IG9mIERpbWVib248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Q3VyciBBbHpoZWltZXIg

UmVzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q3Vy

ciBBbHpoZWltZXIgUmVzPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+OTctMTEyPC9w

YWdlcz48dm9sdW1lPjc8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48ZWRpdGlvbj4yMDA5LzEx

LzI3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qZHJ1ZyB0

aGVyYXB5L21ldGFib2xpc20vcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1h

bHM8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKmRydWcgZWZmZWN0cy9tZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPkJyYWluIENoZW1pc3RyeS9kcnVnIGVmZmVjdHMvcGh5c2lvbG9neTwva2V5

d29yZD48a2V5d29yZD5CdXR5cnlsY2hvbGluZXN0ZXJhc2UvZHJ1ZyBlZmZlY3RzL21ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+Q0hPIENlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgTGlu

ZTwva2V5d29yZD48a2V5d29yZD5DZWxsIExpbmUsIFR1bW9yPC9rZXl3b3JkPjxrZXl3b3JkPkNy

aWNldGluYWU8L2tleXdvcmQ+PGtleXdvcmQ+Q3JpY2V0dWx1czwva2V5d29yZD48a2V5d29yZD5E

cnVnIEV2YWx1YXRpb24sIFByZWNsaW5pY2FsPC9rZXl3b3JkPjxrZXl3b3JkPkVuenltZSBJbmhp

Yml0b3JzL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5IaXN0YW1pbmUgQW50YWdvbmlz

dHMvY2hlbWlzdHJ5L3BoYXJtYWNvbG9neS90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdv

cmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkluZG9sZXMvY2hlbWlzdHJ5LypwaGFybWFjb2xv

Z3kvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPk5vb3Ryb3BpYyBBZ2VudHMvY2hl

bWlzdHJ5LypwaGFybWFjb2xvZ3kvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPlJh

dHM8L2tleXdvcmQ+PGtleXdvcmQ+UmF0cywgV2lzdGFyPC9rZXl3b3JkPjxrZXl3b3JkPlJlY2Vw

dG9ycywgQWRyZW5lcmdpYywgYWxwaGEvZHJ1ZyBlZmZlY3RzL21ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+UmVjZXB0b3JzLCBEb3BhbWluZS9kcnVnIGVmZmVjdHMvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5SZWNlcHRvcnMsIEhpc3RhbWluZS9kcnVnIGVmZmVjdHMvbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5SZWNlcHRvcnMsIE5ldXJvdHJhbnNtaXR0ZXIvKmRydWcgZWZm

ZWN0cy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlJlY2VwdG9ycywgU2Vyb3RvbmluL2Ry

dWcgZWZmZWN0cy9tZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTA8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xODc1LTU4MjggKEVsZWN0cm9uaWMpJiN4RDsxNTY3LTIwNTAgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjE5OTM5MjIyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xOTkzOTIyMjwvdXJs

PjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Pa3VuPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48UmVj

TnVtPjI0Njk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4x

MDE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yNDY5PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ5MzI4ODYiPjI0Njk8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk9rdW4sIEkuPC9hdXRob3I+PGF1dGhvcj5U

a2FjaGVua28sIFMuIEUuPC9hdXRob3I+PGF1dGhvcj5LaHZhdCwgQS48L2F1dGhvcj48YXV0aG9y

Pk1pdGtpbiwgTy48L2F1dGhvcj48YXV0aG9yPkthemV5LCBWLjwvYXV0aG9yPjxhdXRob3I+SXZh

Y2h0Y2hlbmtvLCBBLiBWLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1h

ZGRyZXNzPkF2aW5ldXJvIFBoYXJtYWNldXRpY2xhcyBJbmMuLCBTYW4gRGllZ28sIENBIDkyMTIx

LCBVU0EuIG9rdW5AY2hlbWRpdi5jb208L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Gcm9t

IGFudGktYWxsZXJnaWMgdG8gYW50aS1BbHpoZWltZXImYXBvcztzOiBNb2xlY3VsYXIgcGhhcm1h

Y29sb2d5IG9mIERpbWVib248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Q3VyciBBbHpoZWltZXIg

UmVzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q3Vy

ciBBbHpoZWltZXIgUmVzPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+OTctMTEyPC9w

YWdlcz48dm9sdW1lPjc8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48ZWRpdGlvbj4yMDA5LzEx

LzI3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qZHJ1ZyB0

aGVyYXB5L21ldGFib2xpc20vcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1h

bHM8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKmRydWcgZWZmZWN0cy9tZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPkJyYWluIENoZW1pc3RyeS9kcnVnIGVmZmVjdHMvcGh5c2lvbG9neTwva2V5

d29yZD48a2V5d29yZD5CdXR5cnlsY2hvbGluZXN0ZXJhc2UvZHJ1ZyBlZmZlY3RzL21ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+Q0hPIENlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgTGlu

ZTwva2V5d29yZD48a2V5d29yZD5DZWxsIExpbmUsIFR1bW9yPC9rZXl3b3JkPjxrZXl3b3JkPkNy

aWNldGluYWU8L2tleXdvcmQ+PGtleXdvcmQ+Q3JpY2V0dWx1czwva2V5d29yZD48a2V5d29yZD5E

cnVnIEV2YWx1YXRpb24sIFByZWNsaW5pY2FsPC9rZXl3b3JkPjxrZXl3b3JkPkVuenltZSBJbmhp

Yml0b3JzL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5IaXN0YW1pbmUgQW50YWdvbmlz

dHMvY2hlbWlzdHJ5L3BoYXJtYWNvbG9neS90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdv

cmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkluZG9sZXMvY2hlbWlzdHJ5LypwaGFybWFjb2xv

Z3kvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPk5vb3Ryb3BpYyBBZ2VudHMvY2hl

bWlzdHJ5LypwaGFybWFjb2xvZ3kvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPlJh

dHM8L2tleXdvcmQ+PGtleXdvcmQ+UmF0cywgV2lzdGFyPC9rZXl3b3JkPjxrZXl3b3JkPlJlY2Vw

dG9ycywgQWRyZW5lcmdpYywgYWxwaGEvZHJ1ZyBlZmZlY3RzL21ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+UmVjZXB0b3JzLCBEb3BhbWluZS9kcnVnIGVmZmVjdHMvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5SZWNlcHRvcnMsIEhpc3RhbWluZS9kcnVnIGVmZmVjdHMvbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5SZWNlcHRvcnMsIE5ldXJvdHJhbnNtaXR0ZXIvKmRydWcgZWZm

ZWN0cy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlJlY2VwdG9ycywgU2Vyb3RvbmluL2Ry

dWcgZWZmZWN0cy9tZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTA8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xODc1LTU4MjggKEVsZWN0cm9uaWMpJiN4RDsxNTY3LTIwNTAgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjE5OTM5MjIyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xOTkzOTIyMjwvdXJs

PjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 101. Reports of neuroprotective effects in models for AD led to a first randomized clinical trial that was successful even in terms of MMSE score improvement, daily life activity and global cognition PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb29keTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

Y051bT4yNDc1PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTAyPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjQ3NTwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0OTMzMDM1Ij4yNDc1PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Eb29keSwgUi4gUy48L2F1dGhvcj48YXV0

aG9yPkdhdnJpbG92YSwgUy4gSS48L2F1dGhvcj48YXV0aG9yPlNhbm8sIE0uPC9hdXRob3I+PGF1

dGhvcj5UaG9tYXMsIFIuIEcuPC9hdXRob3I+PGF1dGhvcj5BaXNlbiwgUC4gUy48L2F1dGhvcj48

YXV0aG9yPkJhY2h1cmluLCBTLiBPLjwvYXV0aG9yPjxhdXRob3I+U2VlbHksIEwuPC9hdXRob3I+

PGF1dGhvcj5IdW5nLCBELjwvYXV0aG9yPjxhdXRob3I+ZGltZWJvbiwgaW52ZXN0aWdhdG9yczwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkFsemhlaW1lciZh

cG9zO3MgRGlzZWFzZSBhbmQgTWVtb3J5IERpc29yZGVycyBDZW50ZXIsIEJheWxvciBDb2xsZWdl

IG9mIE1lZGljaW5lLCBIb3VzdG9uLCBUWCwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRp

dGxlPkVmZmVjdCBvZiBkaW1lYm9uIG9uIGNvZ25pdGlvbiwgYWN0aXZpdGllcyBvZiBkYWlseSBs

aXZpbmcsIGJlaGF2aW91ciwgYW5kIGdsb2JhbCBmdW5jdGlvbiBpbiBwYXRpZW50cyB3aXRoIG1p

bGQtdG8tbW9kZXJhdGUgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlOiBhIHJhbmRvbWlzZWQsIGRv

dWJsZS1ibGluZCwgcGxhY2Viby1jb250cm9sbGVkIHN0dWR5PC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPkxhbmNldDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4yMDctMTU8L3BhZ2Vz

Pjx2b2x1bWU+MzcyPC92b2x1bWU+PG51bWJlcj45NjM0PC9udW1iZXI+PGVkaXRpb24+MjAwOC8w

Ny8yMjwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+KkFjdGl2aXRpZXMgb2YgRGFpbHkgTGl2

aW5nPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERp

c2Vhc2UvY2xhc3NpZmljYXRpb24vKmRydWcgdGhlcmFweS9waHlzaW9wYXRob2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+Q29nbml0aW9uL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5Eb3Vi

bGUtQmxpbmQgTWV0aG9kPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29y

ZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW5kb2xlcy9hZHZlcnNlIGVmZmVjdHMvKnRoZXJh

cGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRs

ZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBzeWNob21ldHJpY3M8L2tleXdvcmQ+PGtleXdvcmQ+

UnVzc2lhPC9rZXl3b3JkPjxrZXl3b3JkPlNldmVyaXR5IG9mIElsbG5lc3MgSW5kZXg8L2tleXdv

cmQ+PGtleXdvcmQ+VHJlYXRtZW50IE91dGNvbWU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAwODwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bCAxOTwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxpc2JuPjE0NzQtNTQ3WCAoRWxlY3Ryb25pYykmI3hEOzAxNDAtNjczNiAoTGlu

a2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTg2NDA0NTc8L2FjY2Vzc2lvbi1udW0+PHVybHM+

PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE4

NjQwNDU3PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4xMDE2L1MwMTQwLTY3MzYoMDgpNjEwNzQtMDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb29keTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

Y051bT4yNDc1PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTAyPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjQ3NTwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0OTMzMDM1Ij4yNDc1PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Eb29keSwgUi4gUy48L2F1dGhvcj48YXV0

aG9yPkdhdnJpbG92YSwgUy4gSS48L2F1dGhvcj48YXV0aG9yPlNhbm8sIE0uPC9hdXRob3I+PGF1

dGhvcj5UaG9tYXMsIFIuIEcuPC9hdXRob3I+PGF1dGhvcj5BaXNlbiwgUC4gUy48L2F1dGhvcj48

YXV0aG9yPkJhY2h1cmluLCBTLiBPLjwvYXV0aG9yPjxhdXRob3I+U2VlbHksIEwuPC9hdXRob3I+

PGF1dGhvcj5IdW5nLCBELjwvYXV0aG9yPjxhdXRob3I+ZGltZWJvbiwgaW52ZXN0aWdhdG9yczwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkFsemhlaW1lciZh

cG9zO3MgRGlzZWFzZSBhbmQgTWVtb3J5IERpc29yZGVycyBDZW50ZXIsIEJheWxvciBDb2xsZWdl

IG9mIE1lZGljaW5lLCBIb3VzdG9uLCBUWCwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRp

dGxlPkVmZmVjdCBvZiBkaW1lYm9uIG9uIGNvZ25pdGlvbiwgYWN0aXZpdGllcyBvZiBkYWlseSBs

aXZpbmcsIGJlaGF2aW91ciwgYW5kIGdsb2JhbCBmdW5jdGlvbiBpbiBwYXRpZW50cyB3aXRoIG1p

bGQtdG8tbW9kZXJhdGUgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlOiBhIHJhbmRvbWlzZWQsIGRv

dWJsZS1ibGluZCwgcGxhY2Viby1jb250cm9sbGVkIHN0dWR5PC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPkxhbmNldDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4yMDctMTU8L3BhZ2Vz

Pjx2b2x1bWU+MzcyPC92b2x1bWU+PG51bWJlcj45NjM0PC9udW1iZXI+PGVkaXRpb24+MjAwOC8w

Ny8yMjwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+KkFjdGl2aXRpZXMgb2YgRGFpbHkgTGl2

aW5nPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERp

c2Vhc2UvY2xhc3NpZmljYXRpb24vKmRydWcgdGhlcmFweS9waHlzaW9wYXRob2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+Q29nbml0aW9uL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5Eb3Vi

bGUtQmxpbmQgTWV0aG9kPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29y

ZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW5kb2xlcy9hZHZlcnNlIGVmZmVjdHMvKnRoZXJh

cGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRs

ZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBzeWNob21ldHJpY3M8L2tleXdvcmQ+PGtleXdvcmQ+

UnVzc2lhPC9rZXl3b3JkPjxrZXl3b3JkPlNldmVyaXR5IG9mIElsbG5lc3MgSW5kZXg8L2tleXdv

cmQ+PGtleXdvcmQ+VHJlYXRtZW50IE91dGNvbWU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAwODwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bCAxOTwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxpc2JuPjE0NzQtNTQ3WCAoRWxlY3Ryb25pYykmI3hEOzAxNDAtNjczNiAoTGlu

a2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTg2NDA0NTc8L2FjY2Vzc2lvbi1udW0+PHVybHM+

PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE4

NjQwNDU3PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4xMDE2L1MwMTQwLTY3MzYoMDgpNjEwNzQtMDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 102. However, the following phase 3 clinical trial (CONNECTION, NCT00675623) for dimebon terminated early due to lack of efficacy. One of the mechanisms of action of dimebon is to inhibit mitochondrial pore opening, increasing the membrane potential of the mitochondria and improving ATP synthesis ADDIN EN.CITE <EndNote><Cite><Author>Grigorev</Author><Year>2003</Year><RecNum>2476</RecNum><DisplayText><style face="superscript">103</style></DisplayText><record><rec-number>2476</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1534938428">2476</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Grigorev, V. V.</author><author>Dranyi, O. A.</author><author>Bachurin, S. O.</author></authors></contributors><auth-address>Institute of Physiologically Active Substances, Russian Academy of Sciences, Chernogolovka, Moscow Region, Russia. grigor@ipac.ac.ru.</auth-address><titles><title>Comparative study of action mechanisms of dimebon and memantine on AMPA- and NMDA-subtypes glutamate receptors in rat cerebral neurons</title><secondary-title>Bull Exp Biol Med</secondary-title></titles><pages>474-7</pages><volume>136</volume><number>5</number><edition>2004/02/18</edition><keywords><keyword>Animals</keyword><keyword>Benzothiadiazines/pharmacology</keyword><keyword>Cerebral Cortex/cytology/drug effects/metabolism</keyword><keyword>Excitatory Amino Acid Agonists/pharmacology</keyword><keyword>Excitatory Amino Acid Antagonists/*pharmacology</keyword><keyword>Indoles/*pharmacology</keyword><keyword>Kainic Acid/pharmacology</keyword><keyword>Memantine/*pharmacology</keyword><keyword>N-Methylaspartate/pharmacology</keyword><keyword>Neurons/drug effects/*metabolism</keyword><keyword>Patch-Clamp Techniques</keyword><keyword>Purkinje Cells/cytology/drug effects/metabolism</keyword><keyword>Rats</keyword><keyword>Receptors, AMPA/drug effects/*metabolism</keyword><keyword>Receptors, N-Methyl-D-Aspartate/drug effects/*metabolism</keyword></keywords><dates><year>2003</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0007-4888 (Print)&#xD;0007-4888 (Linking)</isbn><accession-num>14968164</accession-num><urls><related-urls><url>. Since mitochondrial dysfunction is strongly associated with aging and AD, it is logical that small molecules restoring mitochondrial function will serve largely as part of future AD therapies. In summary, several different dementia disorders involve different protein aggregation profiles. Our latest data support the claim that oligomers are more toxic than fibrils for neurons. Although it is very possible that the amyloid beta-peptide is somehow involved in the different stages, we will need a combination therapy. Many trials are ongoing for lowering Aβ levels in either the production or the aggregation or increasing its clearance. Moreover, similar approaches will give rise to therapies for amyloid diseases in other organs such as the heart and kidney, as well as in the peripheral nervous system PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZU1hdHRvczwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+

PFJlY051bT4yNDc4PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MTA0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjQ3ODwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0OTM5MTA0Ij4yNDc4PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5EZU1hdHRvcywgUi4gQi48L2F1dGhv

cj48YXV0aG9yPkJhbGVzLCBLLiBSLjwvYXV0aG9yPjxhdXRob3I+Q3VtbWlucywgRC4gSi48L2F1

dGhvcj48YXV0aG9yPkRvZGFydCwgSi4gQy48L2F1dGhvcj48YXV0aG9yPlBhdWwsIFMuIE0uPC9h

dXRob3I+PGF1dGhvcj5Ib2x0em1hbiwgRC4gTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli

dXRvcnM+PGF1dGgtYWRkcmVzcz5UaGUgQ2VudGVyIGZvciB0aGUgU3R1ZHkgb2YgTmVydm91cyBT

eXN0ZW0gSW5qdXJ5LCBXYXNoaW5ndG9uIFVuaXZlcnNpdHkgU2Nob29sIG9mIE1lZGljaW5lLCA2

NjAgU291dGggRXVjbGlkIEF2ZW51ZSwgQm94IDgxMTEsIFN0LiBMb3VpcywgTU8gNjMxMTAsIFVT

QS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5QZXJpcGhlcmFsIGFudGktQSBiZXRhIGFu

dGlib2R5IGFsdGVycyBDTlMgYW5kIHBsYXNtYSBBIGJldGEgY2xlYXJhbmNlIGFuZCBkZWNyZWFz

ZXMgYnJhaW4gQSBiZXRhIGJ1cmRlbiBpbiBhIG1vdXNlIG1vZGVsIG9mIEFsemhlaW1lciZhcG9z

O3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Qcm9jIE5hdGwgQWNhZCBTY2kgVSBT

IEE8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Qcm9j

IE5hdGwgQWNhZCBTY2kgVSBTIEE8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz44ODUw

LTU8L3BhZ2VzPjx2b2x1bWU+OTg8L3ZvbHVtZT48bnVtYmVyPjE1PC9udW1iZXI+PGVkaXRpb24+

MjAwMS8wNy8wNTwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2Uv

Ymxvb2QvY2VyZWJyb3NwaW5hbCBmbHVpZC8qbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL2NlcmVicm9zcGluYWwgZmx1aWQvaW1tdW5v

bG9neS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3

b3JkPkFudGlib2RpZXMsIE1vbm9jbG9uYWwvYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlL2lt

bXVub2xvZ3kvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKm1ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+Q2VudHJhbCBOZXJ2b3VzIFN5c3RlbS8qbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5EaXNlYXNlIE1vZGVscywgQW5pbWFsPC9rZXl3b3JkPjxrZXl3b3JkPkh1

bWFuczwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIFRyYW5z

Z2VuaWM8L2tleXdvcmQ+PGtleXdvcmQ+UGVwdGlkZSBGcmFnbWVudHMvY2VyZWJyb3NwaW5hbCBm

bHVpZC9pbW11bm9sb2d5LyptZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5

ZWFyPjIwMDE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWwgMTc8L2RhdGU+PC9wdWItZGF0ZXM+

PC9kYXRlcz48aXNibj4wMDI3LTg0MjQgKFByaW50KSYjeEQ7MDAyNy04NDI0IChMaW5raW5nKTwv

aXNibj48YWNjZXNzaW9uLW51bT4xMTQzODcxMjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRl

ZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTE0Mzg3MTI8

L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMzc1MjQ8L2N1c3RvbTI+PGVs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwNzMvcG5hcy4xNTEyNjEzOTg8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZU1hdHRvczwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+

PFJlY051bT4yNDc4PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MTA0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjQ3ODwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0OTM5MTA0Ij4yNDc4PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5EZU1hdHRvcywgUi4gQi48L2F1dGhv

cj48YXV0aG9yPkJhbGVzLCBLLiBSLjwvYXV0aG9yPjxhdXRob3I+Q3VtbWlucywgRC4gSi48L2F1

dGhvcj48YXV0aG9yPkRvZGFydCwgSi4gQy48L2F1dGhvcj48YXV0aG9yPlBhdWwsIFMuIE0uPC9h

dXRob3I+PGF1dGhvcj5Ib2x0em1hbiwgRC4gTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli

dXRvcnM+PGF1dGgtYWRkcmVzcz5UaGUgQ2VudGVyIGZvciB0aGUgU3R1ZHkgb2YgTmVydm91cyBT

eXN0ZW0gSW5qdXJ5LCBXYXNoaW5ndG9uIFVuaXZlcnNpdHkgU2Nob29sIG9mIE1lZGljaW5lLCA2

NjAgU291dGggRXVjbGlkIEF2ZW51ZSwgQm94IDgxMTEsIFN0LiBMb3VpcywgTU8gNjMxMTAsIFVT

QS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5QZXJpcGhlcmFsIGFudGktQSBiZXRhIGFu

dGlib2R5IGFsdGVycyBDTlMgYW5kIHBsYXNtYSBBIGJldGEgY2xlYXJhbmNlIGFuZCBkZWNyZWFz

ZXMgYnJhaW4gQSBiZXRhIGJ1cmRlbiBpbiBhIG1vdXNlIG1vZGVsIG9mIEFsemhlaW1lciZhcG9z

O3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Qcm9jIE5hdGwgQWNhZCBTY2kgVSBT

IEE8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Qcm9j

IE5hdGwgQWNhZCBTY2kgVSBTIEE8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz44ODUw

LTU8L3BhZ2VzPjx2b2x1bWU+OTg8L3ZvbHVtZT48bnVtYmVyPjE1PC9udW1iZXI+PGVkaXRpb24+

MjAwMS8wNy8wNTwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2Uv

Ymxvb2QvY2VyZWJyb3NwaW5hbCBmbHVpZC8qbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL2NlcmVicm9zcGluYWwgZmx1aWQvaW1tdW5v

bG9neS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3

b3JkPkFudGlib2RpZXMsIE1vbm9jbG9uYWwvYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlL2lt

bXVub2xvZ3kvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKm1ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+Q2VudHJhbCBOZXJ2b3VzIFN5c3RlbS8qbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5EaXNlYXNlIE1vZGVscywgQW5pbWFsPC9rZXl3b3JkPjxrZXl3b3JkPkh1

bWFuczwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIFRyYW5z

Z2VuaWM8L2tleXdvcmQ+PGtleXdvcmQ+UGVwdGlkZSBGcmFnbWVudHMvY2VyZWJyb3NwaW5hbCBm

bHVpZC9pbW11bm9sb2d5LyptZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5

ZWFyPjIwMDE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWwgMTc8L2RhdGU+PC9wdWItZGF0ZXM+

PC9kYXRlcz48aXNibj4wMDI3LTg0MjQgKFByaW50KSYjeEQ7MDAyNy04NDI0IChMaW5raW5nKTwv

aXNibj48YWNjZXNzaW9uLW51bT4xMTQzODcxMjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRl

ZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTE0Mzg3MTI8

L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMzc1MjQ8L2N1c3RvbTI+PGVs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwNzMvcG5hcy4xNTEyNjEzOTg8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 104. There is still a lot to do, but what the scientific community and society must do first is to re-stimulate public and private interests in going back to basic science if we are to have a pharmacological treatment strategy as early as possible.Tauopathies In late stages of AD, we have an end-stage picture of the disease where amyloid deposits are formed, together with neurofibrillary degeneration, meaning extracellular Aβ and intracellular Tau. However, as mentioned before, early in the process, intracellular Aβ might be more toxic than the extracellular one. We also know that Tau can be secreted in the extracellular space.With our current knowledge, the amyloid cascade is likely to be more complicated than initially described. The linear cascade of events leading to the formation of Aβ oligomers, aggregation, and maybe propagation may not be so simple. In fact, first, there is a relationship with Tau. Does Tau pathology fuel this amyloid cascade? Does the amyloid pathology facilitate Tau secretion and propagation? Finally, in the amyloid cascade hypothesis, inflammation arrives at the end. However, since there are already early extracellular proteins aggregating, inflammation is likely to be present at the beginning of AD as suggested by several studies. Our understanding of the sequence of events has been hampered by the fact that there are not truly faithful animal models of AD for research. Current models mimic either amyloid pathways or Tau pathways. Some studies have attempted to show a link between amyloid and Tau pathways PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJlY051

bT4zOTExPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+MTA1

PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzkxMTwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhw

Znd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2NjcxMjAxIj4zOTExPC9rZXk+PC9mb3Jl

aWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxj

b250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5IZSwgWi48L2F1dGhvcj48YXV0aG9yPkd1bywg

Si4gTC48L2F1dGhvcj48YXV0aG9yPk1jQnJpZGUsIEouIEQuPC9hdXRob3I+PGF1dGhvcj5OYXJh

c2ltaGFuLCBTLjwvYXV0aG9yPjxhdXRob3I+S2ltLCBILjwvYXV0aG9yPjxhdXRob3I+Q2hhbmdv

bGthciwgTC48L2F1dGhvcj48YXV0aG9yPlpoYW5nLCBCLjwvYXV0aG9yPjxhdXRob3I+R2F0aGFn

YW4sIFIuIEouPC9hdXRob3I+PGF1dGhvcj5ZdWUsIEMuPC9hdXRob3I+PGF1dGhvcj5EZW5nbGVy

LCBDLjwvYXV0aG9yPjxhdXRob3I+U3RpZWJlciwgQS48L2F1dGhvcj48YXV0aG9yPk5pdGxhLCBN

LjwvYXV0aG9yPjxhdXRob3I+Q291bHRlciwgRC4gQS48L2F1dGhvcj48YXV0aG9yPkFiZWwsIFQu

PC9hdXRob3I+PGF1dGhvcj5CcnVuZGVuLCBLLiBSLjwvYXV0aG9yPjxhdXRob3I+VHJvamFub3dz

a2ksIEouIFEuPC9hdXRob3I+PGF1dGhvcj5MZWUsIFYuIE0uPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQYXRob2xvZ3kgYW5kIExh

Ym9yYXRvcnkgTWVkaWNpbmUsIEluc3RpdHV0ZSBvbiBBZ2luZyBhbmQgQ2VudGVyIGZvciBOZXVy

b2RlZ2VuZXJhdGl2ZSBEaXNlYXNlIFJlc2VhcmNoLCBVbml2ZXJzaXR5IG9mIFBlbm5zeWx2YW5p

YSBTY2hvb2wgb2YgTWVkaWNpbmUsIFBoaWxhZGVscGhpYSwgUGVubnN5bHZhbmlhLCBVU0EuJiN4

RDtEaXZpc2lvbiBvZiBOZXVyb2xvZ3ksIFRoZSBDaGlsZHJlbiZhcG9zO3MgSG9zcGl0YWwgb2Yg

UGhpbGFkZWxwaGlhLCBQaGlsYWRlbHBoaWEsIFBlbm5zeWx2YW5pYSwgVVNBLiYjeEQ7RGVwYXJ0

bWVudHMgb2YgTmV1cm9zY2llbmNlIGFuZCBvZiBQZWRpYXRyaWNzLCBVbml2ZXJzaXR5IG9mIFBl

bm5zeWx2YW5pYSBTY2hvb2wgb2YgTWVkaWNpbmUsIFBoaWxhZGVscGhpYSwgUGVubnN5bHZhbmlh

LCBVU0EuJiN4RDtJb3dhIE5ldXJvc2NpZW5jZSBJbnN0aXR1dGUgYW5kIERlcGFydG1lbnQgb2Yg

TW9sZWN1bGFyIFBoeXNpb2xvZ3kgYW5kIEJpb3BoeXNpY3MsIENhcnZlciBDb2xsZWdlIG9mIE1l

ZGljaW5lLCBVbml2ZXJzaXR5IG9mIElvd2EsIElvd2EgQ2l0eSwgSW93YSwgVVNBLjwvYXV0aC1h

ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkFteWxvaWQtYmV0YSBwbGFxdWVzIGVuaGFuY2UgQWx6aGVp

bWVyJmFwb3M7cyBicmFpbiB0YXUtc2VlZGVkIHBhdGhvbG9naWVzIGJ5IGZhY2lsaXRhdGluZyBu

ZXVyaXRpYyBwbGFxdWUgdGF1IGFnZ3JlZ2F0aW9uPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5h

dCBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MjktMzg8L3BhZ2VzPjx2b2x1

bWU+MjQ8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4yMDE3LzEyLzA1PC9lZGl0

aW9uPjxkYXRlcz48eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SmFuPC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU0Ni0xNzBYIChFbGVjdHJvbmljKSYjeEQ7MTA3OC04

OTU2IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yOTIwMDIwNTwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9w

dWJtZWQvMjkyMDAyMDU8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNTc2

MDM1MzwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9ubS40NDQzPC9l

bGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJlY051

bT4zOTExPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+MTA1

PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzkxMTwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhw

Znd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2NjcxMjAxIj4zOTExPC9rZXk+PC9mb3Jl

aWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxj

b250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5IZSwgWi48L2F1dGhvcj48YXV0aG9yPkd1bywg

Si4gTC48L2F1dGhvcj48YXV0aG9yPk1jQnJpZGUsIEouIEQuPC9hdXRob3I+PGF1dGhvcj5OYXJh

c2ltaGFuLCBTLjwvYXV0aG9yPjxhdXRob3I+S2ltLCBILjwvYXV0aG9yPjxhdXRob3I+Q2hhbmdv

bGthciwgTC48L2F1dGhvcj48YXV0aG9yPlpoYW5nLCBCLjwvYXV0aG9yPjxhdXRob3I+R2F0aGFn

YW4sIFIuIEouPC9hdXRob3I+PGF1dGhvcj5ZdWUsIEMuPC9hdXRob3I+PGF1dGhvcj5EZW5nbGVy

LCBDLjwvYXV0aG9yPjxhdXRob3I+U3RpZWJlciwgQS48L2F1dGhvcj48YXV0aG9yPk5pdGxhLCBN

LjwvYXV0aG9yPjxhdXRob3I+Q291bHRlciwgRC4gQS48L2F1dGhvcj48YXV0aG9yPkFiZWwsIFQu

PC9hdXRob3I+PGF1dGhvcj5CcnVuZGVuLCBLLiBSLjwvYXV0aG9yPjxhdXRob3I+VHJvamFub3dz

a2ksIEouIFEuPC9hdXRob3I+PGF1dGhvcj5MZWUsIFYuIE0uPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQYXRob2xvZ3kgYW5kIExh

Ym9yYXRvcnkgTWVkaWNpbmUsIEluc3RpdHV0ZSBvbiBBZ2luZyBhbmQgQ2VudGVyIGZvciBOZXVy

b2RlZ2VuZXJhdGl2ZSBEaXNlYXNlIFJlc2VhcmNoLCBVbml2ZXJzaXR5IG9mIFBlbm5zeWx2YW5p

YSBTY2hvb2wgb2YgTWVkaWNpbmUsIFBoaWxhZGVscGhpYSwgUGVubnN5bHZhbmlhLCBVU0EuJiN4

RDtEaXZpc2lvbiBvZiBOZXVyb2xvZ3ksIFRoZSBDaGlsZHJlbiZhcG9zO3MgSG9zcGl0YWwgb2Yg

UGhpbGFkZWxwaGlhLCBQaGlsYWRlbHBoaWEsIFBlbm5zeWx2YW5pYSwgVVNBLiYjeEQ7RGVwYXJ0

bWVudHMgb2YgTmV1cm9zY2llbmNlIGFuZCBvZiBQZWRpYXRyaWNzLCBVbml2ZXJzaXR5IG9mIFBl

bm5zeWx2YW5pYSBTY2hvb2wgb2YgTWVkaWNpbmUsIFBoaWxhZGVscGhpYSwgUGVubnN5bHZhbmlh

LCBVU0EuJiN4RDtJb3dhIE5ldXJvc2NpZW5jZSBJbnN0aXR1dGUgYW5kIERlcGFydG1lbnQgb2Yg

TW9sZWN1bGFyIFBoeXNpb2xvZ3kgYW5kIEJpb3BoeXNpY3MsIENhcnZlciBDb2xsZWdlIG9mIE1l

ZGljaW5lLCBVbml2ZXJzaXR5IG9mIElvd2EsIElvd2EgQ2l0eSwgSW93YSwgVVNBLjwvYXV0aC1h

ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkFteWxvaWQtYmV0YSBwbGFxdWVzIGVuaGFuY2UgQWx6aGVp

bWVyJmFwb3M7cyBicmFpbiB0YXUtc2VlZGVkIHBhdGhvbG9naWVzIGJ5IGZhY2lsaXRhdGluZyBu

ZXVyaXRpYyBwbGFxdWUgdGF1IGFnZ3JlZ2F0aW9uPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5h

dCBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MjktMzg8L3BhZ2VzPjx2b2x1

bWU+MjQ8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4yMDE3LzEyLzA1PC9lZGl0

aW9uPjxkYXRlcz48eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SmFuPC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU0Ni0xNzBYIChFbGVjdHJvbmljKSYjeEQ7MTA3OC04

OTU2IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yOTIwMDIwNTwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9w

dWJtZWQvMjkyMDAyMDU8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNTc2

MDM1MzwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9ubS40NDQzPC9l

bGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 105. This work shows the possible interaction of both systems. Also including the idea of prion-like propagation and seeding. Still, we do not know the real links between amyloid and Tau pathways. For example in several GWAS PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj

TnVtPjM5MTU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4x

MDYtMTA5PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzkxNTwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2NjcxNTA4Ij4zOTE1PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5BbmRvLCBLLjwvYXV0aG9yPjxhdXRo

b3I+QnJpb24sIEouIFAuPC9hdXRob3I+PGF1dGhvcj5TdHlnZWxib3V0LCBWLjwvYXV0aG9yPjxh

dXRob3I+U3VhaW4sIFYuPC9hdXRob3I+PGF1dGhvcj5BdXRoZWxldCwgTS48L2F1dGhvcj48YXV0

aG9yPkRlZGVja2VyLCBSLjwvYXV0aG9yPjxhdXRob3I+Q2hhbnV0LCBBLjwvYXV0aG9yPjxhdXRo

b3I+TGFjb3IsIFAuPC9hdXRob3I+PGF1dGhvcj5MYXZhdXIsIEouPC9hdXRob3I+PGF1dGhvcj5T

YXpkb3ZpdGNoLCBWLjwvYXV0aG9yPjxhdXRob3I+Um9nYWV2YSwgRS48L2F1dGhvcj48YXV0aG9y

PlBvdGllciwgTS4gQy48L2F1dGhvcj48YXV0aG9yPkR1eWNrYWVydHMsIEMuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+TGFib3JhdG9pcmUgZGUgTmV1cm9w

YXRob2xvZ2llIEVzY291cm9sbGUsIEhvcGl0YWwgZGUgbGEgUGl0aWUtU2FscGV0cmllcmUsIEFQ

LUhQLCBQYXJpcywgRnJhbmNlLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNsYXRocmlu

IGFkYXB0b3IgQ0FMTS9QSUNBTE0gaXMgYXNzb2NpYXRlZCB3aXRoIG5ldXJvZmlicmlsbGFyeSB0

YW5nbGVzIGFuZCBpcyBjbGVhdmVkIGluIEFsemhlaW1lciZhcG9zO3MgYnJhaW5zPC90aXRsZT48

c2Vjb25kYXJ5LXRpdGxlPkFjdGEgTmV1cm9wYXRob2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxl

cz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BY3RhIE5ldXJvcGF0aG9sPC9mdWxsLXRpdGxlPjwv

cGVyaW9kaWNhbD48cGFnZXM+ODYxLTc4PC9wYWdlcz48dm9sdW1lPjEyNTwvdm9sdW1lPjxudW1i

ZXI+NjwvbnVtYmVyPjxlZGl0aW9uPjIwMTMvMDQvMTc8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3

b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwg

ODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvZXRpb2xvZ3kv

Km1ldGFib2xpc20vKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DYXNlLUNvbnRyb2wgU3R1

ZGllczwva2V5d29yZD48a2V5d29yZD5Eb3duIFN5bmRyb21lL2V0aW9sb2d5L21ldGFib2xpc20v

cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1h

bnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWNyb2dsaWEvcGh5

c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5N

b25vbWVyaWMgQ2xhdGhyaW4gQXNzZW1ibHkgUHJvdGVpbnMvKm1ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+TmV1cm9maWJyaWxsYXJ5IFRhbmdsZXMvKm1ldGFib2xpc20vKnBhdGhvbG9neTwv

a2V5d29yZD48a2V5d29yZD50YXUgUHJvdGVpbnMvbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdv

cmRzPjxkYXRlcz48eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVuPC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQzMi0wNTMzIChFbGVjdHJvbmljKSYjeEQ7MDAwMS02

MzIyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzU4OTAzMDwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9w

dWJtZWQvMjM1ODkwMzA8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjEwLjEwMDcvczAwNDAxLTAxMy0xMTExLXo8L2VsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkNoYXB1aXM8L0F1dGhvcj48WWVhcj4y

MDEzPC9ZZWFyPjxSZWNOdW0+MzkxMjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MzkxMjwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2NjcxMzQ0Ij4zOTEyPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DaGFwdWlzLCBKLjwvYXV0aG9y

PjxhdXRob3I+SGFuc21hbm5lbCwgRi48L2F1dGhvcj48YXV0aG9yPkdpc3RlbGluY2ssIE0uPC9h

dXRob3I+PGF1dGhvcj5Nb3VuaWVyLCBBLjwvYXV0aG9yPjxhdXRob3I+VmFuIENhdXdlbmJlcmdo

ZSwgQy48L2F1dGhvcj48YXV0aG9yPktvbGVuLCBLLiBWLjwvYXV0aG9yPjxhdXRob3I+R2VsbGVy

LCBGLjwvYXV0aG9yPjxhdXRob3I+U290dGVqZWF1LCBZLjwvYXV0aG9yPjxhdXRob3I+SGFyb2xk

LCBELjwvYXV0aG9yPjxhdXRob3I+RG91cmxlbiwgUC48L2F1dGhvcj48YXV0aG9yPkdyZW5pZXIt

Qm9sZXksIEIuPC9hdXRob3I+PGF1dGhvcj5LYW1hdGFuaSwgWS48L2F1dGhvcj48YXV0aG9yPkRl

bGVwaW5lLCBCLjwvYXV0aG9yPjxhdXRob3I+RGVtaWF1dHRlLCBGLjwvYXV0aG9yPjxhdXRob3I+

WmVsZW5pa2EsIEQuPC9hdXRob3I+PGF1dGhvcj5ab21tZXIsIE4uPC9hdXRob3I+PGF1dGhvcj5I

YW1kYW5lLCBNLjwvYXV0aG9yPjxhdXRob3I+QmVsbGVuZ3VleiwgQy48L2F1dGhvcj48YXV0aG9y

PkRhcnRpZ3VlcywgSi4gRi48L2F1dGhvcj48YXV0aG9yPkhhdXcsIEouIEouPC9hdXRob3I+PGF1

dGhvcj5MZXRyb25uZSwgRi48L2F1dGhvcj48YXV0aG9yPkF5cmFsLCBBLiBNLjwvYXV0aG9yPjxh

dXRob3I+U2xlZWdlcnMsIEsuPC9hdXRob3I+PGF1dGhvcj5TY2hlbGxlbnMsIEEuPC9hdXRob3I+

PGF1dGhvcj5Ccm9lY2ssIEwuIFYuPC9hdXRob3I+PGF1dGhvcj5FbmdlbGJvcmdocywgUy48L2F1

dGhvcj48YXV0aG9yPkRlIERleW4sIFAuIFAuPC9hdXRob3I+PGF1dGhvcj5WYW5kZW5iZXJnaGUs

IFIuPC9hdXRob3I+PGF1dGhvcj5PJmFwb3M7RG9ub3ZhbiwgTS48L2F1dGhvcj48YXV0aG9yPk93

ZW4sIE0uPC9hdXRob3I+PGF1dGhvcj5FcGVsYmF1bSwgSi48L2F1dGhvcj48YXV0aG9yPk1lcmNr

ZW4sIE0uPC9hdXRob3I+PGF1dGhvcj5LYXJyYW4sIEUuPC9hdXRob3I+PGF1dGhvcj5CYW50c2No

ZWZmLCBNLjwvYXV0aG9yPjxhdXRob3I+RHJld2VzLCBHLjwvYXV0aG9yPjxhdXRob3I+Sm9iZXJ0

eSwgRy48L2F1dGhvcj48YXV0aG9yPkNhbXBpb24sIEQuPC9hdXRob3I+PGF1dGhvcj5PY3RhdmUs

IEouIE4uPC9hdXRob3I+PGF1dGhvcj5CZXJyLCBDLjwvYXV0aG9yPjxhdXRob3I+TGF0aHJvcCwg

TS48L2F1dGhvcj48YXV0aG9yPkNhbGxhZXJ0cywgUC48L2F1dGhvcj48YXV0aG9yPk1hbm4sIEQu

PC9hdXRob3I+PGF1dGhvcj5XaWxsaWFtcywgSi48L2F1dGhvcj48YXV0aG9yPkJ1ZWUsIEwuPC9h

dXRob3I+PGF1dGhvcj5EZXdhY2h0ZXIsIEkuPC9hdXRob3I+PGF1dGhvcj5WYW4gQnJvZWNraG92

ZW4sIEMuPC9hdXRob3I+PGF1dGhvcj5BbW91eWVsLCBQLjwvYXV0aG9yPjxhdXRob3I+TW9lY2hh

cnMsIEQuPC9hdXRob3I+PGF1dGhvcj5EZXJtYXV0LCBCLjwvYXV0aG9yPjxhdXRob3I+TGFtYmVy

dCwgSi4gQy48L2F1dGhvcj48YXV0aG9yPkdlcmFkIGNvbnNvcnRpdW08L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz4xXSBJTlNFUk0gVTc0NCwgVW5pdmVyc2l0

ZSBMaWxsZSBOb3JkIGRlIEZyYW5jZSwgSW5zdGl0dXQgcGFzdGV1ciBkZSBMaWxsZSwgTGlsbGUs

IEZyYW5jZSBbMl0gVW5pdmVyc2l0ZSBMaWxsZSBOb3JkIGRlIEZyYW5jZSwgSW5zdGl0dXQgcGFz

dGV1ciBkZSBMaWxsZSwgTGlsbGUsIEZyYW5jZSBbM10gVW5pdmVyc2l0ZSBMaWxsZS1Ob3JkIGRl

IEZyYW5jZSwgSW5zdGl0dXQgcGFzdGV1ciBkZSBMaWxsZSwgTGlsbGUsIEZyYW5jZS48L2F1dGgt

YWRkcmVzcz48dGl0bGVzPjx0aXRsZT5JbmNyZWFzZWQgZXhwcmVzc2lvbiBvZiBCSU4xIG1lZGlh

dGVzIEFsemhlaW1lciBnZW5ldGljIHJpc2sgYnkgbW9kdWxhdGluZyB0YXUgcGF0aG9sb2d5PC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk1vbCBQc3ljaGlhdHJ5PC9zZWNvbmRhcnktdGl0bGU+PC90

aXRsZXM+PHBhZ2VzPjEyMjUtMzQ8L3BhZ2VzPjx2b2x1bWU+MTg8L3ZvbHVtZT48bnVtYmVyPjEx

PC9udW1iZXI+PGVkaXRpb24+MjAxMy8wMi8xMzwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+

QWRhcHRvciBQcm90ZWlucywgU2lnbmFsIFRyYW5zZHVjaW5nL2Jpb3N5bnRoZXNpcy8qZ2VuZXRp

Y3M8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmdlbmV0aWNzL21ldGFib2xp

c20vKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3Jk

PkJyYWluL21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNhcnJpZXIgUHJv

dGVpbnMvZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DYXNlLUNvbnRyb2wg

U3R1ZGllczwva2V5d29yZD48a2V5d29yZD5DZWxscywgQ3VsdHVyZWQ8L2tleXdvcmQ+PGtleXdv

cmQ+RHJvc29waGlsYSBQcm90ZWlucy9kZWZpY2llbmN5L2dlbmV0aWNzL21ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+RHJvc29waGlsYSBtZWxhbm9nYXN0ZXIvZ2VuZXRpY3MvbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5FbmRvcGhlbm90eXBlczwva2V5d29yZD48a2V5d29yZD5HZW5l

IEV4cHJlc3Npb24vZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXRpYyBQcmVkaXNwb3Np

dGlvbiB0byBEaXNlYXNlLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdv

cmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5OZXJ2ZSBEZWdlbmVyYXRpb24vZ2Vu

ZXRpY3MvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk51Y2xlYXIgUHJvdGVpbnMvYmlvc3lu

dGhlc2lzLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5QbGFxdWUsIEFteWxvaWQvcGF0aG9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBvbHltb3JwaGlzbSwgU2luZ2xlIE51Y2xlb3RpZGUvZ2Vu

ZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+U3luYXB0b3NvbWVzL3BhdGhvbG9neTwva2V5d29yZD48

a2V5d29yZD5UcmFuc2NyaXB0aW9uIEZhY3RvcnMvZGVmaWNpZW5jeS9nZW5ldGljcy9tZXRhYm9s

aXNtPC9rZXl3b3JkPjxrZXl3b3JkPlR1bW9yIFN1cHByZXNzb3IgUHJvdGVpbnMvYmlvc3ludGhl

c2lzLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD50YXUgUHJvdGVpbnMvYW50YWdvbmlzdHMg

JmFtcDsgaW5oaWJpdG9ycy8qbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+Tm92PC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PGlzYm4+MTQ3Ni01NTc4IChFbGVjdHJvbmljKSYjeEQ7MTM1OS00MTg0IChMaW5raW5n

KTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzM5OTkxNDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVs

YXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjMzOTk5

MTQ8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMzgwNzY2MTwvY3VzdG9t

Mj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9tcC4yMDEzLjE8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkRvdXJsZW48L0F1dGhv

cj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNOdW0+MzkxNDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1i

ZXI+MzkxNDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3

YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2NjcxNDMw

Ij4zOTE0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs

ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Eb3VybGVuLCBQ

LjwvYXV0aG9yPjxhdXRob3I+RmVybmFuZGV6LUdvbWV6LCBGLiBKLjwvYXV0aG9yPjxhdXRob3I+

RHVwb250LCBDLjwvYXV0aG9yPjxhdXRob3I+R3Jlbmllci1Cb2xleSwgQi48L2F1dGhvcj48YXV0

aG9yPkJlbGxlbmd1ZXosIEMuPC9hdXRob3I+PGF1dGhvcj5PYnJpb3QsIEguPC9hdXRob3I+PGF1

dGhvcj5DYWlsbGllcmV6LCBSLjwvYXV0aG9yPjxhdXRob3I+U290dGVqZWF1LCBZLjwvYXV0aG9y

PjxhdXRob3I+Q2hhcHVpcywgSi48L2F1dGhvcj48YXV0aG9yPkJyZXR0ZXZpbGxlLCBBLjwvYXV0

aG9yPjxhdXRob3I+QWJkZWxmZXR0YWgsIEYuPC9hdXRob3I+PGF1dGhvcj5EZWxheSwgQy48L2F1

dGhvcj48YXV0aG9yPk1hbG1hbmNoZSwgTi48L2F1dGhvcj48YXV0aG9yPlNvaW5pbmVuLCBILjwv

YXV0aG9yPjxhdXRob3I+SGlsdHVuZW4sIE0uPC9hdXRob3I+PGF1dGhvcj5HYWxhcywgTS4gQy48

L2F1dGhvcj48YXV0aG9yPkFtb3V5ZWwsIFAuPC9hdXRob3I+PGF1dGhvcj5TZXJnZWFudCwgTi48

L2F1dGhvcj48YXV0aG9yPkJ1ZWUsIEwuPC9hdXRob3I+PGF1dGhvcj5MYW1iZXJ0LCBKLiBDLjwv

YXV0aG9yPjxhdXRob3I+RGVybWF1dCwgQi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5JbnN0aXR1dCBQYXN0ZXVyIGRlIExpbGxlLCBMaWxsZSwgRnJhbmNl

LiYjeEQ7SU5TRVJNLCBVTVIgMTE2NywgTGlsbGUsIEZyYW5jZS4mI3hEO1VuaXZlcnNpdGUgZGUg

TGlsbGUsIExpbGxlLCBGcmFuY2UuJiN4RDtJTlNFUk0sIFVNUi1TIDExNzIsIEFsemhlaW1lciBh

bmQgVGF1b3BhdGhpZXMsIExpbGxlLCBGcmFuY2UuJiN4RDtVbml2LkxpbGxlLCBKUEFyYywgTGls

bGUsIEZyYW5jZS4mI3hEO0NIUlUsIE1lbW9yeSBDbGluaWMsIExpbGxlLCBGcmFuY2UuJiN4RDtJ

bnN0aXR1dGUgb2YgQ2xpbmljYWwgTWVkaWNpbmUtTmV1cm9sb2d5IGFuZCBEZXBhcnRtZW50IG9m

IE5ldXJvbG9neSwgVW5pdmVyc2l0eSBvZiBFYXN0ZXJuIEZpbmxhbmQgYW5kIEt1b3BpbyBVbml2

ZXJzaXR5IEhvc3BpdGFsLCBLdW9waW8sIEZpbmxhbmQuJiN4RDtJbnN0aXR1dGUgb2YgQmlvbWVk

aWNpbmUsIFVuaXZlcnNpdHkgb2YgRWFzdGVybiBGaW5sYW5kLCBLdW9waW8sIEZpbmxhbmQuJiN4

RDtDZW50cmUgSG9zcGl0YWxpZXIgUmVnaW9uYWwgVW5pdmVyc2l0YWlyZSBkZSBMaWxsZSwgTGls

bGUsIEZyYW5jZS4mI3hEO0NlbnRlciBmb3IgTWVkaWNhbCBHZW5ldGljcywgR2hlbnQgVW5pdmVy

c2l0eSBIb3NwaXRhbCwgR2hlbnQsIEJlbGdpdW0uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+RnVuY3Rpb25hbCBzY3JlZW5pbmcgb2YgQWx6aGVpbWVyIHJpc2sgbG9jaSBpZGVudGlmaWVz

IFBUSzJCIGFzIGFuIGluIHZpdm8gbW9kdWxhdG9yIGFuZCBlYXJseSBtYXJrZXIgb2YgVGF1IHBh

dGhvbG9neTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Nb2wgUHN5Y2hpYXRyeTwvc2Vjb25kYXJ5

LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz44NzQtODgzPC9wYWdlcz48dm9sdW1lPjIyPC92b2x1bWU+

PG51bWJlcj42PC9udW1iZXI+PGVkaXRpb24+MjAxNi8wNC8yNzwvZWRpdGlvbj48a2V5d29yZHM+

PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+QW5p

bWFsczwva2V5d29yZD48a2V5d29yZD5CaW9tYXJrZXJzPC9rZXl3b3JkPjxrZXl3b3JkPkRpc2Vh

c2UgTW9kZWxzLCBBbmltYWw8L2tleXdvcmQ+PGtleXdvcmQ+RHJvc29waGlsYS9nZW5ldGljczwv

a2V5d29yZD48a2V5d29yZD5Gb2NhbCBBZGhlc2lvbiBLaW5hc2UgMi8qZ2VuZXRpY3MvbWV0YWJv

bGlzbTwva2V5d29yZD48a2V5d29yZD5HZW5ldGljIExvY2kvZ2VuZXRpY3M8L2tleXdvcmQ+PGtl

eXdvcmQ+R2VuZXRpYyBQcmVkaXNwb3NpdGlvbiB0byBEaXNlYXNlL2dlbmV0aWNzPC9rZXl3b3Jk

PjxrZXl3b3JkPkdlbm9tZS1XaWRlIEFzc29jaWF0aW9uIFN0dWR5PC9rZXl3b3JkPjxrZXl3b3Jk

Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+

dGF1IFByb3RlaW5zL2dlbmV0aWNzLyptZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRh

dGVzPjx5ZWFyPjIwMTc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdW48L2RhdGU+PC9wdWItZGF0

ZXM+PC9kYXRlcz48aXNibj4xNDc2LTU1NzggKEVsZWN0cm9uaWMpJiN4RDsxMzU5LTQxODQgKExp

bmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3MTEzOTk4PC9hY2Nlc3Npb24tbnVtPjx1cmxz

PjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8y

NzExMzk5ODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM1NDQ0MDI0PC9j

dXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDM4L21wLjIwMTYuNTk8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk1vcmVhdTwv

QXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJlY051bT4zOTEzPC9SZWNOdW0+PHJlY29yZD48cmVj

LW51bWJlcj4zOTEzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1p

ZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzY2

NzE0MDUiPjM5MTM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBB

cnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1vcmVh

dSwgSy48L2F1dGhvcj48YXV0aG9yPkZsZW1pbmcsIEEuPC9hdXRob3I+PGF1dGhvcj5JbWFyaXNp

bywgUy48L2F1dGhvcj48YXV0aG9yPkxvcGV6IFJhbWlyZXosIEEuPC9hdXRob3I+PGF1dGhvcj5N

ZXJjZXIsIEouIEwuPC9hdXRob3I+PGF1dGhvcj5KaW1lbmV6LVNhbmNoZXosIE0uPC9hdXRob3I+

PGF1dGhvcj5CZW50bywgQy4gRi48L2F1dGhvcj48YXV0aG9yPlB1cmksIEMuPC9hdXRob3I+PGF1

dGhvcj5aYXZvZHN6a3ksIEUuPC9hdXRob3I+PGF1dGhvcj5TaWRkaXFpLCBGLjwvYXV0aG9yPjxh

dXRob3I+TGF2YXUsIEMuIFAuPC9hdXRob3I+PGF1dGhvcj5CZXR0b24sIE0uPC9hdXRob3I+PGF1

dGhvcj5PJmFwb3M7S2FuZSwgQy4gSi48L2F1dGhvcj48YXV0aG9yPldlY2hzbGVyLCBELiBTLjwv

YXV0aG9yPjxhdXRob3I+UnViaW5zenRlaW4sIEQuIEMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBNZWRpY2FsIEdlbmV0aWNzLCBV

bml2ZXJzaXR5IG9mIENhbWJyaWRnZSwgQ2FtYnJpZGdlIEluc3RpdHV0ZSBmb3IgTWVkaWNhbCBS

ZXNlYXJjaCwgQWRkZW5icm9va2UmYXBvcztzIEhvc3BpdGFsLCBDYW1icmlkZ2UgQmlvbWVkaWNh

bCBDYW1wdXMsIEhpbGxzIFJvYWQsIENhbWJyaWRnZSBDQjIgMFhZLCBVSy4mI3hEOzFdIERlcGFy

dG1lbnQgb2YgTWVkaWNhbCBHZW5ldGljcywgVW5pdmVyc2l0eSBvZiBDYW1icmlkZ2UsIENhbWJy

aWRnZSBJbnN0aXR1dGUgZm9yIE1lZGljYWwgUmVzZWFyY2gsIEFkZGVuYnJvb2tlJmFwb3M7cyBI

b3NwaXRhbCwgQ2FtYnJpZGdlIEJpb21lZGljYWwgQ2FtcHVzLCBIaWxscyBSb2FkLCBDYW1icmlk

Z2UgQ0IyIDBYWSwgVUsgWzJdIERlcGFydG1lbnQgb2YgUGh5c2lvbG9neSwgRGV2ZWxvcG1lbnQg

YW5kIE5ldXJvc2NpZW5jZSwgVW5pdmVyc2l0eSBvZiBDYW1icmlkZ2UsIERvd25pbmcgU3RyZWV0

LCBDYW1icmlkZ2UgQ0IyIDNFRywgVUsuJiN4RDtEZXBhcnRtZW50IG9mIEdlbmV0aWNzLCBVbml2

ZXJzaXR5IG9mIENhbWJyaWRnZSwgRG93bmluZyBTdHJlZXQsIENhbWJyaWRnZSBDQjIgM0VHLCBV

Sy4mI3hEOzFdIERlcGFydG1lbnQgb2YgUGVkaWF0cmljcywgRHVrZSBVbml2ZXJzaXR5IE1lZGlj

YWwgQ2VudGVyLCBEdXJoYW0sIE5vcnRoIENhcm9saW5hIDI3NzEwLCBVU0EgWzJdIERlcGFydG1l

bnQgb2YgUGhhcm1hY29sb2d5IGFuZCBDYW5jZXIgQmlvbG9neSwgRHVrZSBVbml2ZXJzaXR5IE1l

ZGljYWwgQ2VudGVyLCBEdXJoYW0sIE5vcnRoIENhcm9saW5hIDI3NzEwLCBVU0EuJiN4RDtEZXBh

cnRtZW50IG9mIFBlZGlhdHJpY3MsIER1a2UgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRlciwgRHVy

aGFtLCBOb3J0aCBDYXJvbGluYSAyNzcxMCwgVVNBLiYjeEQ7MV0gRGVwYXJ0bWVudCBvZiBNZWRp

Y2FsIEdlbmV0aWNzLCBVbml2ZXJzaXR5IG9mIENhbWJyaWRnZSwgQ2FtYnJpZGdlIEluc3RpdHV0

ZSBmb3IgTWVkaWNhbCBSZXNlYXJjaCwgQWRkZW5icm9va2UmYXBvcztzIEhvc3BpdGFsLCBDYW1i

cmlkZ2UgQmlvbWVkaWNhbCBDYW1wdXMsIEhpbGxzIFJvYWQsIENhbWJyaWRnZSBDQjIgMFhZLCBV

SyBbMl0gRGVwYXJ0bWVudCBvZiBHZW5ldGljcywgVW5pdmVyc2l0eSBvZiBDYW1icmlkZ2UsIERv

d25pbmcgU3RyZWV0LCBDYW1icmlkZ2UgQ0IyIDNFRywgVUsuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+UElDQUxNIG1vZHVsYXRlcyBhdXRvcGhhZ3kgYWN0aXZpdHkgYW5kIHRhdSBhY2N1

bXVsYXRpb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0IENvbW11bjwvc2Vjb25kYXJ5LXRp

dGxlPjwvdGl0bGVzPjxwYWdlcz40OTk4PC9wYWdlcz48dm9sdW1lPjU8L3ZvbHVtZT48ZWRpdGlv

bj4yMDE0LzA5LzIzPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9rZXl3b3Jk

PjxrZXl3b3JkPipBdXRvcGhhZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QXV0b3BoYWd5LVJlbGF0ZWQg

UHJvdGVpbiAxMjwva2V5d29yZD48a2V5d29yZD5DZWxsIExpbmU8L2tleXdvcmQ+PGtleXdvcmQ+

RHJvc29waGlsYTwva2V5d29yZD48a2V5d29yZD5FbmRvY3l0b3Npczwva2V5d29yZD48a2V5d29y

ZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+Rmlicm9ibGFzdHMvbWV0YWJvbGlzbTwva2V5d29y

ZD48a2V5d29yZD5HZW5vbWUtV2lkZSBBc3NvY2lhdGlvbiBTdHVkeTwva2V5d29yZD48a2V5d29y

ZD5IRUsyOTMgQ2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+SGVMYSBDZWxsczwva2V5d29yZD48a2V5

d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWNl

PC9rZXl3b3JkPjxrZXl3b3JkPk1vbm9tZXJpYyBDbGF0aHJpbiBBc3NlbWJseSBQcm90ZWlucy8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5QaGFnb3NvbWVzPC9rZXl3b3JkPjxrZXl3b3Jk

PlByb3RlaW4gQmluZGluZzwva2V5d29yZD48a2V5d29yZD5STkEsIFNtYWxsIEludGVyZmVyaW5n

L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3

b3JkPlNtYWxsIFViaXF1aXRpbi1SZWxhdGVkIE1vZGlmaWVyIFByb3RlaW5zL21ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+VHJhbnNmZWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlZlc2ljbGUt

QXNzb2NpYXRlZCBNZW1icmFuZSBQcm90ZWluIDIvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29y

ZD5aZWJyYWZpc2g8L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5zLyptZXRhYm9saXNtPC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5TZXAgMjI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4yMDQxLTE3MjMgKEVsZWN0

cm9uaWMpJiN4RDsyMDQxLTE3MjMgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1MjQx

OTI5PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNTI0MTkyOTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48Y3VzdG9tMj5QTUM0MTk5Mjg1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4x

MC4xMDM4L25jb21tczU5OTg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0

ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj

TnVtPjM5MTU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4x

MDYtMTA5PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzkxNTwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2NjcxNTA4Ij4zOTE1PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5BbmRvLCBLLjwvYXV0aG9yPjxhdXRo

b3I+QnJpb24sIEouIFAuPC9hdXRob3I+PGF1dGhvcj5TdHlnZWxib3V0LCBWLjwvYXV0aG9yPjxh

dXRob3I+U3VhaW4sIFYuPC9hdXRob3I+PGF1dGhvcj5BdXRoZWxldCwgTS48L2F1dGhvcj48YXV0

aG9yPkRlZGVja2VyLCBSLjwvYXV0aG9yPjxhdXRob3I+Q2hhbnV0LCBBLjwvYXV0aG9yPjxhdXRo

b3I+TGFjb3IsIFAuPC9hdXRob3I+PGF1dGhvcj5MYXZhdXIsIEouPC9hdXRob3I+PGF1dGhvcj5T

YXpkb3ZpdGNoLCBWLjwvYXV0aG9yPjxhdXRob3I+Um9nYWV2YSwgRS48L2F1dGhvcj48YXV0aG9y

PlBvdGllciwgTS4gQy48L2F1dGhvcj48YXV0aG9yPkR1eWNrYWVydHMsIEMuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+TGFib3JhdG9pcmUgZGUgTmV1cm9w

YXRob2xvZ2llIEVzY291cm9sbGUsIEhvcGl0YWwgZGUgbGEgUGl0aWUtU2FscGV0cmllcmUsIEFQ

LUhQLCBQYXJpcywgRnJhbmNlLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNsYXRocmlu

IGFkYXB0b3IgQ0FMTS9QSUNBTE0gaXMgYXNzb2NpYXRlZCB3aXRoIG5ldXJvZmlicmlsbGFyeSB0

YW5nbGVzIGFuZCBpcyBjbGVhdmVkIGluIEFsemhlaW1lciZhcG9zO3MgYnJhaW5zPC90aXRsZT48

c2Vjb25kYXJ5LXRpdGxlPkFjdGEgTmV1cm9wYXRob2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxl

cz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BY3RhIE5ldXJvcGF0aG9sPC9mdWxsLXRpdGxlPjwv

cGVyaW9kaWNhbD48cGFnZXM+ODYxLTc4PC9wYWdlcz48dm9sdW1lPjEyNTwvdm9sdW1lPjxudW1i

ZXI+NjwvbnVtYmVyPjxlZGl0aW9uPjIwMTMvMDQvMTc8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3

b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwg

ODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvZXRpb2xvZ3kv

Km1ldGFib2xpc20vKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DYXNlLUNvbnRyb2wgU3R1

ZGllczwva2V5d29yZD48a2V5d29yZD5Eb3duIFN5bmRyb21lL2V0aW9sb2d5L21ldGFib2xpc20v

cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1h

bnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWNyb2dsaWEvcGh5

c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5N

b25vbWVyaWMgQ2xhdGhyaW4gQXNzZW1ibHkgUHJvdGVpbnMvKm1ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+TmV1cm9maWJyaWxsYXJ5IFRhbmdsZXMvKm1ldGFib2xpc20vKnBhdGhvbG9neTwv

a2V5d29yZD48a2V5d29yZD50YXUgUHJvdGVpbnMvbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdv

cmRzPjxkYXRlcz48eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVuPC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQzMi0wNTMzIChFbGVjdHJvbmljKSYjeEQ7MDAwMS02

MzIyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzU4OTAzMDwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9w

dWJtZWQvMjM1ODkwMzA8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjEwLjEwMDcvczAwNDAxLTAxMy0xMTExLXo8L2VsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkNoYXB1aXM8L0F1dGhvcj48WWVhcj4y

MDEzPC9ZZWFyPjxSZWNOdW0+MzkxMjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MzkxMjwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2NjcxMzQ0Ij4zOTEyPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DaGFwdWlzLCBKLjwvYXV0aG9y

PjxhdXRob3I+SGFuc21hbm5lbCwgRi48L2F1dGhvcj48YXV0aG9yPkdpc3RlbGluY2ssIE0uPC9h

dXRob3I+PGF1dGhvcj5Nb3VuaWVyLCBBLjwvYXV0aG9yPjxhdXRob3I+VmFuIENhdXdlbmJlcmdo

ZSwgQy48L2F1dGhvcj48YXV0aG9yPktvbGVuLCBLLiBWLjwvYXV0aG9yPjxhdXRob3I+R2VsbGVy

LCBGLjwvYXV0aG9yPjxhdXRob3I+U290dGVqZWF1LCBZLjwvYXV0aG9yPjxhdXRob3I+SGFyb2xk

LCBELjwvYXV0aG9yPjxhdXRob3I+RG91cmxlbiwgUC48L2F1dGhvcj48YXV0aG9yPkdyZW5pZXIt

Qm9sZXksIEIuPC9hdXRob3I+PGF1dGhvcj5LYW1hdGFuaSwgWS48L2F1dGhvcj48YXV0aG9yPkRl

bGVwaW5lLCBCLjwvYXV0aG9yPjxhdXRob3I+RGVtaWF1dHRlLCBGLjwvYXV0aG9yPjxhdXRob3I+

WmVsZW5pa2EsIEQuPC9hdXRob3I+PGF1dGhvcj5ab21tZXIsIE4uPC9hdXRob3I+PGF1dGhvcj5I

YW1kYW5lLCBNLjwvYXV0aG9yPjxhdXRob3I+QmVsbGVuZ3VleiwgQy48L2F1dGhvcj48YXV0aG9y

PkRhcnRpZ3VlcywgSi4gRi48L2F1dGhvcj48YXV0aG9yPkhhdXcsIEouIEouPC9hdXRob3I+PGF1

dGhvcj5MZXRyb25uZSwgRi48L2F1dGhvcj48YXV0aG9yPkF5cmFsLCBBLiBNLjwvYXV0aG9yPjxh

dXRob3I+U2xlZWdlcnMsIEsuPC9hdXRob3I+PGF1dGhvcj5TY2hlbGxlbnMsIEEuPC9hdXRob3I+

PGF1dGhvcj5Ccm9lY2ssIEwuIFYuPC9hdXRob3I+PGF1dGhvcj5FbmdlbGJvcmdocywgUy48L2F1

dGhvcj48YXV0aG9yPkRlIERleW4sIFAuIFAuPC9hdXRob3I+PGF1dGhvcj5WYW5kZW5iZXJnaGUs

IFIuPC9hdXRob3I+PGF1dGhvcj5PJmFwb3M7RG9ub3ZhbiwgTS48L2F1dGhvcj48YXV0aG9yPk93

ZW4sIE0uPC9hdXRob3I+PGF1dGhvcj5FcGVsYmF1bSwgSi48L2F1dGhvcj48YXV0aG9yPk1lcmNr

ZW4sIE0uPC9hdXRob3I+PGF1dGhvcj5LYXJyYW4sIEUuPC9hdXRob3I+PGF1dGhvcj5CYW50c2No

ZWZmLCBNLjwvYXV0aG9yPjxhdXRob3I+RHJld2VzLCBHLjwvYXV0aG9yPjxhdXRob3I+Sm9iZXJ0

eSwgRy48L2F1dGhvcj48YXV0aG9yPkNhbXBpb24sIEQuPC9hdXRob3I+PGF1dGhvcj5PY3RhdmUs

IEouIE4uPC9hdXRob3I+PGF1dGhvcj5CZXJyLCBDLjwvYXV0aG9yPjxhdXRob3I+TGF0aHJvcCwg

TS48L2F1dGhvcj48YXV0aG9yPkNhbGxhZXJ0cywgUC48L2F1dGhvcj48YXV0aG9yPk1hbm4sIEQu

PC9hdXRob3I+PGF1dGhvcj5XaWxsaWFtcywgSi48L2F1dGhvcj48YXV0aG9yPkJ1ZWUsIEwuPC9h

dXRob3I+PGF1dGhvcj5EZXdhY2h0ZXIsIEkuPC9hdXRob3I+PGF1dGhvcj5WYW4gQnJvZWNraG92

ZW4sIEMuPC9hdXRob3I+PGF1dGhvcj5BbW91eWVsLCBQLjwvYXV0aG9yPjxhdXRob3I+TW9lY2hh

cnMsIEQuPC9hdXRob3I+PGF1dGhvcj5EZXJtYXV0LCBCLjwvYXV0aG9yPjxhdXRob3I+TGFtYmVy

dCwgSi4gQy48L2F1dGhvcj48YXV0aG9yPkdlcmFkIGNvbnNvcnRpdW08L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz4xXSBJTlNFUk0gVTc0NCwgVW5pdmVyc2l0

ZSBMaWxsZSBOb3JkIGRlIEZyYW5jZSwgSW5zdGl0dXQgcGFzdGV1ciBkZSBMaWxsZSwgTGlsbGUs

IEZyYW5jZSBbMl0gVW5pdmVyc2l0ZSBMaWxsZSBOb3JkIGRlIEZyYW5jZSwgSW5zdGl0dXQgcGFz

dGV1ciBkZSBMaWxsZSwgTGlsbGUsIEZyYW5jZSBbM10gVW5pdmVyc2l0ZSBMaWxsZS1Ob3JkIGRl

IEZyYW5jZSwgSW5zdGl0dXQgcGFzdGV1ciBkZSBMaWxsZSwgTGlsbGUsIEZyYW5jZS48L2F1dGgt

YWRkcmVzcz48dGl0bGVzPjx0aXRsZT5JbmNyZWFzZWQgZXhwcmVzc2lvbiBvZiBCSU4xIG1lZGlh

dGVzIEFsemhlaW1lciBnZW5ldGljIHJpc2sgYnkgbW9kdWxhdGluZyB0YXUgcGF0aG9sb2d5PC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk1vbCBQc3ljaGlhdHJ5PC9zZWNvbmRhcnktdGl0bGU+PC90

aXRsZXM+PHBhZ2VzPjEyMjUtMzQ8L3BhZ2VzPjx2b2x1bWU+MTg8L3ZvbHVtZT48bnVtYmVyPjEx

PC9udW1iZXI+PGVkaXRpb24+MjAxMy8wMi8xMzwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+

QWRhcHRvciBQcm90ZWlucywgU2lnbmFsIFRyYW5zZHVjaW5nL2Jpb3N5bnRoZXNpcy8qZ2VuZXRp

Y3M8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmdlbmV0aWNzL21ldGFib2xp

c20vKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3Jk

PkJyYWluL21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNhcnJpZXIgUHJv

dGVpbnMvZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DYXNlLUNvbnRyb2wg

U3R1ZGllczwva2V5d29yZD48a2V5d29yZD5DZWxscywgQ3VsdHVyZWQ8L2tleXdvcmQ+PGtleXdv

cmQ+RHJvc29waGlsYSBQcm90ZWlucy9kZWZpY2llbmN5L2dlbmV0aWNzL21ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+RHJvc29waGlsYSBtZWxhbm9nYXN0ZXIvZ2VuZXRpY3MvbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5FbmRvcGhlbm90eXBlczwva2V5d29yZD48a2V5d29yZD5HZW5l

IEV4cHJlc3Npb24vZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXRpYyBQcmVkaXNwb3Np

dGlvbiB0byBEaXNlYXNlLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdv

cmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5OZXJ2ZSBEZWdlbmVyYXRpb24vZ2Vu

ZXRpY3MvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk51Y2xlYXIgUHJvdGVpbnMvYmlvc3lu

dGhlc2lzLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5QbGFxdWUsIEFteWxvaWQvcGF0aG9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBvbHltb3JwaGlzbSwgU2luZ2xlIE51Y2xlb3RpZGUvZ2Vu

ZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+U3luYXB0b3NvbWVzL3BhdGhvbG9neTwva2V5d29yZD48

a2V5d29yZD5UcmFuc2NyaXB0aW9uIEZhY3RvcnMvZGVmaWNpZW5jeS9nZW5ldGljcy9tZXRhYm9s

aXNtPC9rZXl3b3JkPjxrZXl3b3JkPlR1bW9yIFN1cHByZXNzb3IgUHJvdGVpbnMvYmlvc3ludGhl

c2lzLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD50YXUgUHJvdGVpbnMvYW50YWdvbmlzdHMg

JmFtcDsgaW5oaWJpdG9ycy8qbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+Tm92PC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PGlzYm4+MTQ3Ni01NTc4IChFbGVjdHJvbmljKSYjeEQ7MTM1OS00MTg0IChMaW5raW5n

KTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzM5OTkxNDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVs

YXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjMzOTk5

MTQ8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMzgwNzY2MTwvY3VzdG9t

Mj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9tcC4yMDEzLjE8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkRvdXJsZW48L0F1dGhv

cj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNOdW0+MzkxNDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1i

ZXI+MzkxNDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3

YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2NjcxNDMw

Ij4zOTE0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs

ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Eb3VybGVuLCBQ

LjwvYXV0aG9yPjxhdXRob3I+RmVybmFuZGV6LUdvbWV6LCBGLiBKLjwvYXV0aG9yPjxhdXRob3I+

RHVwb250LCBDLjwvYXV0aG9yPjxhdXRob3I+R3Jlbmllci1Cb2xleSwgQi48L2F1dGhvcj48YXV0

aG9yPkJlbGxlbmd1ZXosIEMuPC9hdXRob3I+PGF1dGhvcj5PYnJpb3QsIEguPC9hdXRob3I+PGF1

dGhvcj5DYWlsbGllcmV6LCBSLjwvYXV0aG9yPjxhdXRob3I+U290dGVqZWF1LCBZLjwvYXV0aG9y

PjxhdXRob3I+Q2hhcHVpcywgSi48L2F1dGhvcj48YXV0aG9yPkJyZXR0ZXZpbGxlLCBBLjwvYXV0

aG9yPjxhdXRob3I+QWJkZWxmZXR0YWgsIEYuPC9hdXRob3I+PGF1dGhvcj5EZWxheSwgQy48L2F1

dGhvcj48YXV0aG9yPk1hbG1hbmNoZSwgTi48L2F1dGhvcj48YXV0aG9yPlNvaW5pbmVuLCBILjwv

YXV0aG9yPjxhdXRob3I+SGlsdHVuZW4sIE0uPC9hdXRob3I+PGF1dGhvcj5HYWxhcywgTS4gQy48

L2F1dGhvcj48YXV0aG9yPkFtb3V5ZWwsIFAuPC9hdXRob3I+PGF1dGhvcj5TZXJnZWFudCwgTi48

L2F1dGhvcj48YXV0aG9yPkJ1ZWUsIEwuPC9hdXRob3I+PGF1dGhvcj5MYW1iZXJ0LCBKLiBDLjwv

YXV0aG9yPjxhdXRob3I+RGVybWF1dCwgQi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5JbnN0aXR1dCBQYXN0ZXVyIGRlIExpbGxlLCBMaWxsZSwgRnJhbmNl

LiYjeEQ7SU5TRVJNLCBVTVIgMTE2NywgTGlsbGUsIEZyYW5jZS4mI3hEO1VuaXZlcnNpdGUgZGUg

TGlsbGUsIExpbGxlLCBGcmFuY2UuJiN4RDtJTlNFUk0sIFVNUi1TIDExNzIsIEFsemhlaW1lciBh

bmQgVGF1b3BhdGhpZXMsIExpbGxlLCBGcmFuY2UuJiN4RDtVbml2LkxpbGxlLCBKUEFyYywgTGls

bGUsIEZyYW5jZS4mI3hEO0NIUlUsIE1lbW9yeSBDbGluaWMsIExpbGxlLCBGcmFuY2UuJiN4RDtJ

bnN0aXR1dGUgb2YgQ2xpbmljYWwgTWVkaWNpbmUtTmV1cm9sb2d5IGFuZCBEZXBhcnRtZW50IG9m

IE5ldXJvbG9neSwgVW5pdmVyc2l0eSBvZiBFYXN0ZXJuIEZpbmxhbmQgYW5kIEt1b3BpbyBVbml2

ZXJzaXR5IEhvc3BpdGFsLCBLdW9waW8sIEZpbmxhbmQuJiN4RDtJbnN0aXR1dGUgb2YgQmlvbWVk

aWNpbmUsIFVuaXZlcnNpdHkgb2YgRWFzdGVybiBGaW5sYW5kLCBLdW9waW8sIEZpbmxhbmQuJiN4

RDtDZW50cmUgSG9zcGl0YWxpZXIgUmVnaW9uYWwgVW5pdmVyc2l0YWlyZSBkZSBMaWxsZSwgTGls

bGUsIEZyYW5jZS4mI3hEO0NlbnRlciBmb3IgTWVkaWNhbCBHZW5ldGljcywgR2hlbnQgVW5pdmVy

c2l0eSBIb3NwaXRhbCwgR2hlbnQsIEJlbGdpdW0uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+RnVuY3Rpb25hbCBzY3JlZW5pbmcgb2YgQWx6aGVpbWVyIHJpc2sgbG9jaSBpZGVudGlmaWVz

IFBUSzJCIGFzIGFuIGluIHZpdm8gbW9kdWxhdG9yIGFuZCBlYXJseSBtYXJrZXIgb2YgVGF1IHBh

dGhvbG9neTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Nb2wgUHN5Y2hpYXRyeTwvc2Vjb25kYXJ5

LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz44NzQtODgzPC9wYWdlcz48dm9sdW1lPjIyPC92b2x1bWU+

PG51bWJlcj42PC9udW1iZXI+PGVkaXRpb24+MjAxNi8wNC8yNzwvZWRpdGlvbj48a2V5d29yZHM+

PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+QW5p

bWFsczwva2V5d29yZD48a2V5d29yZD5CaW9tYXJrZXJzPC9rZXl3b3JkPjxrZXl3b3JkPkRpc2Vh

c2UgTW9kZWxzLCBBbmltYWw8L2tleXdvcmQ+PGtleXdvcmQ+RHJvc29waGlsYS9nZW5ldGljczwv

a2V5d29yZD48a2V5d29yZD5Gb2NhbCBBZGhlc2lvbiBLaW5hc2UgMi8qZ2VuZXRpY3MvbWV0YWJv

bGlzbTwva2V5d29yZD48a2V5d29yZD5HZW5ldGljIExvY2kvZ2VuZXRpY3M8L2tleXdvcmQ+PGtl

eXdvcmQ+R2VuZXRpYyBQcmVkaXNwb3NpdGlvbiB0byBEaXNlYXNlL2dlbmV0aWNzPC9rZXl3b3Jk

PjxrZXl3b3JkPkdlbm9tZS1XaWRlIEFzc29jaWF0aW9uIFN0dWR5PC9rZXl3b3JkPjxrZXl3b3Jk

Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+

dGF1IFByb3RlaW5zL2dlbmV0aWNzLyptZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRh

dGVzPjx5ZWFyPjIwMTc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdW48L2RhdGU+PC9wdWItZGF0

ZXM+PC9kYXRlcz48aXNibj4xNDc2LTU1NzggKEVsZWN0cm9uaWMpJiN4RDsxMzU5LTQxODQgKExp

bmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3MTEzOTk4PC9hY2Nlc3Npb24tbnVtPjx1cmxz

PjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8y

NzExMzk5ODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM1NDQ0MDI0PC9j

dXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDM4L21wLjIwMTYuNTk8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk1vcmVhdTwv

QXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJlY051bT4zOTEzPC9SZWNOdW0+PHJlY29yZD48cmVj

LW51bWJlcj4zOTEzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1p

ZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzY2

NzE0MDUiPjM5MTM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBB

cnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1vcmVh

dSwgSy48L2F1dGhvcj48YXV0aG9yPkZsZW1pbmcsIEEuPC9hdXRob3I+PGF1dGhvcj5JbWFyaXNp

bywgUy48L2F1dGhvcj48YXV0aG9yPkxvcGV6IFJhbWlyZXosIEEuPC9hdXRob3I+PGF1dGhvcj5N

ZXJjZXIsIEouIEwuPC9hdXRob3I+PGF1dGhvcj5KaW1lbmV6LVNhbmNoZXosIE0uPC9hdXRob3I+

PGF1dGhvcj5CZW50bywgQy4gRi48L2F1dGhvcj48YXV0aG9yPlB1cmksIEMuPC9hdXRob3I+PGF1

dGhvcj5aYXZvZHN6a3ksIEUuPC9hdXRob3I+PGF1dGhvcj5TaWRkaXFpLCBGLjwvYXV0aG9yPjxh

dXRob3I+TGF2YXUsIEMuIFAuPC9hdXRob3I+PGF1dGhvcj5CZXR0b24sIE0uPC9hdXRob3I+PGF1

dGhvcj5PJmFwb3M7S2FuZSwgQy4gSi48L2F1dGhvcj48YXV0aG9yPldlY2hzbGVyLCBELiBTLjwv

YXV0aG9yPjxhdXRob3I+UnViaW5zenRlaW4sIEQuIEMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBNZWRpY2FsIEdlbmV0aWNzLCBV

bml2ZXJzaXR5IG9mIENhbWJyaWRnZSwgQ2FtYnJpZGdlIEluc3RpdHV0ZSBmb3IgTWVkaWNhbCBS

ZXNlYXJjaCwgQWRkZW5icm9va2UmYXBvcztzIEhvc3BpdGFsLCBDYW1icmlkZ2UgQmlvbWVkaWNh

bCBDYW1wdXMsIEhpbGxzIFJvYWQsIENhbWJyaWRnZSBDQjIgMFhZLCBVSy4mI3hEOzFdIERlcGFy

dG1lbnQgb2YgTWVkaWNhbCBHZW5ldGljcywgVW5pdmVyc2l0eSBvZiBDYW1icmlkZ2UsIENhbWJy

aWRnZSBJbnN0aXR1dGUgZm9yIE1lZGljYWwgUmVzZWFyY2gsIEFkZGVuYnJvb2tlJmFwb3M7cyBI

b3NwaXRhbCwgQ2FtYnJpZGdlIEJpb21lZGljYWwgQ2FtcHVzLCBIaWxscyBSb2FkLCBDYW1icmlk

Z2UgQ0IyIDBYWSwgVUsgWzJdIERlcGFydG1lbnQgb2YgUGh5c2lvbG9neSwgRGV2ZWxvcG1lbnQg

YW5kIE5ldXJvc2NpZW5jZSwgVW5pdmVyc2l0eSBvZiBDYW1icmlkZ2UsIERvd25pbmcgU3RyZWV0

LCBDYW1icmlkZ2UgQ0IyIDNFRywgVUsuJiN4RDtEZXBhcnRtZW50IG9mIEdlbmV0aWNzLCBVbml2

ZXJzaXR5IG9mIENhbWJyaWRnZSwgRG93bmluZyBTdHJlZXQsIENhbWJyaWRnZSBDQjIgM0VHLCBV

Sy4mI3hEOzFdIERlcGFydG1lbnQgb2YgUGVkaWF0cmljcywgRHVrZSBVbml2ZXJzaXR5IE1lZGlj

YWwgQ2VudGVyLCBEdXJoYW0sIE5vcnRoIENhcm9saW5hIDI3NzEwLCBVU0EgWzJdIERlcGFydG1l

bnQgb2YgUGhhcm1hY29sb2d5IGFuZCBDYW5jZXIgQmlvbG9neSwgRHVrZSBVbml2ZXJzaXR5IE1l

ZGljYWwgQ2VudGVyLCBEdXJoYW0sIE5vcnRoIENhcm9saW5hIDI3NzEwLCBVU0EuJiN4RDtEZXBh

cnRtZW50IG9mIFBlZGlhdHJpY3MsIER1a2UgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRlciwgRHVy

aGFtLCBOb3J0aCBDYXJvbGluYSAyNzcxMCwgVVNBLiYjeEQ7MV0gRGVwYXJ0bWVudCBvZiBNZWRp

Y2FsIEdlbmV0aWNzLCBVbml2ZXJzaXR5IG9mIENhbWJyaWRnZSwgQ2FtYnJpZGdlIEluc3RpdHV0

ZSBmb3IgTWVkaWNhbCBSZXNlYXJjaCwgQWRkZW5icm9va2UmYXBvcztzIEhvc3BpdGFsLCBDYW1i

cmlkZ2UgQmlvbWVkaWNhbCBDYW1wdXMsIEhpbGxzIFJvYWQsIENhbWJyaWRnZSBDQjIgMFhZLCBV

SyBbMl0gRGVwYXJ0bWVudCBvZiBHZW5ldGljcywgVW5pdmVyc2l0eSBvZiBDYW1icmlkZ2UsIERv

d25pbmcgU3RyZWV0LCBDYW1icmlkZ2UgQ0IyIDNFRywgVUsuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+UElDQUxNIG1vZHVsYXRlcyBhdXRvcGhhZ3kgYWN0aXZpdHkgYW5kIHRhdSBhY2N1

bXVsYXRpb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0IENvbW11bjwvc2Vjb25kYXJ5LXRp

dGxlPjwvdGl0bGVzPjxwYWdlcz40OTk4PC9wYWdlcz48dm9sdW1lPjU8L3ZvbHVtZT48ZWRpdGlv

bj4yMDE0LzA5LzIzPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9rZXl3b3Jk

PjxrZXl3b3JkPipBdXRvcGhhZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QXV0b3BoYWd5LVJlbGF0ZWQg

UHJvdGVpbiAxMjwva2V5d29yZD48a2V5d29yZD5DZWxsIExpbmU8L2tleXdvcmQ+PGtleXdvcmQ+

RHJvc29waGlsYTwva2V5d29yZD48a2V5d29yZD5FbmRvY3l0b3Npczwva2V5d29yZD48a2V5d29y

ZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+Rmlicm9ibGFzdHMvbWV0YWJvbGlzbTwva2V5d29y

ZD48a2V5d29yZD5HZW5vbWUtV2lkZSBBc3NvY2lhdGlvbiBTdHVkeTwva2V5d29yZD48a2V5d29y

ZD5IRUsyOTMgQ2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+SGVMYSBDZWxsczwva2V5d29yZD48a2V5

d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWNl

PC9rZXl3b3JkPjxrZXl3b3JkPk1vbm9tZXJpYyBDbGF0aHJpbiBBc3NlbWJseSBQcm90ZWlucy8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5QaGFnb3NvbWVzPC9rZXl3b3JkPjxrZXl3b3Jk

PlByb3RlaW4gQmluZGluZzwva2V5d29yZD48a2V5d29yZD5STkEsIFNtYWxsIEludGVyZmVyaW5n

L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3

b3JkPlNtYWxsIFViaXF1aXRpbi1SZWxhdGVkIE1vZGlmaWVyIFByb3RlaW5zL21ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+VHJhbnNmZWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlZlc2ljbGUt

QXNzb2NpYXRlZCBNZW1icmFuZSBQcm90ZWluIDIvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29y

ZD5aZWJyYWZpc2g8L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5zLyptZXRhYm9saXNtPC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5TZXAgMjI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4yMDQxLTE3MjMgKEVsZWN0

cm9uaWMpJiN4RDsyMDQxLTE3MjMgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1MjQx

OTI5PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNTI0MTkyOTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48Y3VzdG9tMj5QTUM0MTk5Mjg1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4x

MC4xMDM4L25jb21tczU5OTg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0

ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 106-109, there are a number of genes identified like PICALM, BIN1, PPK2B. These genes are involved in Tau-mediated synaptic dysfunctions but also in APP metabolism and Aβ clearance, meaning that some of these genes are really at the border between amyloid and Tau pathologies, and thus research has to focus on them. EtiologyTau lesionsIsoformsRefsAlzheimer’s?diseaseDown syndromeA?, aging, genetics…Neurofibrillary tangles (NFTs) & dystrophic neurites3R + 4R ADDIN EN.CITE <EndNote><Cite><Author>Goedert</Author><Year>1992</Year><RecNum>4644</RecNum><DisplayText><style face="superscript">110</style></DisplayText><record><rec-number>4644</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1544482433">4644</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Goedert, M.</author><author>Spillantini, M. G.</author><author>Cairns, N. J.</author><author>Crowther, R. A.</author></authors></contributors><titles><title>Tau proteins of alzheimer paired helical filaments: Abnormal phosphorylation of all six brain isoforms</title><secondary-title>Neuron</secondary-title></titles><periodical><full-title>Neuron</full-title></periodical><pages>159-168</pages><volume>8</volume><number>1</number><dates><year>1992</year><pub-dates><date>1992/01</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>0896-6273</isbn><urls><related-urls><url>(92)90117-v</url></related-urls></urls><electronic-resource-num>10.1016/0896-6273(92)90117-v</electronic-resource-num></record></Cite></EndNote>110Argyrophilic grain diseaseAgingArgyrophilic grains in limbic areas4R>>3R ADDIN EN.CITE <EndNote><Cite><Author>Tolnay</Author><Year>2002</Year><RecNum>4666</RecNum><DisplayText><style face="superscript">111</style></DisplayText><record><rec-number>4666</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1544482561">4666</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tolnay, M.</author><author>Sergeant, N.</author><author>Ghestem, A.</author><author>Chalbot, S.</author><author>De Vos, R. A.</author><author>Jansen Steur, E. N.</author><author>Probst, A.</author><author>Delacourte, A.</author></authors></contributors><auth-address>Institute of Pathology, Division of Neuropathology, Basel University, Schonbeinstrasse 40, 4003 Basel, Switzerland. mtolnay@uhbs.ch</auth-address><titles><title>Argyrophilic grain disease and Alzheimer&apos;s disease are distinguished by their different distribution of tau protein isoforms</title><secondary-title>Acta Neuropathol</secondary-title></titles><periodical><full-title>Acta Neuropathol</full-title></periodical><pages>425-34</pages><volume>104</volume><number>4</number><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Alzheimer Disease/metabolism/*pathology</keyword><keyword>Blotting, Western</keyword><keyword>*Brain Chemistry</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunohistochemistry</keyword><keyword>Male</keyword><keyword>Phosphorylation</keyword><keyword>Protein Isoforms</keyword><keyword>Tauopathies/metabolism/*pathology</keyword><keyword>tau Proteins/*chemistry</keyword></keywords><dates><year>2002</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0001-6322 (Print)&#xD;0001-6322 (Linking)</isbn><accession-num>12200631</accession-num><urls><related-urls><url> with self-injury behaviorChronic traumatic encephalopathiesDementia pugilisticaTraumatic brain injuryRepeated head traumaNFTs & dystrophic neuritesAstrocytic tangles3R + 4RPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib2Y8L0F1dGhvcj48WWVhcj4xOTkyPC9ZZWFyPjxSZWNO

dW0+NDY0NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjEx

Mi0xMTQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40NjQ3PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDQ0ODI0MzMiPjQ2NDc8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhvZiwgUC4gUi48L2F1dGhvcj48YXV0

aG9yPkRlbGFjb3VydGUsIEEuPC9hdXRob3I+PGF1dGhvcj5Cb3VyYXMsIEMuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkRpc3RyaWJ1dGlvbiBvZiBjb3J0

aWNhbCBuZXVyb2ZpYnJpbGxhcnkgdGFuZ2xlcyBpbiBwcm9ncmVzc2l2ZSBzdXByYW51Y2xlYXIg

cGFsc3k6IEEgcXVhbnRpdGF0aXZlIGFuYWx5c2lzIG9mIHNpeCBjYXNlczwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5BY3RhIE5ldXJvcGF0aG9sb2dpY2E8L3NlY29uZGFyeS10aXRsZT48L3RpdGxl

cz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BY3RhIE5ldXJvcGF0aG9sb2dpY2E8L2Z1bGwtdGl0

bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz40NS01MTwvcGFnZXM+PHZvbHVtZT44NDwvdm9sdW1lPjxu

dW1iZXI+MTwvbnVtYmVyPjxkYXRlcz48eWVhcj4xOTkyPC95ZWFyPjwvZGF0ZXM+PHB1Ymxpc2hl

cj5TcHJpbmdlciBOYXR1cmUgQW1lcmljYSwgSW5jPC9wdWJsaXNoZXI+PGlzYm4+MDAwMS02MzIy

JiN4RDsxNDMyLTA1MzM8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5k

b2kub3JnLzEwLjEwMDcvYmYwMDQyNzIxNDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9iZjAwNDI3MjE0PC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5Ib2Y8L0F1dGhvcj48WWVhcj4x

OTkxPC9ZZWFyPjxSZWNOdW0+NDY0NTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+NDY0NTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTQ0NDgyNDMzIj40NjQ1PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Ib2YsIFAuIFIuPC9hdXRob3I+

PGF1dGhvcj5LbmFiZSwgUi48L2F1dGhvcj48YXV0aG9yPkJvdmllciwgUC48L2F1dGhvcj48YXV0

aG9yPkJvdXJhcywgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48

dGl0bGU+TmV1cm9wYXRob2xvZ2ljYWwgb2JzZXJ2YXRpb25zIGluIGEgY2FzZSBvZiBhdXRpc20g

cHJlc2VudGluZyB3aXRoIHNlbGYtaW5qdXJ5IGJlaGF2aW9yPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPkFjdGEgTmV1cm9wYXRob2xvZ2ljYTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJp

b2RpY2FsPjxmdWxsLXRpdGxlPkFjdGEgTmV1cm9wYXRob2xvZ2ljYTwvZnVsbC10aXRsZT48L3Bl

cmlvZGljYWw+PHBhZ2VzPjMyMS0zMjY8L3BhZ2VzPjx2b2x1bWU+ODI8L3ZvbHVtZT48bnVtYmVy

PjQ8L251bWJlcj48ZGF0ZXM+PHllYXI+MTk5MTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjE5OTEv

MDk8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPlNwcmluZ2VyIE5hdHVyZSBB

bWVyaWNhLCBJbmM8L3B1Ymxpc2hlcj48aXNibj4wMDAxLTYzMjImI3hEOzE0MzItMDUzMzwvaXNi

bj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAwNy9iZjAw

MzA4ODE5PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4xMDA3L2JmMDAzMDg4MTk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48Q2l0ZT48QXV0aG9yPlNjaG1pZHQ8L0F1dGhvcj48WWVhcj4yMDAxPC9ZZWFyPjxSZWNO

dW0+NDY2NTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+NDY2NTwvcmVjLW51bWJlcj48Zm9y

ZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0

c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTQ0NDgyNTM4Ij40NjY1PC9rZXk+PC9mb3JlaWduLWtl

eXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmli

dXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TY2htaWR0LCBNLiBMLjwvYXV0aG9yPjxhdXRob3I+Wmh1

a2FyZXZhLCBWLjwvYXV0aG9yPjxhdXRob3I+TmV3ZWxsLCBLLiBMLjwvYXV0aG9yPjxhdXRob3I+

TGVlLCBWLiBNLjwvYXV0aG9yPjxhdXRob3I+VHJvamFub3dza2ksIEouIFEuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQYXRob2xv

Z3kgYW5kIExhYm9yYXRvcnkgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgUGVubnN5bHZhbmlhIFNj

aG9vbCBvZiBNZWRpY2luZSwgUGhpbGFkZWxwaGlhIDE5MTA0LTQyODMsIFVTQS48L2F1dGgtYWRk

cmVzcz48dGl0bGVzPjx0aXRsZT5UYXUgaXNvZm9ybSBwcm9maWxlIGFuZCBwaG9zcGhvcnlsYXRp

b24gc3RhdGUgaW4gZGVtZW50aWEgcHVnaWxpc3RpY2EgcmVjYXBpdHVsYXRlIEFsemhlaW1lciZh

cG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BY3RhIE5ldXJvcGF0aG9sPC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QWN0YSBOZXVy

b3BhdGhvbDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjUxOC0yNDwvcGFnZXM+PHZv

bHVtZT4xMDE8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWdl

ZDwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qbWV0YWJvbGlzbS9wYXRob2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+QXRobGV0aWMgSW5qdXJpZXMvKm1ldGFib2xpc20vcGF0aG9s

b2d5L3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5CbG90dGluZywgV2VzdGVybjwv

a2V5d29yZD48a2V5d29yZD5Cb3hpbmcvKmluanVyaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWlu

IEluanVyaWVzLyptZXRhYm9saXNtL3BhdGhvbG9neS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+Q2VudHJhbCBOZXJ2b3VzIFN5c3RlbS9pbmp1cmllcy8qbWV0YWJvbGlzbS9wYXRo

b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RXBpdG9wZXMvaW1tdW5vbG9neTwva2V5d29yZD48a2V5

d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vaGlzdG9jaGVtaXN0cnk8L2tleXdv

cmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5OZXVyb2ZpYnJpbGxhcnkgVGFuZ2xl

cy9tZXRhYm9saXNtL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5OZXVyb25zLyptZXRhYm9s

aXNtL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5QaG9zcGhvcnlsYXRpb248L2tleXdvcmQ+

PGtleXdvcmQ+UHJvdGVpbiBJc29mb3Jtcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPnRh

dSBQcm90ZWlucy8qbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDAxPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWF5PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGlzYm4+MDAwMS02MzIyIChQcmludCkmI3hEOzAwMDEtNjMyMiAoTGlua2luZyk8L2lzYm4+PGFj

Y2Vzc2lvbi1udW0+MTE0ODQ4MjQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48

dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTE0ODQ4MjQ8L3VybD48L3Jl

bGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib2Y8L0F1dGhvcj48WWVhcj4xOTkyPC9ZZWFyPjxSZWNO

dW0+NDY0NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjEx

Mi0xMTQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40NjQ3PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDQ0ODI0MzMiPjQ2NDc8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhvZiwgUC4gUi48L2F1dGhvcj48YXV0

aG9yPkRlbGFjb3VydGUsIEEuPC9hdXRob3I+PGF1dGhvcj5Cb3VyYXMsIEMuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkRpc3RyaWJ1dGlvbiBvZiBjb3J0

aWNhbCBuZXVyb2ZpYnJpbGxhcnkgdGFuZ2xlcyBpbiBwcm9ncmVzc2l2ZSBzdXByYW51Y2xlYXIg

cGFsc3k6IEEgcXVhbnRpdGF0aXZlIGFuYWx5c2lzIG9mIHNpeCBjYXNlczwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5BY3RhIE5ldXJvcGF0aG9sb2dpY2E8L3NlY29uZGFyeS10aXRsZT48L3RpdGxl

cz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BY3RhIE5ldXJvcGF0aG9sb2dpY2E8L2Z1bGwtdGl0

bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz40NS01MTwvcGFnZXM+PHZvbHVtZT44NDwvdm9sdW1lPjxu

dW1iZXI+MTwvbnVtYmVyPjxkYXRlcz48eWVhcj4xOTkyPC95ZWFyPjwvZGF0ZXM+PHB1Ymxpc2hl

cj5TcHJpbmdlciBOYXR1cmUgQW1lcmljYSwgSW5jPC9wdWJsaXNoZXI+PGlzYm4+MDAwMS02MzIy

JiN4RDsxNDMyLTA1MzM8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5k

b2kub3JnLzEwLjEwMDcvYmYwMDQyNzIxNDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9iZjAwNDI3MjE0PC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5Ib2Y8L0F1dGhvcj48WWVhcj4x

OTkxPC9ZZWFyPjxSZWNOdW0+NDY0NTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+NDY0NTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTQ0NDgyNDMzIj40NjQ1PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Ib2YsIFAuIFIuPC9hdXRob3I+

PGF1dGhvcj5LbmFiZSwgUi48L2F1dGhvcj48YXV0aG9yPkJvdmllciwgUC48L2F1dGhvcj48YXV0

aG9yPkJvdXJhcywgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48

dGl0bGU+TmV1cm9wYXRob2xvZ2ljYWwgb2JzZXJ2YXRpb25zIGluIGEgY2FzZSBvZiBhdXRpc20g

cHJlc2VudGluZyB3aXRoIHNlbGYtaW5qdXJ5IGJlaGF2aW9yPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPkFjdGEgTmV1cm9wYXRob2xvZ2ljYTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJp

b2RpY2FsPjxmdWxsLXRpdGxlPkFjdGEgTmV1cm9wYXRob2xvZ2ljYTwvZnVsbC10aXRsZT48L3Bl

cmlvZGljYWw+PHBhZ2VzPjMyMS0zMjY8L3BhZ2VzPjx2b2x1bWU+ODI8L3ZvbHVtZT48bnVtYmVy

PjQ8L251bWJlcj48ZGF0ZXM+PHllYXI+MTk5MTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjE5OTEv

MDk8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPlNwcmluZ2VyIE5hdHVyZSBB

bWVyaWNhLCBJbmM8L3B1Ymxpc2hlcj48aXNibj4wMDAxLTYzMjImI3hEOzE0MzItMDUzMzwvaXNi

bj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAwNy9iZjAw

MzA4ODE5PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4xMDA3L2JmMDAzMDg4MTk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48Q2l0ZT48QXV0aG9yPlNjaG1pZHQ8L0F1dGhvcj48WWVhcj4yMDAxPC9ZZWFyPjxSZWNO

dW0+NDY2NTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+NDY2NTwvcmVjLW51bWJlcj48Zm9y

ZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0

c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTQ0NDgyNTM4Ij40NjY1PC9rZXk+PC9mb3JlaWduLWtl

eXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmli

dXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TY2htaWR0LCBNLiBMLjwvYXV0aG9yPjxhdXRob3I+Wmh1

a2FyZXZhLCBWLjwvYXV0aG9yPjxhdXRob3I+TmV3ZWxsLCBLLiBMLjwvYXV0aG9yPjxhdXRob3I+

TGVlLCBWLiBNLjwvYXV0aG9yPjxhdXRob3I+VHJvamFub3dza2ksIEouIFEuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQYXRob2xv

Z3kgYW5kIExhYm9yYXRvcnkgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgUGVubnN5bHZhbmlhIFNj

aG9vbCBvZiBNZWRpY2luZSwgUGhpbGFkZWxwaGlhIDE5MTA0LTQyODMsIFVTQS48L2F1dGgtYWRk

cmVzcz48dGl0bGVzPjx0aXRsZT5UYXUgaXNvZm9ybSBwcm9maWxlIGFuZCBwaG9zcGhvcnlsYXRp

b24gc3RhdGUgaW4gZGVtZW50aWEgcHVnaWxpc3RpY2EgcmVjYXBpdHVsYXRlIEFsemhlaW1lciZh

cG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BY3RhIE5ldXJvcGF0aG9sPC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QWN0YSBOZXVy

b3BhdGhvbDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjUxOC0yNDwvcGFnZXM+PHZv

bHVtZT4xMDE8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWdl

ZDwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qbWV0YWJvbGlzbS9wYXRob2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+QXRobGV0aWMgSW5qdXJpZXMvKm1ldGFib2xpc20vcGF0aG9s

b2d5L3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5CbG90dGluZywgV2VzdGVybjwv

a2V5d29yZD48a2V5d29yZD5Cb3hpbmcvKmluanVyaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWlu

IEluanVyaWVzLyptZXRhYm9saXNtL3BhdGhvbG9neS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+Q2VudHJhbCBOZXJ2b3VzIFN5c3RlbS9pbmp1cmllcy8qbWV0YWJvbGlzbS9wYXRo

b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RXBpdG9wZXMvaW1tdW5vbG9neTwva2V5d29yZD48a2V5

d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vaGlzdG9jaGVtaXN0cnk8L2tleXdv

cmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5OZXVyb2ZpYnJpbGxhcnkgVGFuZ2xl

cy9tZXRhYm9saXNtL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5OZXVyb25zLyptZXRhYm9s

aXNtL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5QaG9zcGhvcnlsYXRpb248L2tleXdvcmQ+

PGtleXdvcmQ+UHJvdGVpbiBJc29mb3Jtcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPnRh

dSBQcm90ZWlucy8qbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDAxPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWF5PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGlzYm4+MDAwMS02MzIyIChQcmludCkmI3hEOzAwMDEtNjMyMiAoTGlua2luZyk8L2lzYm4+PGFj

Y2Vzc2lvbi1udW0+MTE0ODQ4MjQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48

dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTE0ODQ4MjQ8L3VybD48L3Jl

bGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 112-114Postencephalitic ?parkinsonismSubacute sclerosing panencephalitisVirusNFTs & dystrophic neuritesAstrocytic tangles3R + 4R?PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdcOpZS1TY2hlcnJlcjwvQXV0aG9yPjxZZWFyPjE5OTc8

L1llYXI+PFJlY051bT40NjQ4PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBl

cnNjcmlwdCI+MTE1LDExNjwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVy

PjQ2NDg8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ew

cng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0NDQ4MjQzMyI+

NDY0ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi

PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QnXDqWUtU2NoZXJy

ZXIsIFZhbMOpcmllPC9hdXRob3I+PGF1dGhvcj5CdcOpZSwgTHVjPC9hdXRob3I+PGF1dGhvcj5M

ZXZldWdsZSwgQsOhdHJpY2U8L2F1dGhvcj48YXV0aG9yPlBlcmwsIERhbmllbCBQLjwvYXV0aG9y

PjxhdXRob3I+VmVybWVyc2NoLCBQYXRyaWNrPC9hdXRob3I+PGF1dGhvcj5Ib2YsIFBhdHJpY2sg

Ui48L2F1dGhvcj48YXV0aG9yPkRlbGFjb3VydGUsIEFuZHLDqTwvYXV0aG9yPjwvYXV0aG9ycz48

L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5QYXRob2xvZ2ljYWwgz4QgcHJvdGVpbnMgaW4g

cG9zdGVuY2VwaGFsaXRpYyBwYXJraW5zb25pc206IENvbXBhcmlzb24gd2l0aCBBbHpoZWltZXIm

YXBvcztzIGRpc2Vhc2UgYW5kIG90aGVyIG5ldXJvZGVnZW5lcmF0aXZlIGRpc29yZGVyczwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5Bbm5hbHMgb2YgTmV1cm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+

PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW5uYWxzIG9mIE5ldXJvbG9neTwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjM1Ni0zNTk8L3BhZ2VzPjx2b2x1bWU+NDI8L3Zv

bHVtZT48bnVtYmVyPjM8L251bWJlcj48ZGF0ZXM+PHllYXI+MTk5NzwveWVhcj48cHViLWRhdGVz

PjxkYXRlPjE5OTcvMDk8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPldpbGV5

PC9wdWJsaXNoZXI+PGlzYm4+MDM2NC01MTM0PC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy

bD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDAyL2FuYS40MTA0MjAzMTI8L3VybD48L3JlbGF0ZWQt

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDIvYW5hLjQxMDQyMDMx

MjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+

SWtlZGE8L0F1dGhvcj48WWVhcj4xOTk1PC9ZZWFyPjxSZWNOdW0+NDY2NDwvUmVjTnVtPjxyZWNv

cmQ+PHJlYy1udW1iZXI+NDY2NDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1w

PSIxNTQ0NDgyNTE2Ij40NjY0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5Ja2VkYSwgSy48L2F1dGhvcj48YXV0aG9yPkFraXlhbWEsIEguPC9hdXRob3I+PGF1dGhvcj5L

b25kbywgSC48L2F1dGhvcj48YXV0aG9yPkhhZ2EsIEMuPC9hdXRob3I+PGF1dGhvcj5UYW5ubywg

RS48L2F1dGhvcj48YXV0aG9yPlRva3VkYSwgVC48L2F1dGhvcj48YXV0aG9yPklrZWRhLCBTLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQg

b2YgTmV1cm9wYXRob2xvZ3ksIFRva3lvIEluc3RpdHV0ZSBvZiBQc3ljaGlhdHJ5LCBTZXRhZ2F5

YS1rdSwgSmFwYW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGhvcm4tc2hhcGVkIGFz

dHJvY3l0ZXM6IHBvc3NpYmx5IHNlY29uZGFyaWx5IGluZHVjZWQgdGF1LXBvc2l0aXZlIGdsaWFs

IGZpYnJpbGxhcnkgdGFuZ2xlczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BY3RhIE5ldXJvcGF0

aG9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QWN0

YSBOZXVyb3BhdGhvbDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjYyMC01PC9wYWdl

cz48dm9sdW1lPjkwPC92b2x1bWU+PG51bWJlcj42PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3Jk

PkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdv

cmQ+QXN0cm9jeXRlcy8qdWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+PGtleXdvcmQ+Q3l0b3NrZWxl

dG9uL3VsdHJhc3RydWN0dXJlPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5

d29yZD5HbGlhbCBGaWJyaWxsYXJ5IEFjaWRpYyBQcm90ZWluL21ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2hpc3RvY2hlbWlzdHJ5PC9r

ZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWljcm9zY29weSwgRWxlY3Ry

b248L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9m

aWJyaWxsYXJ5IFRhbmdsZXMvKnVsdHJhc3RydWN0dXJlPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJv

Z2xpYS8qbWV0YWJvbGlzbS8qdWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFBy

b3RlaW5zLyptZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTU8

L3llYXI+PC9kYXRlcz48aXNibj4wMDAxLTYzMjIgKFByaW50KSYjeEQ7MDAwMS02MzIyIChMaW5r

aW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT44NjE1MDgzPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxy

ZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzg2MTUw

ODM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdcOpZS1TY2hlcnJlcjwvQXV0aG9yPjxZZWFyPjE5OTc8

L1llYXI+PFJlY051bT40NjQ4PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBl

cnNjcmlwdCI+MTE1LDExNjwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVy

PjQ2NDg8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ew

cng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0NDQ4MjQzMyI+

NDY0ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi

PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QnXDqWUtU2NoZXJy

ZXIsIFZhbMOpcmllPC9hdXRob3I+PGF1dGhvcj5CdcOpZSwgTHVjPC9hdXRob3I+PGF1dGhvcj5M

ZXZldWdsZSwgQsOhdHJpY2U8L2F1dGhvcj48YXV0aG9yPlBlcmwsIERhbmllbCBQLjwvYXV0aG9y

PjxhdXRob3I+VmVybWVyc2NoLCBQYXRyaWNrPC9hdXRob3I+PGF1dGhvcj5Ib2YsIFBhdHJpY2sg

Ui48L2F1dGhvcj48YXV0aG9yPkRlbGFjb3VydGUsIEFuZHLDqTwvYXV0aG9yPjwvYXV0aG9ycz48

L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5QYXRob2xvZ2ljYWwgz4QgcHJvdGVpbnMgaW4g

cG9zdGVuY2VwaGFsaXRpYyBwYXJraW5zb25pc206IENvbXBhcmlzb24gd2l0aCBBbHpoZWltZXIm

YXBvcztzIGRpc2Vhc2UgYW5kIG90aGVyIG5ldXJvZGVnZW5lcmF0aXZlIGRpc29yZGVyczwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5Bbm5hbHMgb2YgTmV1cm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+

PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW5uYWxzIG9mIE5ldXJvbG9neTwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjM1Ni0zNTk8L3BhZ2VzPjx2b2x1bWU+NDI8L3Zv

bHVtZT48bnVtYmVyPjM8L251bWJlcj48ZGF0ZXM+PHllYXI+MTk5NzwveWVhcj48cHViLWRhdGVz

PjxkYXRlPjE5OTcvMDk8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPldpbGV5

PC9wdWJsaXNoZXI+PGlzYm4+MDM2NC01MTM0PC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy

bD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDAyL2FuYS40MTA0MjAzMTI8L3VybD48L3JlbGF0ZWQt

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDIvYW5hLjQxMDQyMDMx

MjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+

SWtlZGE8L0F1dGhvcj48WWVhcj4xOTk1PC9ZZWFyPjxSZWNOdW0+NDY2NDwvUmVjTnVtPjxyZWNv

cmQ+PHJlYy1udW1iZXI+NDY2NDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1w

PSIxNTQ0NDgyNTE2Ij40NjY0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5Ja2VkYSwgSy48L2F1dGhvcj48YXV0aG9yPkFraXlhbWEsIEguPC9hdXRob3I+PGF1dGhvcj5L

b25kbywgSC48L2F1dGhvcj48YXV0aG9yPkhhZ2EsIEMuPC9hdXRob3I+PGF1dGhvcj5UYW5ubywg

RS48L2F1dGhvcj48YXV0aG9yPlRva3VkYSwgVC48L2F1dGhvcj48YXV0aG9yPklrZWRhLCBTLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQg

b2YgTmV1cm9wYXRob2xvZ3ksIFRva3lvIEluc3RpdHV0ZSBvZiBQc3ljaGlhdHJ5LCBTZXRhZ2F5

YS1rdSwgSmFwYW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGhvcm4tc2hhcGVkIGFz

dHJvY3l0ZXM6IHBvc3NpYmx5IHNlY29uZGFyaWx5IGluZHVjZWQgdGF1LXBvc2l0aXZlIGdsaWFs

IGZpYnJpbGxhcnkgdGFuZ2xlczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BY3RhIE5ldXJvcGF0

aG9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QWN0

YSBOZXVyb3BhdGhvbDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjYyMC01PC9wYWdl

cz48dm9sdW1lPjkwPC92b2x1bWU+PG51bWJlcj42PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3Jk

PkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdv

cmQ+QXN0cm9jeXRlcy8qdWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+PGtleXdvcmQ+Q3l0b3NrZWxl

dG9uL3VsdHJhc3RydWN0dXJlPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5

d29yZD5HbGlhbCBGaWJyaWxsYXJ5IEFjaWRpYyBQcm90ZWluL21ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2hpc3RvY2hlbWlzdHJ5PC9r

ZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWljcm9zY29weSwgRWxlY3Ry

b248L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9m

aWJyaWxsYXJ5IFRhbmdsZXMvKnVsdHJhc3RydWN0dXJlPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJv

Z2xpYS8qbWV0YWJvbGlzbS8qdWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFBy

b3RlaW5zLyptZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTU8

L3llYXI+PC9kYXRlcz48aXNibj4wMDAxLTYzMjIgKFByaW50KSYjeEQ7MDAwMS02MzIyIChMaW5r

aW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT44NjE1MDgzPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxy

ZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzg2MTUw

ODM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 115,116Progressive supranuclear palsyFrench Caribbean islandsNorthern FranceAmyotrophic lateral sclerosis/ parkinsonism dementia syndrome of GuamUnknownFood toxinsIndustrial wasteUnknown environment (food, heavy metals…)NFTs & dystrophic neuritesTufted astrocytes4R?>>3R3R + 4RPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXBhcnJvczwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+

PFJlY051bT40NjQ5PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MTE3LTExOTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQ2NDk8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0NDQ4MjQzMyI+NDY0OTwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Q2FwYXJyb3MsIEVybmVzdDwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5bQXZhbnQtcHJv

cG9zXTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5SZXZ1ZSBnw6luw6lyYWxlIGRlIGRyb2l0PC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UmV2dWUgZ8Op

bsOpcmFsZSBkZSBkcm9pdDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIwNTwvcGFn

ZXM+PHZvbHVtZT4zMjwvdm9sdW1lPjxudW1iZXI+MjwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDAy

PC95ZWFyPjwvZGF0ZXM+PHB1Ymxpc2hlcj5Db25zb3J0aXVtIEVydWRpdDwvcHVibGlzaGVyPjxp

c2JuPjAwMzUtMzA4NiYjeEQ7MjI5Mi0yNTEyPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy

bD5odHRwOi8vZHguZG9pLm9yZy8xMC43MjAyLzEwMjgwNjhhcjwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuNzIwMi8xMDI4MDY4YXI8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkNhcGFycm9z

LUxlZmVidnJlPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVtPjQ2NTA8L1JlY051bT48

cmVjb3JkPjxyZWMtbnVtYmVyPjQ2NTA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw

cD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVz

dGFtcD0iMTU0NDQ4MjQzMyI+NDY1MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+Q2FwYXJyb3MtTGVmZWJ2cmUsIERvbWluaXF1ZTwvYXV0aG9yPjxhdXRob3I+R29sYmUs

IExhd3JlbmNlIEkuPC9hdXRob3I+PGF1dGhvcj5EZXJhbWVjb3VydCwgVmluY2VudDwvYXV0aG9y

PjxhdXRob3I+TWF1cmFnZSwgQ2xhdWRlLUFsYWluPC9hdXRob3I+PGF1dGhvcj5IdWluLCBWaW5j

ZW50PC9hdXRob3I+PGF1dGhvcj5CdcOpZS1TY2hlcnJlciwgVmFsZXJpZTwvYXV0aG9yPjxhdXRo

b3I+T2JyaW90LCBIZWxlbmU8L2F1dGhvcj48YXV0aG9yPlNhYmxvbm5pw6hyZSwgQmVybmFyZDwv

YXV0aG9yPjxhdXRob3I+Q2FwYXJyb3MsIEZyYW5jb2lzPC9hdXRob3I+PGF1dGhvcj5CdcOpZSwg

THVjPC9hdXRob3I+PGF1dGhvcj5MZWVzLCBBbmRyZXcgSi48L2F1dGhvcj48L2F1dGhvcnM+PC9j

b250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QSBnZW9ncmFwaGljYWwgY2x1c3RlciBvZiBwcm9n

cmVzc2l2ZSBzdXByYW51Y2xlYXIgcGFsc3kgaW4gbm9ydGhlcm4gRnJhbmNlPC90aXRsZT48c2Vj

b25kYXJ5LXRpdGxlPk5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2Rp

Y2FsPjxmdWxsLXRpdGxlPk5ldXJvbG9neTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2Vz

PjEyOTMtMTMwMDwvcGFnZXM+PHZvbHVtZT44NTwvdm9sdW1lPjxudW1iZXI+MTU8L251bWJlcj48

ZGF0ZXM+PHllYXI+MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTUvMDkvMDk8L2RhdGU+

PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPk92aWQgVGVjaG5vbG9naWVzIChXb2x0ZXJz

IEtsdXdlciBIZWFsdGgpPC9wdWJsaXNoZXI+PGlzYm4+MDAyOC0zODc4JiN4RDsxNTI2LTYzMlg8

L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjEyMTIv

d25sLjAwMDAwMDAwMDAwMDE5OTc8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjEwLjEyMTIvd25sLjAwMDAwMDAwMDAwMDE5OTc8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkJ1w6llLVNjaGVycmVy

PC9BdXRob3I+PFllYXI+MTk5NTwvWWVhcj48UmVjTnVtPjQ2NTE8L1JlY051bT48cmVjb3JkPjxy

ZWMtbnVtYmVyPjQ2NTE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRi

LWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0

NDQ4MjQzMyI+NDY1MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJHZW5lcmlj

Ij4xMzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJ1w6llLVNjaGVy

cmVyLCBWLjwvYXV0aG9yPjxhdXRob3I+QnXDqWUsIEwuPC9hdXRob3I+PGF1dGhvcj5Ib2YsIFAu

IFIuPC9hdXRob3I+PGF1dGhvcj5WZXJtZXJzY2gsIFAuPC9hdXRob3I+PGF1dGhvcj5MZXZldWds

ZSwgQi48L2F1dGhvcj48YXV0aG9yPldhdHRleiwgQS48L2F1dGhvcj48YXV0aG9yPkJvdXJhcywg

Qy48L2F1dGhvcj48YXV0aG9yPlBlcmwsIEQuIFAuPC9hdXRob3I+PGF1dGhvcj5EZWxhY291cnRl

LCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5UYXUg

VmFyaWFudHMgaW4gQWdpbmcgYW5kIE5ldXJvZGVnZW5lcmF0aXZlIERpc29yZGVyczwvdGl0bGU+

PHNlY29uZGFyeS10aXRsZT5BbHpoZWltZXLigJlzIERpc2Vhc2U6IExlc3NvbnMgZnJvbSBDZWxs

IEJpb2xvZ3k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTMyLTE0OTwvcGFnZXM+

PGRhdGVzPjx5ZWFyPjE5OTU8L3llYXI+PC9kYXRlcz48cHVibGlzaGVyPlNwcmluZ2VyIEJlcmxp

biBIZWlkZWxiZXJnPC9wdWJsaXNoZXI+PGlzYm4+OTc4MzY0Mjc5NDI1NCYjeEQ7OTc4MzY0Mjc5

NDIzMDwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAu

MTAwNy85NzgtMy02NDItNzk0MjMtMF8xMjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy85NzgtMy02NDItNzk0MjMtMF8xMjwvZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXBhcnJvczwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+

PFJlY051bT40NjQ5PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MTE3LTExOTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQ2NDk8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0NDQ4MjQzMyI+NDY0OTwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Q2FwYXJyb3MsIEVybmVzdDwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5bQXZhbnQtcHJv

cG9zXTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5SZXZ1ZSBnw6luw6lyYWxlIGRlIGRyb2l0PC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UmV2dWUgZ8Op

bsOpcmFsZSBkZSBkcm9pdDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIwNTwvcGFn

ZXM+PHZvbHVtZT4zMjwvdm9sdW1lPjxudW1iZXI+MjwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDAy

PC95ZWFyPjwvZGF0ZXM+PHB1Ymxpc2hlcj5Db25zb3J0aXVtIEVydWRpdDwvcHVibGlzaGVyPjxp

c2JuPjAwMzUtMzA4NiYjeEQ7MjI5Mi0yNTEyPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy

bD5odHRwOi8vZHguZG9pLm9yZy8xMC43MjAyLzEwMjgwNjhhcjwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuNzIwMi8xMDI4MDY4YXI8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkNhcGFycm9z

LUxlZmVidnJlPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVtPjQ2NTA8L1JlY051bT48

cmVjb3JkPjxyZWMtbnVtYmVyPjQ2NTA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw

cD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVz

dGFtcD0iMTU0NDQ4MjQzMyI+NDY1MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+Q2FwYXJyb3MtTGVmZWJ2cmUsIERvbWluaXF1ZTwvYXV0aG9yPjxhdXRob3I+R29sYmUs

IExhd3JlbmNlIEkuPC9hdXRob3I+PGF1dGhvcj5EZXJhbWVjb3VydCwgVmluY2VudDwvYXV0aG9y

PjxhdXRob3I+TWF1cmFnZSwgQ2xhdWRlLUFsYWluPC9hdXRob3I+PGF1dGhvcj5IdWluLCBWaW5j

ZW50PC9hdXRob3I+PGF1dGhvcj5CdcOpZS1TY2hlcnJlciwgVmFsZXJpZTwvYXV0aG9yPjxhdXRo

b3I+T2JyaW90LCBIZWxlbmU8L2F1dGhvcj48YXV0aG9yPlNhYmxvbm5pw6hyZSwgQmVybmFyZDwv

YXV0aG9yPjxhdXRob3I+Q2FwYXJyb3MsIEZyYW5jb2lzPC9hdXRob3I+PGF1dGhvcj5CdcOpZSwg

THVjPC9hdXRob3I+PGF1dGhvcj5MZWVzLCBBbmRyZXcgSi48L2F1dGhvcj48L2F1dGhvcnM+PC9j

b250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QSBnZW9ncmFwaGljYWwgY2x1c3RlciBvZiBwcm9n

cmVzc2l2ZSBzdXByYW51Y2xlYXIgcGFsc3kgaW4gbm9ydGhlcm4gRnJhbmNlPC90aXRsZT48c2Vj

b25kYXJ5LXRpdGxlPk5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2Rp

Y2FsPjxmdWxsLXRpdGxlPk5ldXJvbG9neTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2Vz

PjEyOTMtMTMwMDwvcGFnZXM+PHZvbHVtZT44NTwvdm9sdW1lPjxudW1iZXI+MTU8L251bWJlcj48

ZGF0ZXM+PHllYXI+MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTUvMDkvMDk8L2RhdGU+

PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPk92aWQgVGVjaG5vbG9naWVzIChXb2x0ZXJz

IEtsdXdlciBIZWFsdGgpPC9wdWJsaXNoZXI+PGlzYm4+MDAyOC0zODc4JiN4RDsxNTI2LTYzMlg8

L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjEyMTIv

d25sLjAwMDAwMDAwMDAwMDE5OTc8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjEwLjEyMTIvd25sLjAwMDAwMDAwMDAwMDE5OTc8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkJ1w6llLVNjaGVycmVy

PC9BdXRob3I+PFllYXI+MTk5NTwvWWVhcj48UmVjTnVtPjQ2NTE8L1JlY051bT48cmVjb3JkPjxy

ZWMtbnVtYmVyPjQ2NTE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRi

LWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0

NDQ4MjQzMyI+NDY1MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJHZW5lcmlj

Ij4xMzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJ1w6llLVNjaGVy

cmVyLCBWLjwvYXV0aG9yPjxhdXRob3I+QnXDqWUsIEwuPC9hdXRob3I+PGF1dGhvcj5Ib2YsIFAu

IFIuPC9hdXRob3I+PGF1dGhvcj5WZXJtZXJzY2gsIFAuPC9hdXRob3I+PGF1dGhvcj5MZXZldWds

ZSwgQi48L2F1dGhvcj48YXV0aG9yPldhdHRleiwgQS48L2F1dGhvcj48YXV0aG9yPkJvdXJhcywg

Qy48L2F1dGhvcj48YXV0aG9yPlBlcmwsIEQuIFAuPC9hdXRob3I+PGF1dGhvcj5EZWxhY291cnRl

LCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5UYXUg

VmFyaWFudHMgaW4gQWdpbmcgYW5kIE5ldXJvZGVnZW5lcmF0aXZlIERpc29yZGVyczwvdGl0bGU+

PHNlY29uZGFyeS10aXRsZT5BbHpoZWltZXLigJlzIERpc2Vhc2U6IExlc3NvbnMgZnJvbSBDZWxs

IEJpb2xvZ3k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTMyLTE0OTwvcGFnZXM+

PGRhdGVzPjx5ZWFyPjE5OTU8L3llYXI+PC9kYXRlcz48cHVibGlzaGVyPlNwcmluZ2VyIEJlcmxp

biBIZWlkZWxiZXJnPC9wdWJsaXNoZXI+PGlzYm4+OTc4MzY0Mjc5NDI1NCYjeEQ7OTc4MzY0Mjc5

NDIzMDwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAu

MTAwNy85NzgtMy02NDItNzk0MjMtMF8xMjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy85NzgtMy02NDItNzk0MjMtMF8xMjwvZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 117-119Corticobasal degenerationUnknownMAPT haplotypesNFTs & neuritesAstrocytic plaques4R?>>3RPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdcOpZS1TY2hlcnJlcjwvQXV0aG9yPjxZZWFyPjE5OTY8

L1llYXI+PFJlY051bT40NjUyPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBl

cnNjcmlwdCI+MTIwLDEyMTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVy

PjQ2NTI8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ew

cng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0NDQ4MjQzMyI+

NDY1Mjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi

PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QnXDqWUtU2NoZXJy

ZXIsIFYuPC9hdXRob3I+PGF1dGhvcj5Ib2YsIFAuIFIuPC9hdXRob3I+PGF1dGhvcj5CdcOpZSwg

TC48L2F1dGhvcj48YXV0aG9yPkxldmV1Z2xlLCBCLjwvYXV0aG9yPjxhdXRob3I+VmVybWVyc2No

LCBQLjwvYXV0aG9yPjxhdXRob3I+UGVybCwgRC4gUC48L2F1dGhvcj48YXV0aG9yPk9sYW5vdywg

Qy4gVy48L2F1dGhvcj48YXV0aG9yPkRlbGFjb3VydGUsIEEuPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkh5cGVycGhvc3Bob3J5bGF0ZWQgdGF1IHByb3Rl

aW5zIGRpZmZlcmVudGlhdGUgY29ydGljb2Jhc2FsIGRlZ2VuZXJhdGlvbiBhbmQgUGljayZhcG9z

O3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BY3RhIE5ldXJvcGF0aG9sb2dpY2E8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BY3RhIE5l

dXJvcGF0aG9sb2dpY2E8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4zNTEtMzU5PC9w

YWdlcz48dm9sdW1lPjkxPC92b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PGRhdGVzPjx5ZWFyPjE5

OTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xOTk2LzAzLzA3PC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PHB1Ymxpc2hlcj5TcHJpbmdlciBOYXR1cmU8L3B1Ymxpc2hlcj48aXNibj4wMDAxLTYz

MjImI3hEOzE0MzItMDUzMzwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4

LmRvaS5vcmcvMTAuMTAwNy9zMDA0MDEwMDUwNDM2PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxz

PjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDA3L3MwMDQwMTAwNTA0MzY8L2VsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk1haWxsaW90PC9B

dXRob3I+PFllYXI+MTk5ODwvWWVhcj48UmVjTnVtPjQ2NTM8L1JlY051bT48cmVjb3JkPjxyZWMt

bnVtYmVyPjQ2NTM8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk

PSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0NDQ4

MjQzMyI+NDY1Mzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFy

dGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWFpbGxp

b3QsIENocmlzdGVsPC9hdXRob3I+PGF1dGhvcj5TZXJnZWFudCwgTmljb2xhczwvYXV0aG9yPjxh

dXRob3I+QnVzc2nDqHJlLCBUaGllcnJ5PC9hdXRob3I+PGF1dGhvcj5DYWlsbGV0LUJvdWRpbiwg

TWFyaWUtTGF1cmU8L2F1dGhvcj48YXV0aG9yPkRlbGFjb3VydGUsIEFuZHLDqTwvYXV0aG9yPjxh

dXRob3I+QnXDqWUsIEx1YzwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVz

Pjx0aXRsZT5QaG9zcGhvcnlsYXRpb24gb2Ygc3BlY2lmaWMgc2V0cyBvZiB0YXUgaXNvZm9ybXMg

cmVmbGVjdHMgZGlmZmVyZW50IG5ldXJvZmlicmlsbGFyeSBkZWdlbmVyYXRpb24gcHJvY2Vzc2Vz

PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkZFQlMgTGV0dGVyczwvc2Vjb25kYXJ5LXRpdGxlPjwv

dGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkZFQlMgTGV0dGVyczwvZnVsbC10aXRsZT48

L3BlcmlvZGljYWw+PHBhZ2VzPjIwMS0yMDQ8L3BhZ2VzPjx2b2x1bWU+NDMzPC92b2x1bWU+PG51

bWJlcj4zPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjE5OTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4x

OTk4LzA4LzIxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5XaWxleTwvcHVi

bGlzaGVyPjxpc2JuPjAwMTQtNTc5MzwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL2R4LmRvaS5vcmcvMTAuMTAxNi9zMDAxNC01NzkzKDk4KTAwOTEwLTc8L3VybD48L3JlbGF0

ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvczAwMTQtNTc5

Myg5OCkwMDkxMC03PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdcOpZS1TY2hlcnJlcjwvQXV0aG9yPjxZZWFyPjE5OTY8

L1llYXI+PFJlY051bT40NjUyPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBl

cnNjcmlwdCI+MTIwLDEyMTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVy

PjQ2NTI8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ew

cng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0NDQ4MjQzMyI+

NDY1Mjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi

PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QnXDqWUtU2NoZXJy

ZXIsIFYuPC9hdXRob3I+PGF1dGhvcj5Ib2YsIFAuIFIuPC9hdXRob3I+PGF1dGhvcj5CdcOpZSwg

TC48L2F1dGhvcj48YXV0aG9yPkxldmV1Z2xlLCBCLjwvYXV0aG9yPjxhdXRob3I+VmVybWVyc2No

LCBQLjwvYXV0aG9yPjxhdXRob3I+UGVybCwgRC4gUC48L2F1dGhvcj48YXV0aG9yPk9sYW5vdywg

Qy4gVy48L2F1dGhvcj48YXV0aG9yPkRlbGFjb3VydGUsIEEuPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkh5cGVycGhvc3Bob3J5bGF0ZWQgdGF1IHByb3Rl

aW5zIGRpZmZlcmVudGlhdGUgY29ydGljb2Jhc2FsIGRlZ2VuZXJhdGlvbiBhbmQgUGljayZhcG9z

O3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BY3RhIE5ldXJvcGF0aG9sb2dpY2E8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BY3RhIE5l

dXJvcGF0aG9sb2dpY2E8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4zNTEtMzU5PC9w

YWdlcz48dm9sdW1lPjkxPC92b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PGRhdGVzPjx5ZWFyPjE5

OTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xOTk2LzAzLzA3PC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PHB1Ymxpc2hlcj5TcHJpbmdlciBOYXR1cmU8L3B1Ymxpc2hlcj48aXNibj4wMDAxLTYz

MjImI3hEOzE0MzItMDUzMzwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4

LmRvaS5vcmcvMTAuMTAwNy9zMDA0MDEwMDUwNDM2PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxz

PjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDA3L3MwMDQwMTAwNTA0MzY8L2VsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk1haWxsaW90PC9B

dXRob3I+PFllYXI+MTk5ODwvWWVhcj48UmVjTnVtPjQ2NTM8L1JlY051bT48cmVjb3JkPjxyZWMt

bnVtYmVyPjQ2NTM8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk

PSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0NDQ4

MjQzMyI+NDY1Mzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFy

dGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWFpbGxp

b3QsIENocmlzdGVsPC9hdXRob3I+PGF1dGhvcj5TZXJnZWFudCwgTmljb2xhczwvYXV0aG9yPjxh

dXRob3I+QnVzc2nDqHJlLCBUaGllcnJ5PC9hdXRob3I+PGF1dGhvcj5DYWlsbGV0LUJvdWRpbiwg

TWFyaWUtTGF1cmU8L2F1dGhvcj48YXV0aG9yPkRlbGFjb3VydGUsIEFuZHLDqTwvYXV0aG9yPjxh

dXRob3I+QnXDqWUsIEx1YzwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVz

Pjx0aXRsZT5QaG9zcGhvcnlsYXRpb24gb2Ygc3BlY2lmaWMgc2V0cyBvZiB0YXUgaXNvZm9ybXMg

cmVmbGVjdHMgZGlmZmVyZW50IG5ldXJvZmlicmlsbGFyeSBkZWdlbmVyYXRpb24gcHJvY2Vzc2Vz

PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkZFQlMgTGV0dGVyczwvc2Vjb25kYXJ5LXRpdGxlPjwv

dGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkZFQlMgTGV0dGVyczwvZnVsbC10aXRsZT48

L3BlcmlvZGljYWw+PHBhZ2VzPjIwMS0yMDQ8L3BhZ2VzPjx2b2x1bWU+NDMzPC92b2x1bWU+PG51

bWJlcj4zPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjE5OTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4x

OTk4LzA4LzIxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5XaWxleTwvcHVi

bGlzaGVyPjxpc2JuPjAwMTQtNTc5MzwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL2R4LmRvaS5vcmcvMTAuMTAxNi9zMDAxNC01NzkzKDk4KTAwOTEwLTc8L3VybD48L3JlbGF0

ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvczAwMTQtNTc5

Myg5OCkwMDkxMC03PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPn==

ADDIN EN.CITE.DATA 120,121Pick’s?diseaseUnknownPick bodies3R>>4RPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdcOpZS1TY2hlcnJlcjwvQXV0aG9yPjxZZWFyPjE5OTY8

L1llYXI+PFJlY051bT40NjUyPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBl

cnNjcmlwdCI+MTIwLDEyMiwxMjM8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51

bWJlcj40NjUyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0i

ZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDQ0ODI0

MzMiPjQ2NTI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRp

Y2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJ1w6llLVNj

aGVycmVyLCBWLjwvYXV0aG9yPjxhdXRob3I+SG9mLCBQLiBSLjwvYXV0aG9yPjxhdXRob3I+QnXD

qWUsIEwuPC9hdXRob3I+PGF1dGhvcj5MZXZldWdsZSwgQi48L2F1dGhvcj48YXV0aG9yPlZlcm1l

cnNjaCwgUC48L2F1dGhvcj48YXV0aG9yPlBlcmwsIEQuIFAuPC9hdXRob3I+PGF1dGhvcj5PbGFu

b3csIEMuIFcuPC9hdXRob3I+PGF1dGhvcj5EZWxhY291cnRlLCBBLjwvYXV0aG9yPjwvYXV0aG9y

cz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5IeXBlcnBob3NwaG9yeWxhdGVkIHRhdSBw

cm90ZWlucyBkaWZmZXJlbnRpYXRlIGNvcnRpY29iYXNhbCBkZWdlbmVyYXRpb24gYW5kIFBpY2sm

YXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWN0YSBOZXVyb3BhdGhvbG9n

aWNhPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QWN0

YSBOZXVyb3BhdGhvbG9naWNhPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzUxLTM1

OTwvcGFnZXM+PHZvbHVtZT45MTwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxkYXRlcz48eWVh

cj4xOTk2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTk5Ni8wMy8wNzwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxwdWJsaXNoZXI+U3ByaW5nZXIgTmF0dXJlPC9wdWJsaXNoZXI+PGlzYm4+MDAw

MS02MzIyJiN4RDsxNDMyLTA1MzM8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6

Ly9keC5kb2kub3JnLzEwLjEwMDcvczAwNDAxMDA1MDQzNjwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMDA0MDEwMDUwNDM2PC9lbGVj

dHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5EZWxhY291

cnRlPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48UmVjTnVtPjQ2NTU8L1JlY051bT48cmVjb3Jk

PjxyZWMtbnVtYmVyPjQ2NTU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0i

MTU0NDQ4MjQzMyI+NDY1NTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy

bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+

RGVsYWNvdXJ0ZSwgQW5kcsOpPC9hdXRob3I+PGF1dGhvcj5Sb2JpdGFpbGxlLCBZdmVzPC9hdXRo

b3I+PGF1dGhvcj5TZXJnZWFudCwgTmljb2xhczwvYXV0aG9yPjxhdXRob3I+QnXDqWUsIEx1Yzwv

YXV0aG9yPjxhdXRob3I+SG9mLCBQYXRyaWNrIFIuPC9hdXRob3I+PGF1dGhvcj5XYXR0ZXosIEFu

bmljazwvYXV0aG9yPjxhdXRob3I+TGFyb2NoZS1DaG9sZXR0ZSwgQW5kcsOpZTwvYXV0aG9yPjxh

dXRob3I+TWF0aGlldSwgSmVhbjwvYXV0aG9yPjxhdXRob3I+Q2hhZ25vbiwgUGllcnJlPC9hdXRo

b3I+PGF1dGhvcj5HYXV2cmVhdSwgRGVuaXM8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PHRpdGxlcz48dGl0bGU+U3BlY2lmaWMgUGF0aG9sb2dpY2FsIFRhdSBQcm90ZWluIFZhcmlh

bnRzIENoYXJhY3Rlcml6ZSBQaWNryrxzIERpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+

Sm91cm5hbCBvZiBOZXVyb3BhdGhvbG9neSBhbmQgRXhwZXJpbWVudGFsIE5ldXJvbG9neTwvc2Vj

b25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkpvdXJuYWwgb2Yg

TmV1cm9wYXRob2xvZ3kgYW5kIEV4cGVyaW1lbnRhbCBOZXVyb2xvZ3k8L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxwYWdlcz4xNTktMTY4PC9wYWdlcz48dm9sdW1lPjU1PC92b2x1bWU+PG51bWJl

cj4yPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjE5OTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xOTk2

LzAyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5PeGZvcmQgVW5pdmVyc2l0

eSBQcmVzcyAoT1VQKTwvcHVibGlzaGVyPjxpc2JuPjAwMjItMzA2OTwvaXNibj48dXJscz48cmVs

YXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTA5Ny8wMDAwNTA3Mi0xOTk2MDIw

MDAtMDAwMDQ8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjEwLjEwOTcvMDAwMDUwNzItMTk5NjAyMDAwLTAwMDA0PC9lbGVjdHJvbmljLXJlc291cmNl

LW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5EZWxhY291cnRlPC9BdXRob3I+PFll

YXI+MTk5ODwvWWVhcj48UmVjTnVtPjQ2NTY8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjQ2

NTY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1

MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0NDQ4MjQzMyI+NDY1

Njwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3

PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RGVsYWNvdXJ0ZSwgQS48

L2F1dGhvcj48YXV0aG9yPlNlcmdlYW50LCBOLjwvYXV0aG9yPjxhdXRob3I+V2F0dGV6LCBBLjwv

YXV0aG9yPjxhdXRob3I+R2F1dnJlYXUsIEQuPC9hdXRob3I+PGF1dGhvcj5Sb2JpdGFpbGxlLCBZ

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5WdWxuZXJh

YmxlIG5ldXJvbmFsIHN1YnNldHMgaW4gQWx6aGVpbWVyJmFwb3M7cyBhbmQgUGljayZhcG9zO3Mg

ZGlzZWFzZSBhcmUgZGlzdGluZ3Vpc2hlZCBieSB0aGVpciA/IGlzb2Zvcm0gZGlzdHJpYnV0aW9u

IGFuZCBwaG9zcGhvcnlsYXRpb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW5uYWxzIG9mIE5l

dXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxl

PkFubmFscyBvZiBOZXVyb2xvZ3k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xOTMt

MjA0PC9wYWdlcz48dm9sdW1lPjQzPC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGRhdGVzPjx5

ZWFyPjE5OTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xOTk4LzAyPC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PHB1Ymxpc2hlcj5XaWxleTwvcHVibGlzaGVyPjxpc2JuPjAzNjQtNTEzNCYjeEQ7

MTUzMS04MjQ5PC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9y

Zy8xMC4xMDAyL2FuYS40MTA0MzAyMDk8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDIvYW5hLjQxMDQzMDIwOTwvZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdcOpZS1TY2hlcnJlcjwvQXV0aG9yPjxZZWFyPjE5OTY8

L1llYXI+PFJlY051bT40NjUyPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBl

cnNjcmlwdCI+MTIwLDEyMiwxMjM8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51

bWJlcj40NjUyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0i

ZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDQ0ODI0

MzMiPjQ2NTI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRp

Y2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJ1w6llLVNj

aGVycmVyLCBWLjwvYXV0aG9yPjxhdXRob3I+SG9mLCBQLiBSLjwvYXV0aG9yPjxhdXRob3I+QnXD

qWUsIEwuPC9hdXRob3I+PGF1dGhvcj5MZXZldWdsZSwgQi48L2F1dGhvcj48YXV0aG9yPlZlcm1l

cnNjaCwgUC48L2F1dGhvcj48YXV0aG9yPlBlcmwsIEQuIFAuPC9hdXRob3I+PGF1dGhvcj5PbGFu

b3csIEMuIFcuPC9hdXRob3I+PGF1dGhvcj5EZWxhY291cnRlLCBBLjwvYXV0aG9yPjwvYXV0aG9y

cz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5IeXBlcnBob3NwaG9yeWxhdGVkIHRhdSBw

cm90ZWlucyBkaWZmZXJlbnRpYXRlIGNvcnRpY29iYXNhbCBkZWdlbmVyYXRpb24gYW5kIFBpY2sm

YXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWN0YSBOZXVyb3BhdGhvbG9n

aWNhPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QWN0

YSBOZXVyb3BhdGhvbG9naWNhPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzUxLTM1

OTwvcGFnZXM+PHZvbHVtZT45MTwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxkYXRlcz48eWVh

cj4xOTk2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTk5Ni8wMy8wNzwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxwdWJsaXNoZXI+U3ByaW5nZXIgTmF0dXJlPC9wdWJsaXNoZXI+PGlzYm4+MDAw

MS02MzIyJiN4RDsxNDMyLTA1MzM8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6

Ly9keC5kb2kub3JnLzEwLjEwMDcvczAwNDAxMDA1MDQzNjwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMDA0MDEwMDUwNDM2PC9lbGVj

dHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5EZWxhY291

cnRlPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48UmVjTnVtPjQ2NTU8L1JlY051bT48cmVjb3Jk

PjxyZWMtbnVtYmVyPjQ2NTU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0i

MTU0NDQ4MjQzMyI+NDY1NTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy

bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+

RGVsYWNvdXJ0ZSwgQW5kcsOpPC9hdXRob3I+PGF1dGhvcj5Sb2JpdGFpbGxlLCBZdmVzPC9hdXRo

b3I+PGF1dGhvcj5TZXJnZWFudCwgTmljb2xhczwvYXV0aG9yPjxhdXRob3I+QnXDqWUsIEx1Yzwv

YXV0aG9yPjxhdXRob3I+SG9mLCBQYXRyaWNrIFIuPC9hdXRob3I+PGF1dGhvcj5XYXR0ZXosIEFu

bmljazwvYXV0aG9yPjxhdXRob3I+TGFyb2NoZS1DaG9sZXR0ZSwgQW5kcsOpZTwvYXV0aG9yPjxh

dXRob3I+TWF0aGlldSwgSmVhbjwvYXV0aG9yPjxhdXRob3I+Q2hhZ25vbiwgUGllcnJlPC9hdXRo

b3I+PGF1dGhvcj5HYXV2cmVhdSwgRGVuaXM8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PHRpdGxlcz48dGl0bGU+U3BlY2lmaWMgUGF0aG9sb2dpY2FsIFRhdSBQcm90ZWluIFZhcmlh

bnRzIENoYXJhY3Rlcml6ZSBQaWNryrxzIERpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+

Sm91cm5hbCBvZiBOZXVyb3BhdGhvbG9neSBhbmQgRXhwZXJpbWVudGFsIE5ldXJvbG9neTwvc2Vj

b25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkpvdXJuYWwgb2Yg

TmV1cm9wYXRob2xvZ3kgYW5kIEV4cGVyaW1lbnRhbCBOZXVyb2xvZ3k8L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxwYWdlcz4xNTktMTY4PC9wYWdlcz48dm9sdW1lPjU1PC92b2x1bWU+PG51bWJl

cj4yPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjE5OTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xOTk2

LzAyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5PeGZvcmQgVW5pdmVyc2l0

eSBQcmVzcyAoT1VQKTwvcHVibGlzaGVyPjxpc2JuPjAwMjItMzA2OTwvaXNibj48dXJscz48cmVs

YXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTA5Ny8wMDAwNTA3Mi0xOTk2MDIw

MDAtMDAwMDQ8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjEwLjEwOTcvMDAwMDUwNzItMTk5NjAyMDAwLTAwMDA0PC9lbGVjdHJvbmljLXJlc291cmNl

LW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5EZWxhY291cnRlPC9BdXRob3I+PFll

YXI+MTk5ODwvWWVhcj48UmVjTnVtPjQ2NTY8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjQ2

NTY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1

MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0NDQ4MjQzMyI+NDY1

Njwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3

PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RGVsYWNvdXJ0ZSwgQS48

L2F1dGhvcj48YXV0aG9yPlNlcmdlYW50LCBOLjwvYXV0aG9yPjxhdXRob3I+V2F0dGV6LCBBLjwv

YXV0aG9yPjxhdXRob3I+R2F1dnJlYXUsIEQuPC9hdXRob3I+PGF1dGhvcj5Sb2JpdGFpbGxlLCBZ

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5WdWxuZXJh

YmxlIG5ldXJvbmFsIHN1YnNldHMgaW4gQWx6aGVpbWVyJmFwb3M7cyBhbmQgUGljayZhcG9zO3Mg

ZGlzZWFzZSBhcmUgZGlzdGluZ3Vpc2hlZCBieSB0aGVpciA/IGlzb2Zvcm0gZGlzdHJpYnV0aW9u

IGFuZCBwaG9zcGhvcnlsYXRpb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW5uYWxzIG9mIE5l

dXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxl

PkFubmFscyBvZiBOZXVyb2xvZ3k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xOTMt

MjA0PC9wYWdlcz48dm9sdW1lPjQzPC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGRhdGVzPjx5

ZWFyPjE5OTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xOTk4LzAyPC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PHB1Ymxpc2hlcj5XaWxleTwvcHVibGlzaGVyPjxpc2JuPjAzNjQtNTEzNCYjeEQ7

MTUzMS04MjQ5PC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9y

Zy8xMC4xMDAyL2FuYS40MTA0MzAyMDk8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDIvYW5hLjQxMDQzMDIwOTwvZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 120,122,123Niemann Pick disease type CMetabolism, geneticsNFTs & neurites3R + 4RPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb3ZlPC9BdXRob3I+PFllYXI+MTk5NTwvWWVhcj48UmVj

TnVtPjQ2NTc8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4x

MjQsMTI1PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDY1NzwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTQ0NDgyNDMzIj40NjU3PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Mb3ZlLCBTZXRoPC9hdXRob3I+PGF1

dGhvcj5CcmlkZ2VzLCBMZXNsaWUgUi48L2F1dGhvcj48YXV0aG9yPkNhc2UsIEMuIFBhdHJpY2s8

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+TmV1cm9maWJy

aWxsYXJ5IHRhbmdsZXMgaW4gTmllbWFubuKAlFBpY2sgZGlzZWFzZSB0eXBlIEM8L3RpdGxlPjxz

ZWNvbmRhcnktdGl0bGU+QnJhaW48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh

bD48ZnVsbC10aXRsZT5CcmFpbjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjExOS0x

Mjk8L3BhZ2VzPjx2b2x1bWU+MTE4PC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGRhdGVzPjx5

ZWFyPjE5OTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xOTk1LzAyPC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PHB1Ymxpc2hlcj5PeGZvcmQgVW5pdmVyc2l0eSBQcmVzcyAoT1VQKTwvcHVibGlz

aGVyPjxpc2JuPjAwMDYtODk1MCYjeEQ7MTQ2MC0yMTU2PC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDkzL2JyYWluLzExOC4xLjExOTwvdXJsPjwv

cmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA5My9icmFp

bi8xMTguMS4xMTk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0

ZT48QXV0aG9yPlNwaWxsYW50aW5pPC9BdXRob3I+PFllYXI+MTk5OTwvWWVhcj48UmVjTnVtPjQ2

Njc8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjQ2Njc8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBy

cHQ1YXYiIHRpbWVzdGFtcD0iMTU0NDQ4Mzc5MyI+NDY2Nzwva2V5PjwvZm9yZWlnbi1rZXlzPjxy

ZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3Jz

PjxhdXRob3JzPjxhdXRob3I+U3BpbGxhbnRpbmksIE0uIEcuPC9hdXRob3I+PGF1dGhvcj5Ub2xu

YXksIE0uPC9hdXRob3I+PGF1dGhvcj5Mb3ZlLCBTLjwvYXV0aG9yPjxhdXRob3I+R29lZGVydCwg

TS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5NUkMgQnJh

aW4gUmVwYWlyIENlbnRyZSBhbmQgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIFVuaXZlcnNpdHkg

b2YgQ2FtYnJpZGdlLCBVSy4gbWdzMTFAY2FtLmFjLnVrPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48

dGl0bGU+TWljcm90dWJ1bGUtYXNzb2NpYXRlZCBwcm90ZWluIHRhdSwgaGVwYXJhbiBzdWxwaGF0

ZSBhbmQgYWxwaGEtc3ludWNsZWluIGluIHNldmVyYWwgbmV1cm9kZWdlbmVyYXRpdmUgZGlzZWFz

ZXMgd2l0aCBkZW1lbnRpYTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BY3RhIE5ldXJvcGF0aG9s

PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QWN0YSBO

ZXVyb3BhdGhvbDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjU4NS05NDwvcGFnZXM+

PHZvbHVtZT45Nzwvdm9sdW1lPjxudW1iZXI+NjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5B

ZG9sZXNjZW50PC9rZXl3b3JkPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8

L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+RGVt

ZW50aWEvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdv

cmQ+SGVwYXJpdGluIFN1bGZhdGUvKmFuYWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwv

a2V5d29yZD48a2V5d29yZD5JbW11bm9oaXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5N

YWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY3JvdHVidWxlLUFzc29jaWF0ZWQgUHJvdGVpbnMvKmFu

YWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPk5lcnZlIFRpc3N1ZSBQcm90ZWlucy8qYW5hbHlzaXM8

L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9kZWdlbmVyYXRpdmUgRGlzZWFzZXMvKnBhdGhvbG9neTwv

a2V5d29yZD48a2V5d29yZD5OZXVyb2ZpYnJpbHMvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PlN5bnVjbGVpbnM8L2tleXdvcmQ+PGtleXdvcmQ+YWxwaGEtU3ludWNsZWluPC9rZXl3b3JkPjxr

ZXl3b3JkPnRhdSBQcm90ZWlucy8qYW5hbHlzaXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MTk5OTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bjwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjAwMDEtNjMyMiAoUHJpbnQpJiN4RDswMDAxLTYzMjIgKExpbmtpbmcpPC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjEwMzc4Mzc3PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzEwMzc4Mzc3PC91

cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb3ZlPC9BdXRob3I+PFllYXI+MTk5NTwvWWVhcj48UmVj

TnVtPjQ2NTc8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4x

MjQsMTI1PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDY1NzwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTQ0NDgyNDMzIj40NjU3PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Mb3ZlLCBTZXRoPC9hdXRob3I+PGF1

dGhvcj5CcmlkZ2VzLCBMZXNsaWUgUi48L2F1dGhvcj48YXV0aG9yPkNhc2UsIEMuIFBhdHJpY2s8

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+TmV1cm9maWJy

aWxsYXJ5IHRhbmdsZXMgaW4gTmllbWFubuKAlFBpY2sgZGlzZWFzZSB0eXBlIEM8L3RpdGxlPjxz

ZWNvbmRhcnktdGl0bGU+QnJhaW48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh

bD48ZnVsbC10aXRsZT5CcmFpbjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjExOS0x

Mjk8L3BhZ2VzPjx2b2x1bWU+MTE4PC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGRhdGVzPjx5

ZWFyPjE5OTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xOTk1LzAyPC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PHB1Ymxpc2hlcj5PeGZvcmQgVW5pdmVyc2l0eSBQcmVzcyAoT1VQKTwvcHVibGlz

aGVyPjxpc2JuPjAwMDYtODk1MCYjeEQ7MTQ2MC0yMTU2PC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDkzL2JyYWluLzExOC4xLjExOTwvdXJsPjwv

cmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA5My9icmFp

bi8xMTguMS4xMTk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0

ZT48QXV0aG9yPlNwaWxsYW50aW5pPC9BdXRob3I+PFllYXI+MTk5OTwvWWVhcj48UmVjTnVtPjQ2

Njc8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjQ2Njc8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBy

cHQ1YXYiIHRpbWVzdGFtcD0iMTU0NDQ4Mzc5MyI+NDY2Nzwva2V5PjwvZm9yZWlnbi1rZXlzPjxy

ZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3Jz

PjxhdXRob3JzPjxhdXRob3I+U3BpbGxhbnRpbmksIE0uIEcuPC9hdXRob3I+PGF1dGhvcj5Ub2xu

YXksIE0uPC9hdXRob3I+PGF1dGhvcj5Mb3ZlLCBTLjwvYXV0aG9yPjxhdXRob3I+R29lZGVydCwg

TS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5NUkMgQnJh

aW4gUmVwYWlyIENlbnRyZSBhbmQgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIFVuaXZlcnNpdHkg

b2YgQ2FtYnJpZGdlLCBVSy4gbWdzMTFAY2FtLmFjLnVrPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48

dGl0bGU+TWljcm90dWJ1bGUtYXNzb2NpYXRlZCBwcm90ZWluIHRhdSwgaGVwYXJhbiBzdWxwaGF0

ZSBhbmQgYWxwaGEtc3ludWNsZWluIGluIHNldmVyYWwgbmV1cm9kZWdlbmVyYXRpdmUgZGlzZWFz

ZXMgd2l0aCBkZW1lbnRpYTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BY3RhIE5ldXJvcGF0aG9s

PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QWN0YSBO

ZXVyb3BhdGhvbDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjU4NS05NDwvcGFnZXM+

PHZvbHVtZT45Nzwvdm9sdW1lPjxudW1iZXI+NjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5B

ZG9sZXNjZW50PC9rZXl3b3JkPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8

L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+RGVt

ZW50aWEvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdv

cmQ+SGVwYXJpdGluIFN1bGZhdGUvKmFuYWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwv

a2V5d29yZD48a2V5d29yZD5JbW11bm9oaXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5N

YWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY3JvdHVidWxlLUFzc29jaWF0ZWQgUHJvdGVpbnMvKmFu

YWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPk5lcnZlIFRpc3N1ZSBQcm90ZWlucy8qYW5hbHlzaXM8

L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9kZWdlbmVyYXRpdmUgRGlzZWFzZXMvKnBhdGhvbG9neTwv

a2V5d29yZD48a2V5d29yZD5OZXVyb2ZpYnJpbHMvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PlN5bnVjbGVpbnM8L2tleXdvcmQ+PGtleXdvcmQ+YWxwaGEtU3ludWNsZWluPC9rZXl3b3JkPjxr

ZXl3b3JkPnRhdSBQcm90ZWlucy8qYW5hbHlzaXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MTk5OTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bjwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjAwMDEtNjMyMiAoUHJpbnQpJiN4RDswMDAxLTYzMjIgKExpbmtpbmcpPC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjEwMzc4Mzc3PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzEwMzc4Mzc3PC91

cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 124,125Myotonic dystrophy?type 1Indirect genetics:DMPK mutations (consequences on alternative splicing)NFTs & neurites0N3RPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZXJnZWFudDwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+

PFJlY051bT40Njc3PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MTI2LDEyNzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQ2Nzc8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0NDQ4MzkzNCI+NDY3Nzwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U2VyZ2VhbnQsIE4uPC9hdXRo

b3I+PGF1dGhvcj5TYWJsb25uaWVyZSwgQi48L2F1dGhvcj48YXV0aG9yPlNjaHJhZW4tTWFzY2hr

ZSwgUy48L2F1dGhvcj48YXV0aG9yPkdoZXN0ZW0sIEEuPC9hdXRob3I+PGF1dGhvcj5NYXVyYWdl

LCBDLiBBLjwvYXV0aG9yPjxhdXRob3I+V2F0dGV6LCBBLjwvYXV0aG9yPjxhdXRob3I+VmVybWVy

c2NoLCBQLjwvYXV0aG9yPjxhdXRob3I+RGVsYWNvdXJ0ZSwgQS48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5JTlNFUk0gVTQyMiwgR3JvdXBlIFZDRE4sIDEg

cGxhY2UgZGUgVmVyZHVuLCA1OTA0NSBMaWxsZSBDZWRleCwgRnJhbmNlLjwvYXV0aC1hZGRyZXNz

Pjx0aXRsZXM+PHRpdGxlPkR5c3JlZ3VsYXRpb24gb2YgaHVtYW4gYnJhaW4gbWljcm90dWJ1bGUt

YXNzb2NpYXRlZCB0YXUgbVJOQSBtYXR1cmF0aW9uIGluIG15b3RvbmljIGR5c3Ryb3BoeSB0eXBl

IDE8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SHVtIE1vbCBHZW5ldDwvc2Vjb25kYXJ5LXRpdGxl

PjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkh1bSBNb2wgR2VuZXQ8L2Z1bGwtdGl0

bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yMTQzLTU1PC9wYWdlcz48dm9sdW1lPjEwPC92b2x1bWU+

PG51bWJlcj4xOTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5

d29yZD5CbG90dGluZywgV2VzdGVybjwva2V5d29yZD48a2V5d29yZD5CcmFpbi8qbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5ETkEgUHJpbWVycy9jaGVtaXN0cnk8L2tleXdvcmQ+PGtleXdv

cmQ+RWxlY3Ryb3Bob3Jlc2lzLCBQb2x5YWNyeWxhbWlkZSBHZWw8L2tleXdvcmQ+PGtleXdvcmQ+

RXhvbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPklzb2Vuenlt

ZXMvZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxr

ZXl3b3JkPk1pY3JvdHVidWxlcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUg

QWdlZDwva2V5d29yZD48a2V5d29yZD5NeW90b25pYyBEeXN0cm9waHkvKm1ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+UGhvc3Bob3J5bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlJOQSBTcGxp

Y2luZzwva2V5d29yZD48a2V5d29yZD5STkEsIE1lc3Nlbmdlci9tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPlJldmVyc2UgVHJhbnNjcmlwdGFzZSBQb2x5bWVyYXNlIENoYWluIFJlYWN0aW9u

PC9rZXl3b3JkPjxrZXl3b3JkPlRyaW51Y2xlb3RpZGUgUmVwZWF0cy9nZW5ldGljczwva2V5d29y

ZD48a2V5d29yZD50YXUgUHJvdGVpbnMvKm1ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3b3Jkcz48

ZGF0ZXM+PHllYXI+MjAwMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPlNlcCAxNTwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjA5NjQtNjkwNiAoUHJpbnQpJiN4RDswOTY0LTY5MDYgKExp

bmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjExNTkwMTMxPC9hY2Nlc3Npb24tbnVtPjx1cmxz

PjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzEx

NTkwMTMxPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48

QXV0aG9yPlZlcm1lcnNjaDwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJlY051bT40NjY4PC9S

ZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj40NjY4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+

PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2

IiB0aW1lc3RhbXA9IjE1NDQ0ODM4OTQiPjQ2Njg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5

cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0

aG9ycz48YXV0aG9yPlZlcm1lcnNjaCwgUC48L2F1dGhvcj48YXV0aG9yPlNlcmdlYW50LCBOLjwv

YXV0aG9yPjxhdXRob3I+UnVjaG91eCwgTS4gTS48L2F1dGhvcj48YXV0aG9yPkhvZm1hbm4tUmFk

dmFueWksIEguPC9hdXRob3I+PGF1dGhvcj5XYXR0ZXosIEEuPC9hdXRob3I+PGF1dGhvcj5QZXRp

dCwgSC48L2F1dGhvcj48YXV0aG9yPkR3YWlsbHksIFAuPC9hdXRob3I+PGF1dGhvcj5EZWxhY291

cnRlLCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlVu

aXRlIElOU0VSTSA0MjIsIExpbGxlLCBGcmFuY2UuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+U3BlY2lmaWMgdGF1IHZhcmlhbnRzIGluIHRoZSBicmFpbnMgb2YgcGF0aWVudHMgd2l0aCBt

eW90b25pYyBkeXN0cm9waHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmV1cm9sb2d5PC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmV1cm9sb2d5PC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NzExLTc8L3BhZ2VzPjx2b2x1bWU+NDc8L3Zv

bHVtZT48bnVtYmVyPjM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QnJhaW4vKm1ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2Jsb3R0

aW5nPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2hpc3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3

b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+

TXlvdG9uaWMgRHlzdHJvcGh5LyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPnRhdSBQcm90

ZWlucy8qYW5hbHlzaXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MTk5NjwveWVh

cj48cHViLWRhdGVzPjxkYXRlPlNlcDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAw

MjgtMzg3OCAoUHJpbnQpJiN4RDswMDI4LTM4NzggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24t

bnVtPjg3OTc0Njk8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6

Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvODc5NzQ2OTwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZXJnZWFudDwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+

PFJlY051bT40Njc3PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MTI2LDEyNzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQ2Nzc8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0NDQ4MzkzNCI+NDY3Nzwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U2VyZ2VhbnQsIE4uPC9hdXRo

b3I+PGF1dGhvcj5TYWJsb25uaWVyZSwgQi48L2F1dGhvcj48YXV0aG9yPlNjaHJhZW4tTWFzY2hr

ZSwgUy48L2F1dGhvcj48YXV0aG9yPkdoZXN0ZW0sIEEuPC9hdXRob3I+PGF1dGhvcj5NYXVyYWdl

LCBDLiBBLjwvYXV0aG9yPjxhdXRob3I+V2F0dGV6LCBBLjwvYXV0aG9yPjxhdXRob3I+VmVybWVy

c2NoLCBQLjwvYXV0aG9yPjxhdXRob3I+RGVsYWNvdXJ0ZSwgQS48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5JTlNFUk0gVTQyMiwgR3JvdXBlIFZDRE4sIDEg

cGxhY2UgZGUgVmVyZHVuLCA1OTA0NSBMaWxsZSBDZWRleCwgRnJhbmNlLjwvYXV0aC1hZGRyZXNz

Pjx0aXRsZXM+PHRpdGxlPkR5c3JlZ3VsYXRpb24gb2YgaHVtYW4gYnJhaW4gbWljcm90dWJ1bGUt

YXNzb2NpYXRlZCB0YXUgbVJOQSBtYXR1cmF0aW9uIGluIG15b3RvbmljIGR5c3Ryb3BoeSB0eXBl

IDE8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SHVtIE1vbCBHZW5ldDwvc2Vjb25kYXJ5LXRpdGxl

PjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkh1bSBNb2wgR2VuZXQ8L2Z1bGwtdGl0

bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yMTQzLTU1PC9wYWdlcz48dm9sdW1lPjEwPC92b2x1bWU+

PG51bWJlcj4xOTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5

d29yZD5CbG90dGluZywgV2VzdGVybjwva2V5d29yZD48a2V5d29yZD5CcmFpbi8qbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5ETkEgUHJpbWVycy9jaGVtaXN0cnk8L2tleXdvcmQ+PGtleXdv

cmQ+RWxlY3Ryb3Bob3Jlc2lzLCBQb2x5YWNyeWxhbWlkZSBHZWw8L2tleXdvcmQ+PGtleXdvcmQ+

RXhvbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPklzb2Vuenlt

ZXMvZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxr

ZXl3b3JkPk1pY3JvdHVidWxlcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUg

QWdlZDwva2V5d29yZD48a2V5d29yZD5NeW90b25pYyBEeXN0cm9waHkvKm1ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+UGhvc3Bob3J5bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlJOQSBTcGxp

Y2luZzwva2V5d29yZD48a2V5d29yZD5STkEsIE1lc3Nlbmdlci9tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPlJldmVyc2UgVHJhbnNjcmlwdGFzZSBQb2x5bWVyYXNlIENoYWluIFJlYWN0aW9u

PC9rZXl3b3JkPjxrZXl3b3JkPlRyaW51Y2xlb3RpZGUgUmVwZWF0cy9nZW5ldGljczwva2V5d29y

ZD48a2V5d29yZD50YXUgUHJvdGVpbnMvKm1ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3b3Jkcz48

ZGF0ZXM+PHllYXI+MjAwMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPlNlcCAxNTwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjA5NjQtNjkwNiAoUHJpbnQpJiN4RDswOTY0LTY5MDYgKExp

bmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjExNTkwMTMxPC9hY2Nlc3Npb24tbnVtPjx1cmxz

PjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzEx

NTkwMTMxPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48

QXV0aG9yPlZlcm1lcnNjaDwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJlY051bT40NjY4PC9S

ZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj40NjY4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+

PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2

IiB0aW1lc3RhbXA9IjE1NDQ0ODM4OTQiPjQ2Njg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5

cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0

aG9ycz48YXV0aG9yPlZlcm1lcnNjaCwgUC48L2F1dGhvcj48YXV0aG9yPlNlcmdlYW50LCBOLjwv

YXV0aG9yPjxhdXRob3I+UnVjaG91eCwgTS4gTS48L2F1dGhvcj48YXV0aG9yPkhvZm1hbm4tUmFk

dmFueWksIEguPC9hdXRob3I+PGF1dGhvcj5XYXR0ZXosIEEuPC9hdXRob3I+PGF1dGhvcj5QZXRp

dCwgSC48L2F1dGhvcj48YXV0aG9yPkR3YWlsbHksIFAuPC9hdXRob3I+PGF1dGhvcj5EZWxhY291

cnRlLCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlVu

aXRlIElOU0VSTSA0MjIsIExpbGxlLCBGcmFuY2UuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+U3BlY2lmaWMgdGF1IHZhcmlhbnRzIGluIHRoZSBicmFpbnMgb2YgcGF0aWVudHMgd2l0aCBt

eW90b25pYyBkeXN0cm9waHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmV1cm9sb2d5PC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmV1cm9sb2d5PC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NzExLTc8L3BhZ2VzPjx2b2x1bWU+NDc8L3Zv

bHVtZT48bnVtYmVyPjM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QnJhaW4vKm1ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2Jsb3R0

aW5nPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2hpc3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3

b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+

TXlvdG9uaWMgRHlzdHJvcGh5LyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPnRhdSBQcm90

ZWlucy8qYW5hbHlzaXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MTk5NjwveWVh

cj48cHViLWRhdGVzPjxkYXRlPlNlcDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAw

MjgtMzg3OCAoUHJpbnQpJiN4RDswMDI4LTM4NzggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24t

bnVtPjg3OTc0Njk8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6

Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvODc5NzQ2OTwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 126,127Frontotemporal lobar degeneration (FTDP-17)Direct genetics: MAPT mutationsNFTs & dystrophic neuritesAstrocytic tanglesPick bodies… (highly dependent of mutations)3R + 4Ror4R>>3RPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb2VkZXJ0PC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

UmVjTnVtPjQ2OTU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4xMjg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40Njk1PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDQ0ODQwODkiPjQ2OTU8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkdvZWRlcnQsIE0uPC9hdXRob3I+PGF1

dGhvcj5HaGV0dGksIEIuPC9hdXRob3I+PGF1dGhvcj5TcGlsbGFudGluaSwgTS4gRy48L2F1dGhv

cj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5NUkMgTGFib3JhdG9yeSBv

ZiBNb2xlY3VsYXIgQmlvbG9neSwgQ2FtYnJpZGdlIENCMiAwUUgsIFVuaXRlZCBLaW5nZG9tLiBt

Z0BtcmMtbG1iLmNhbS5hYzwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkZyb250b3RlbXBv

cmFsIGRlbWVudGlhOiBpbXBsaWNhdGlvbnMgZm9yIHVuZGVyc3RhbmRpbmcgQWx6aGVpbWVyIGRp

c2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Q29sZCBTcHJpbmcgSGFyYiBQZXJzcGVjdCBN

ZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Db2xk

IFNwcmluZyBIYXJiIFBlcnNwZWN0IE1lZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2Vz

PmEwMDYyNTQ8L3BhZ2VzPjx2b2x1bWU+Mjwvdm9sdW1lPjxudW1iZXI+MjwvbnVtYmVyPjxrZXl3

b3Jkcz48a2V5d29yZD5BZGVub3NpbmUgVHJpcGhvc3BoYXRhc2VzL2dlbmV0aWNzPC9rZXl3b3Jk

PjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypnZW5ldGljcy9oaXN0b3J5PC9rZXl3b3JkPjxr

ZXl3b3JkPkM5b3JmNzIgUHJvdGVpbjwva2V5d29yZD48a2V5d29yZD5DZWxsIEN5Y2xlIFByb3Rl

aW5zL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkNocm9tb3NvbWVzLCBIdW1hbiwgUGFpciAx

Ny9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5ETkEtQmluZGluZyBQcm90ZWlucy9nZW5ldGlj

cy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkVuZG9zb21hbCBTb3J0aW5nIENvbXBsZXhl

cyBSZXF1aXJlZCBmb3IgVHJhbnNwb3J0L2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkZyb250

b3RlbXBvcmFsIERlbWVudGlhLypnZW5ldGljcy9oaXN0b3J5PC9rZXl3b3JkPjxrZXl3b3JkPkhp

c3RvcnksIDE5dGggQ2VudHVyeTwva2V5d29yZD48a2V5d29yZD5IaXN0b3J5LCAyMHRoIENlbnR1

cnk8L2tleXdvcmQ+PGtleXdvcmQ+SGlzdG9yeSwgMjFzdCBDZW50dXJ5PC9rZXl3b3JkPjxrZXl3

b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbnRlcmNlbGx1bGFyIFNpZ25hbGluZyBQZXB0

aWRlcyBhbmQgUHJvdGVpbnMvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+TW90b3IgTmV1cm9u

IERpc2Vhc2UvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+TXV0YXRpb24vZ2VuZXRpY3M8L2tl

eXdvcmQ+PGtleXdvcmQ+UGVyc29uYWxpdHkgRGlzb3JkZXJzL2dlbmV0aWNzPC9rZXl3b3JkPjxr

ZXl3b3JkPlByb3RlaW5zL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPlJOQS1CaW5kaW5nIFBy

b3RlaW5zL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPlN1cHJhbnVjbGVhciBQYWxzeSwgUHJv

Z3Jlc3NpdmUvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+VmFsb3NpbiBDb250YWluaW5nIFBy

b3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+WGVub3B1cyBQcm90ZWlucy9nZW5ldGljczwva2V5d29y

ZD48a2V5d29yZD50YXUgUHJvdGVpbnMvZ2VuZXRpY3M8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0

ZXM+PHllYXI+MjAxMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkZlYjwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxpc2JuPjIxNTctMTQyMiAoRWxlY3Ryb25pYykmI3hEOzIxNTctMTQyMiAoTGlu

a2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjIzNTU3OTM8L2FjY2Vzc2lvbi1udW0+PHVybHM+

PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjIz

NTU3OTM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMzI4MTU5MzwvY3Vz

dG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTEwMS9jc2hwZXJzcGVjdC5hMDA2MjU0

PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb2VkZXJ0PC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

UmVjTnVtPjQ2OTU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4xMjg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40Njk1PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDQ0ODQwODkiPjQ2OTU8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkdvZWRlcnQsIE0uPC9hdXRob3I+PGF1

dGhvcj5HaGV0dGksIEIuPC9hdXRob3I+PGF1dGhvcj5TcGlsbGFudGluaSwgTS4gRy48L2F1dGhv

cj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5NUkMgTGFib3JhdG9yeSBv

ZiBNb2xlY3VsYXIgQmlvbG9neSwgQ2FtYnJpZGdlIENCMiAwUUgsIFVuaXRlZCBLaW5nZG9tLiBt

Z0BtcmMtbG1iLmNhbS5hYzwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkZyb250b3RlbXBv

cmFsIGRlbWVudGlhOiBpbXBsaWNhdGlvbnMgZm9yIHVuZGVyc3RhbmRpbmcgQWx6aGVpbWVyIGRp

c2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Q29sZCBTcHJpbmcgSGFyYiBQZXJzcGVjdCBN

ZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Db2xk

IFNwcmluZyBIYXJiIFBlcnNwZWN0IE1lZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2Vz

PmEwMDYyNTQ8L3BhZ2VzPjx2b2x1bWU+Mjwvdm9sdW1lPjxudW1iZXI+MjwvbnVtYmVyPjxrZXl3

b3Jkcz48a2V5d29yZD5BZGVub3NpbmUgVHJpcGhvc3BoYXRhc2VzL2dlbmV0aWNzPC9rZXl3b3Jk

PjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypnZW5ldGljcy9oaXN0b3J5PC9rZXl3b3JkPjxr

ZXl3b3JkPkM5b3JmNzIgUHJvdGVpbjwva2V5d29yZD48a2V5d29yZD5DZWxsIEN5Y2xlIFByb3Rl

aW5zL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkNocm9tb3NvbWVzLCBIdW1hbiwgUGFpciAx

Ny9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5ETkEtQmluZGluZyBQcm90ZWlucy9nZW5ldGlj

cy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkVuZG9zb21hbCBTb3J0aW5nIENvbXBsZXhl

cyBSZXF1aXJlZCBmb3IgVHJhbnNwb3J0L2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkZyb250

b3RlbXBvcmFsIERlbWVudGlhLypnZW5ldGljcy9oaXN0b3J5PC9rZXl3b3JkPjxrZXl3b3JkPkhp

c3RvcnksIDE5dGggQ2VudHVyeTwva2V5d29yZD48a2V5d29yZD5IaXN0b3J5LCAyMHRoIENlbnR1

cnk8L2tleXdvcmQ+PGtleXdvcmQ+SGlzdG9yeSwgMjFzdCBDZW50dXJ5PC9rZXl3b3JkPjxrZXl3

b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbnRlcmNlbGx1bGFyIFNpZ25hbGluZyBQZXB0

aWRlcyBhbmQgUHJvdGVpbnMvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+TW90b3IgTmV1cm9u

IERpc2Vhc2UvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+TXV0YXRpb24vZ2VuZXRpY3M8L2tl

eXdvcmQ+PGtleXdvcmQ+UGVyc29uYWxpdHkgRGlzb3JkZXJzL2dlbmV0aWNzPC9rZXl3b3JkPjxr

ZXl3b3JkPlByb3RlaW5zL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPlJOQS1CaW5kaW5nIFBy

b3RlaW5zL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPlN1cHJhbnVjbGVhciBQYWxzeSwgUHJv

Z3Jlc3NpdmUvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+VmFsb3NpbiBDb250YWluaW5nIFBy

b3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+WGVub3B1cyBQcm90ZWlucy9nZW5ldGljczwva2V5d29y

ZD48a2V5d29yZD50YXUgUHJvdGVpbnMvZ2VuZXRpY3M8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0

ZXM+PHllYXI+MjAxMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkZlYjwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxpc2JuPjIxNTctMTQyMiAoRWxlY3Ryb25pYykmI3hEOzIxNTctMTQyMiAoTGlu

a2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjIzNTU3OTM8L2FjY2Vzc2lvbi1udW0+PHVybHM+

PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjIz

NTU3OTM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMzI4MTU5MzwvY3Vz

dG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTEwMS9jc2hwZXJzcGVjdC5hMDA2MjU0

PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 128Progressive supranuclear palsyMAPT haplotypesmiR-132NFTs & dystrophic neuritesTufted astrocytes4R>>3RPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TbWl0aDwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl

Y051bT40Njk3PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTI5LDEzMDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQ2OTc8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0NDQ4NDI4MiI+NDY5Nzwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U21pdGgsIFAuIFkuPC9hdXRob3I+

PGF1dGhvcj5EZWxheSwgQy48L2F1dGhvcj48YXV0aG9yPkdpcmFyZCwgSi48L2F1dGhvcj48YXV0

aG9yPlBhcG9uLCBNLiBBLjwvYXV0aG9yPjxhdXRob3I+UGxhbmVsLCBFLjwvYXV0aG9yPjxhdXRo

b3I+U2VyZ2VhbnQsIE4uPC9hdXRob3I+PGF1dGhvcj5CdWVlLCBMLjwvYXV0aG9yPjxhdXRob3I+

SGViZXJ0LCBTLiBTLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRy

ZXNzPkNlbnRyZSBkZSByZWNoZXJjaGUgZHUgQ0hVUSwgQXhlIE5ldXJvc2NpZW5jZXMsIFF1ZWJl

YywgQ2FuYWRhLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPk1pY3JvUk5BLTEzMiBsb3Nz

IGlzIGFzc29jaWF0ZWQgd2l0aCB0YXUgZXhvbiAxMCBpbmNsdXNpb24gaW4gcHJvZ3Jlc3NpdmUg

c3VwcmFudWNsZWFyIHBhbHN5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkh1bSBNb2wgR2VuZXQ8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5IdW0gTW9s

IEdlbmV0PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NDAxNi0yNDwvcGFnZXM+PHZv

bHVtZT4yMDwvdm9sdW1lPjxudW1iZXI+MjA8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWdl

ZDwva2V5d29yZD48a2V5d29yZD5BbHRlcm5hdGl2ZSBTcGxpY2luZy8qZ2VuZXRpY3M8L2tleXdv

cmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CcmFpbi9tZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPkNlbGwgTGluZSwgVHVtb3I8L2tleXdvcmQ+PGtleXdvcmQ+KkV4b25z

PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5HZW5lIEV4cHJlc3Np

b24gUHJvZmlsaW5nPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmUgRXhwcmVzc2lvbiBSZWd1bGF0aW9u

LCBEZXZlbG9wbWVudGFsPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29y

ZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWljcm9STkFz

L2dlbmV0aWNzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3

b3JkPjxrZXl3b3JkPk5lcnZlIFRpc3N1ZSBQcm90ZWlucy9nZW5ldGljcy9tZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPlBvbHlweXJpbWlkaW5lIFRyYWN0LUJpbmRpbmcgUHJvdGVpbi9nZW5l

dGljcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlByb3RlaW4gSXNvZm9ybXMvZ2VuZXRp

Y3MvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5TdXByYW51Y2xlYXIgUGFsc3ksIFByb2dy

ZXNzaXZlLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD50YXUgUHJvdGVpbnMvKmdlbmV0aWNz

L21ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMTwveWVhcj48

cHViLWRhdGVzPjxkYXRlPk9jdCAxNTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0

NjAtMjA4MyAoRWxlY3Ryb25pYykmI3hEOzA5NjQtNjkwNiAoTGlua2luZyk8L2lzYm4+PGFjY2Vz

c2lvbi1udW0+MjE4MDc3NjU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJs

Pmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjE4MDc3NjU8L3VybD48L3JlbGF0

ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwOTMvaG1nL2RkcjMz

MDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+

QmFrZXI8L0F1dGhvcj48WWVhcj4xOTk5PC9ZZWFyPjxSZWNOdW0+NDY5NjwvUmVjTnVtPjxyZWNv

cmQ+PHJlYy1udW1iZXI+NDY5NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1w

PSIxNTQ0NDg0MTkyIj40Njk2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5CYWtlciwgTS48L2F1dGhvcj48YXV0aG9yPkxpdHZhbiwgSS48L2F1dGhvcj48YXV0aG9yPkhv

dWxkZW4sIEguPC9hdXRob3I+PGF1dGhvcj5BZGFtc29uLCBKLjwvYXV0aG9yPjxhdXRob3I+RGlj

a3NvbiwgRC48L2F1dGhvcj48YXV0aG9yPlBlcmV6LVR1ciwgSi48L2F1dGhvcj48YXV0aG9yPkhh

cmR5LCBKLjwvYXV0aG9yPjxhdXRob3I+THluY2gsIFQuPC9hdXRob3I+PGF1dGhvcj5CaWdpbywg

RS48L2F1dGhvcj48YXV0aG9yPkh1dHRvbiwgTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli

dXRvcnM+PGF1dGgtYWRkcmVzcz5NYXlvIENsaW5pYyBKYWNrc29udmlsbGUsIDQ1MDAgU2FuIFBh

YmxvIFJvYWQsIEphY2tzb252aWxsZSwgRkwgMzIyMjQsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0

bGVzPjx0aXRsZT5Bc3NvY2lhdGlvbiBvZiBhbiBleHRlbmRlZCBoYXBsb3R5cGUgaW4gdGhlIHRh

dSBnZW5lIHdpdGggcHJvZ3Jlc3NpdmUgc3VwcmFudWNsZWFyIHBhbHN5PC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPkh1bSBNb2wgR2VuZXQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9k

aWNhbD48ZnVsbC10aXRsZT5IdW0gTW9sIEdlbmV0PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48

cGFnZXM+NzExLTU8L3BhZ2VzPjx2b2x1bWU+ODwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxr

ZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFsbGVsZXM8L2tleXdvcmQ+

PGtleXdvcmQ+RE5BIE11dGF0aW9uYWwgQW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+RXhvbnM8

L2tleXdvcmQ+PGtleXdvcmQ+R2VuZSBGcmVxdWVuY3k8L2tleXdvcmQ+PGtleXdvcmQ+R2Vub3R5

cGU8L2tleXdvcmQ+PGtleXdvcmQ+SGFwbG90eXBlczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8

L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UG9seW1vcnBo

aXNtLCBHZW5ldGljPC9rZXl3b3JkPjxrZXl3b3JkPlN1cHJhbnVjbGVhciBQYWxzeSwgUHJvZ3Jl

c3NpdmUvKmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPnRhdSBQcm90ZWlucy8qZ2VuZXRpY3M8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MTk5OTwveWVhcj48cHViLWRhdGVzPjxk

YXRlPkFwcjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjA5NjQtNjkwNiAoUHJpbnQp

JiN4RDswOTY0LTY5MDYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjEwMDcyNDQxPC9h

Y2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxt

Lm5paC5nb3YvcHVibWVkLzEwMDcyNDQxPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVj

b3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TbWl0aDwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl

Y051bT40Njk3PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTI5LDEzMDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQ2OTc8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0NDQ4NDI4MiI+NDY5Nzwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U21pdGgsIFAuIFkuPC9hdXRob3I+

PGF1dGhvcj5EZWxheSwgQy48L2F1dGhvcj48YXV0aG9yPkdpcmFyZCwgSi48L2F1dGhvcj48YXV0

aG9yPlBhcG9uLCBNLiBBLjwvYXV0aG9yPjxhdXRob3I+UGxhbmVsLCBFLjwvYXV0aG9yPjxhdXRo

b3I+U2VyZ2VhbnQsIE4uPC9hdXRob3I+PGF1dGhvcj5CdWVlLCBMLjwvYXV0aG9yPjxhdXRob3I+

SGViZXJ0LCBTLiBTLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRy

ZXNzPkNlbnRyZSBkZSByZWNoZXJjaGUgZHUgQ0hVUSwgQXhlIE5ldXJvc2NpZW5jZXMsIFF1ZWJl

YywgQ2FuYWRhLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPk1pY3JvUk5BLTEzMiBsb3Nz

IGlzIGFzc29jaWF0ZWQgd2l0aCB0YXUgZXhvbiAxMCBpbmNsdXNpb24gaW4gcHJvZ3Jlc3NpdmUg

c3VwcmFudWNsZWFyIHBhbHN5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkh1bSBNb2wgR2VuZXQ8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5IdW0gTW9s

IEdlbmV0PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NDAxNi0yNDwvcGFnZXM+PHZv

bHVtZT4yMDwvdm9sdW1lPjxudW1iZXI+MjA8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWdl

ZDwva2V5d29yZD48a2V5d29yZD5BbHRlcm5hdGl2ZSBTcGxpY2luZy8qZ2VuZXRpY3M8L2tleXdv

cmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CcmFpbi9tZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPkNlbGwgTGluZSwgVHVtb3I8L2tleXdvcmQ+PGtleXdvcmQ+KkV4b25z

PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5HZW5lIEV4cHJlc3Np

b24gUHJvZmlsaW5nPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmUgRXhwcmVzc2lvbiBSZWd1bGF0aW9u

LCBEZXZlbG9wbWVudGFsPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29y

ZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWljcm9STkFz

L2dlbmV0aWNzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3

b3JkPjxrZXl3b3JkPk5lcnZlIFRpc3N1ZSBQcm90ZWlucy9nZW5ldGljcy9tZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPlBvbHlweXJpbWlkaW5lIFRyYWN0LUJpbmRpbmcgUHJvdGVpbi9nZW5l

dGljcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlByb3RlaW4gSXNvZm9ybXMvZ2VuZXRp

Y3MvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5TdXByYW51Y2xlYXIgUGFsc3ksIFByb2dy

ZXNzaXZlLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD50YXUgUHJvdGVpbnMvKmdlbmV0aWNz

L21ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMTwveWVhcj48

cHViLWRhdGVzPjxkYXRlPk9jdCAxNTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0

NjAtMjA4MyAoRWxlY3Ryb25pYykmI3hEOzA5NjQtNjkwNiAoTGlua2luZyk8L2lzYm4+PGFjY2Vz

c2lvbi1udW0+MjE4MDc3NjU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJs

Pmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjE4MDc3NjU8L3VybD48L3JlbGF0

ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwOTMvaG1nL2RkcjMz

MDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+

QmFrZXI8L0F1dGhvcj48WWVhcj4xOTk5PC9ZZWFyPjxSZWNOdW0+NDY5NjwvUmVjTnVtPjxyZWNv

cmQ+PHJlYy1udW1iZXI+NDY5NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1w

PSIxNTQ0NDg0MTkyIj40Njk2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5CYWtlciwgTS48L2F1dGhvcj48YXV0aG9yPkxpdHZhbiwgSS48L2F1dGhvcj48YXV0aG9yPkhv

dWxkZW4sIEguPC9hdXRob3I+PGF1dGhvcj5BZGFtc29uLCBKLjwvYXV0aG9yPjxhdXRob3I+RGlj

a3NvbiwgRC48L2F1dGhvcj48YXV0aG9yPlBlcmV6LVR1ciwgSi48L2F1dGhvcj48YXV0aG9yPkhh

cmR5LCBKLjwvYXV0aG9yPjxhdXRob3I+THluY2gsIFQuPC9hdXRob3I+PGF1dGhvcj5CaWdpbywg

RS48L2F1dGhvcj48YXV0aG9yPkh1dHRvbiwgTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli

dXRvcnM+PGF1dGgtYWRkcmVzcz5NYXlvIENsaW5pYyBKYWNrc29udmlsbGUsIDQ1MDAgU2FuIFBh

YmxvIFJvYWQsIEphY2tzb252aWxsZSwgRkwgMzIyMjQsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0

bGVzPjx0aXRsZT5Bc3NvY2lhdGlvbiBvZiBhbiBleHRlbmRlZCBoYXBsb3R5cGUgaW4gdGhlIHRh

dSBnZW5lIHdpdGggcHJvZ3Jlc3NpdmUgc3VwcmFudWNsZWFyIHBhbHN5PC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPkh1bSBNb2wgR2VuZXQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9k

aWNhbD48ZnVsbC10aXRsZT5IdW0gTW9sIEdlbmV0PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48

cGFnZXM+NzExLTU8L3BhZ2VzPjx2b2x1bWU+ODwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxr

ZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFsbGVsZXM8L2tleXdvcmQ+

PGtleXdvcmQ+RE5BIE11dGF0aW9uYWwgQW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+RXhvbnM8

L2tleXdvcmQ+PGtleXdvcmQ+R2VuZSBGcmVxdWVuY3k8L2tleXdvcmQ+PGtleXdvcmQ+R2Vub3R5

cGU8L2tleXdvcmQ+PGtleXdvcmQ+SGFwbG90eXBlczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8

L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UG9seW1vcnBo

aXNtLCBHZW5ldGljPC9rZXl3b3JkPjxrZXl3b3JkPlN1cHJhbnVjbGVhciBQYWxzeSwgUHJvZ3Jl

c3NpdmUvKmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPnRhdSBQcm90ZWlucy8qZ2VuZXRpY3M8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MTk5OTwveWVhcj48cHViLWRhdGVzPjxk

YXRlPkFwcjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjA5NjQtNjkwNiAoUHJpbnQp

JiN4RDswOTY0LTY5MDYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjEwMDcyNDQxPC9h

Y2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxt

Lm5paC5nb3YvcHVibWVkLzEwMDcyNDQxPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVj

b3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 129,130Table 2. Diversity of tauopathies in humans and their main traits. According to Braak stages, it is well considered that neurofibrillary tangle pathology starts within the hippocampal formation. Then it goes to the temporal area, then to polymodal association areas, unimodal association and finally the entire cerebral cortex ADDIN EN.CITE <EndNote><Cite><Author>Jucker</Author><Year>2011</Year><RecNum>3922</RecNum><DisplayText><style face="superscript">131</style></DisplayText><record><rec-number>3922</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1536672097">3922</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jucker, M.</author><author>Walker, L. C.</author></authors></contributors><auth-address>Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tubingen, Tubingen, Germany. mathias.jucker@uni-tuebingen.de</auth-address><titles><title>Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders</title><secondary-title>Ann Neurol</secondary-title></titles><pages>532-40</pages><volume>70</volume><number>4</number><edition>2011/10/27</edition><keywords><keyword>Alzheimer Disease/*metabolism/*pathology</keyword><keyword>Amyloid beta-Peptides/metabolism</keyword><keyword>Animals</keyword><keyword>DNA-Binding Proteins/metabolism</keyword><keyword>Humans</keyword><keyword>Neurodegenerative Diseases/metabolism/pathology</keyword><keyword>Prions/metabolism</keyword><keyword>Proteins/chemistry/*metabolism</keyword><keyword>tau Proteins/metabolism</keyword></keywords><dates><year>2011</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1531-8249 (Electronic)&#xD;0364-5134 (Linking)</isbn><accession-num>22028219</accession-num><urls><related-urls><url>. Recently, researchers proposed a mechanism of prion-like propagation, meaning that these Tau aggregates behave like the prion proteins. In this way, Tau tangles induce normal proteins into conformational changes leading to aggregation. More research focused on this mechanism has shown incremental evidence supporting this hypothesis. It is logical to propose targeting Tau and Aβ together with other targets, since Tau is the main component of aggregates leading to neurodegeneration. Nevertheless, these features represent the end stage of the disease. Does it mean there are other players in the initial process? For Aβ, it is likely because a mutation in APP is sufficient to cause AD. For Tau, it is more complicated. The presence of a mutation in Tau implies neurofibrillary degeneration without amyloid beta. Therefore, it means that by itself, aggregated Tau is toxic but does not lead to amyloid aggregation. In fact, Tau protein does not only aggregate in AD but also in other neurodegenerative disorders. Tau biology is complex due to the presence of six Tau isoforms in the human brain. They are generated by alternative splicing from a unique gene MAPT located on chromosome 17. In the human brain, these six isoforms are in equal ratio of isoforms having three (3R) and four microtubule-binding domains (4R). Nevertheless, this ratio is modified among tauopathies showing different aggregation profiles (Table 2). In addition, these proteins go through post-translational modification such as glycosylation, phosphorylation, oxidation, acetylation, and truncation. These posttranslational modifications and truncation may facilitate Tau aggregation even if the mechanisms are still unclear.Figure 1. Key targets and therapeutic strategies for Tau treatments. Schematic representation of strategies for preventing Tau aggregation and spreading. Modulation of Tau metabolism can occur by regulating transcription, phosphorylation and degradation (e.g. through autophagy in pre and post-synaptic neurons). Blockade of Tau trans-synaptic transfer through immunotherapy is also a strategy under test in the clinic. Thus, Tau is not only found in Alzheimer’s disease, it is also found in progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease and some patients presenting with frontotemporal lobar degeneration. However, Tau aggregates display different regional and laminar distributions, different morphologies and different molecular characteristics. In fact, among these disorders, aetiologies are also different. Head trauma is a risk factor since Tau pathology is also found in traumatic brain injury like dementia pugilistica. It has also been reported in autistic children with self-injury behaviour. Therefore, Tau aggregation is not only related to aging but to other factors that might differ from those belonging to AD. Another etiology may be infectious agents like virus. Measles and Spanish flu viruses have been described to lead to cerebral Tau aggregation in subacute sclerosing panencephalitis and postencephalitic parkinsonism respectively. Therefore, infections may also trigger Tau aggregation. Other metabolism dysfunctions, as encountered in Niemann-Pick’s disease type C (hereditary disorders with lysosomal lipidosis) and PSP (caused either by industrial waste or by mitochondrial toxins), also show Tau aggregation. Finally, Tau alternative splicing is also altered through genetic mechanisms either direct or indirect. For instance, some mutations have been on MAPT that lead to mis-splicing of exon 10 and overexpression of four-microtubule binding domain Tau isoforms. Tau aggregation can also show up indirectly, for instance in myotonic dystrophy type?1, a neuromuscular disorder. In this disease, the mRNA of this protein DMBK have CUG expansion triplets, causing sequestration of splicing factors that can change alternative splicing of many genes (APP, MAPT, Chloride channel, insulin receptor, troponin T, etc.). For MAPT, Tau splicing leads to the formation of the shortest Tau isoform which is found aggregated in some patients presenting with myotonic dystrophy. In the same way, some mutations on the Tau gene, MAPT, change the alternative splicing of Tau. For example, in AD, the six isoforms of Tau co-aggregate, in contrast to pathologies like PSP, in which only the 4R-Tau isoforms aggregate, and Pick’s disease, where the aggregates are only comprised of 3R-Tau. Adding additional complexity, autosomal dominant mutations in MAPT have been reported to promote Tau aggregation and lead to fronto-temporal lobar degeneration. In AD, there is a large therapeutic time window for Tau treatments since neurofibrillary tangles last for decades. This is evident in neurons with pre-tangles that are still integrated into neuronal networks and still functional at early stages of AD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LdWNoaWJob3RsYTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1ll

YXI+PFJlY051bT4zOTE3PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNj

cmlwdCI+MTMyPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzkxNzwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2NjcxODExIj4zOTE3PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LdWNoaWJob3RsYSwgSy4gVi48

L2F1dGhvcj48YXV0aG9yPldlZ21hbm4sIFMuPC9hdXRob3I+PGF1dGhvcj5Lb3BlaWtpbmEsIEsu

IEouPC9hdXRob3I+PGF1dGhvcj5IYXdrZXMsIEouPC9hdXRob3I+PGF1dGhvcj5SdWRpbnNraXks

IE4uPC9hdXRob3I+PGF1dGhvcj5BbmRlcm1hbm4sIE0uIEwuPC9hdXRob3I+PGF1dGhvcj5TcGly

ZXMtSm9uZXMsIFQuIEwuPC9hdXRob3I+PGF1dGhvcj5CYWNza2FpLCBCLiBKLjwvYXV0aG9yPjxh

dXRob3I+SHltYW4sIEIuIFQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo

LWFkZHJlc3M+QWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlIFJlc2VhcmNoIExhYm9yYXRvcnksIERl

cGFydG1lbnQgb2YgTmV1cm9sb2d5LCBNYXNzR2VuZXJhbCBJbnN0aXR1dGUgZm9yIE5ldXJvZGVn

ZW5lcmF0aXZlIERpc2Vhc2UsIE1hc3NhY2h1c2V0dHMgR2VuZXJhbCBIb3NwaXRhbCwgSGFydmFy

ZCBNZWRpY2FsIFNjaG9vbCwgQ2hhcmxlc3Rvd24sIE1BIDAyMTI5LjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPk5ldXJvZmlicmlsbGFyeSB0YW5nbGUtYmVhcmluZyBuZXVyb25zIGFyZSBm

dW5jdGlvbmFsbHkgaW50ZWdyYXRlZCBpbiBjb3J0aWNhbCBjaXJjdWl0cyBpbiB2aXZvPC90aXRs

ZT48c2Vjb25kYXJ5LXRpdGxlPlByb2MgTmF0bCBBY2FkIFNjaSBVIFMgQTwvc2Vjb25kYXJ5LXRp

dGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlByb2MgTmF0bCBBY2FkIFNjaSBV

IFMgQTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjUxMC00PC9wYWdlcz48dm9sdW1l

PjExMTwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxlZGl0aW9uPjIwMTMvMTIvMjY8L2VkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL3BhdGhvbG9neTwva2V5d29y

ZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL3BhdGhvbG9neTwva2V5

d29yZD48a2V5d29yZD5DYWxjaXVtL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+RGVwZW5k

b3ZpcnVzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3

b3JkPkltYWdlIFByb2Nlc3NpbmcsIENvbXB1dGVyLUFzc2lzdGVkPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgVHJhbnNnZW5pYzwva2V5d29yZD48a2V5d29y

ZD5NaWNyb3Njb3B5LCBGbHVvcmVzY2VuY2U8L2tleXdvcmQ+PGtleXdvcmQ+TW9kZWxzLCBOZXVy

b2xvZ2ljYWw8L2tleXdvcmQ+PGtleXdvcmQ+TXV0YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+TmV1

cm9maWJyaWxsYXJ5IFRhbmdsZXMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9u

cy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UGhvdG9uczwva2V5d29yZD48a2V5d29yZD5U

YXVvcGF0aGllcy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+VHJhbnNnZW5lczwva2V5d29y

ZD48a2V5d29yZD50YXUgUHJvdGVpbnMvKmdlbmV0aWNzL21ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+bmV1cm9uYWwgbmV0d29ya3M8L2tleXdvcmQ+PGtleXdvcmQ+cGFpcmVkIGhlbGljYWwg

ZmlsYW1lbnRzPC9rZXl3b3JkPjxrZXl3b3JkPnRhdSBwYXRob2xvZ3k8L2tleXdvcmQ+PC9rZXl3

b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPkphbiA3PC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA5MS02NDkwIChFbGVjdHJvbmljKSYjeEQ7MDAy

Ny04NDI0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNDM2ODg0ODwvYWNjZXNzaW9u

LW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdv

di9wdWJtZWQvMjQzNjg4NDg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1D

Mzg5MDc3NzwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA3My9wbmFzLjEz

MTg4MDcxMTE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5v

dGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LdWNoaWJob3RsYTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1ll

YXI+PFJlY051bT4zOTE3PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNj

cmlwdCI+MTMyPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzkxNzwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2NjcxODExIj4zOTE3PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LdWNoaWJob3RsYSwgSy4gVi48

L2F1dGhvcj48YXV0aG9yPldlZ21hbm4sIFMuPC9hdXRob3I+PGF1dGhvcj5Lb3BlaWtpbmEsIEsu

IEouPC9hdXRob3I+PGF1dGhvcj5IYXdrZXMsIEouPC9hdXRob3I+PGF1dGhvcj5SdWRpbnNraXks

IE4uPC9hdXRob3I+PGF1dGhvcj5BbmRlcm1hbm4sIE0uIEwuPC9hdXRob3I+PGF1dGhvcj5TcGly

ZXMtSm9uZXMsIFQuIEwuPC9hdXRob3I+PGF1dGhvcj5CYWNza2FpLCBCLiBKLjwvYXV0aG9yPjxh

dXRob3I+SHltYW4sIEIuIFQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo

LWFkZHJlc3M+QWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlIFJlc2VhcmNoIExhYm9yYXRvcnksIERl

cGFydG1lbnQgb2YgTmV1cm9sb2d5LCBNYXNzR2VuZXJhbCBJbnN0aXR1dGUgZm9yIE5ldXJvZGVn

ZW5lcmF0aXZlIERpc2Vhc2UsIE1hc3NhY2h1c2V0dHMgR2VuZXJhbCBIb3NwaXRhbCwgSGFydmFy

ZCBNZWRpY2FsIFNjaG9vbCwgQ2hhcmxlc3Rvd24sIE1BIDAyMTI5LjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPk5ldXJvZmlicmlsbGFyeSB0YW5nbGUtYmVhcmluZyBuZXVyb25zIGFyZSBm

dW5jdGlvbmFsbHkgaW50ZWdyYXRlZCBpbiBjb3J0aWNhbCBjaXJjdWl0cyBpbiB2aXZvPC90aXRs

ZT48c2Vjb25kYXJ5LXRpdGxlPlByb2MgTmF0bCBBY2FkIFNjaSBVIFMgQTwvc2Vjb25kYXJ5LXRp

dGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlByb2MgTmF0bCBBY2FkIFNjaSBV

IFMgQTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjUxMC00PC9wYWdlcz48dm9sdW1l

PjExMTwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxlZGl0aW9uPjIwMTMvMTIvMjY8L2VkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL3BhdGhvbG9neTwva2V5d29y

ZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL3BhdGhvbG9neTwva2V5

d29yZD48a2V5d29yZD5DYWxjaXVtL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+RGVwZW5k

b3ZpcnVzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3

b3JkPkltYWdlIFByb2Nlc3NpbmcsIENvbXB1dGVyLUFzc2lzdGVkPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgVHJhbnNnZW5pYzwva2V5d29yZD48a2V5d29y

ZD5NaWNyb3Njb3B5LCBGbHVvcmVzY2VuY2U8L2tleXdvcmQ+PGtleXdvcmQ+TW9kZWxzLCBOZXVy

b2xvZ2ljYWw8L2tleXdvcmQ+PGtleXdvcmQ+TXV0YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+TmV1

cm9maWJyaWxsYXJ5IFRhbmdsZXMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9u

cy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UGhvdG9uczwva2V5d29yZD48a2V5d29yZD5U

YXVvcGF0aGllcy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+VHJhbnNnZW5lczwva2V5d29y

ZD48a2V5d29yZD50YXUgUHJvdGVpbnMvKmdlbmV0aWNzL21ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+bmV1cm9uYWwgbmV0d29ya3M8L2tleXdvcmQ+PGtleXdvcmQ+cGFpcmVkIGhlbGljYWwg

ZmlsYW1lbnRzPC9rZXl3b3JkPjxrZXl3b3JkPnRhdSBwYXRob2xvZ3k8L2tleXdvcmQ+PC9rZXl3

b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPkphbiA3PC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA5MS02NDkwIChFbGVjdHJvbmljKSYjeEQ7MDAy

Ny04NDI0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNDM2ODg0ODwvYWNjZXNzaW9u

LW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdv

di9wdWJtZWQvMjQzNjg4NDg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1D

Mzg5MDc3NzwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA3My9wbmFzLjEz

MTg4MDcxMTE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5v

dGU+

ADDIN EN.CITE.DATA 132. Preclinical studies are possible because of the large number of animal models available PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BaG1lZDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl

Y051bT4zOTQ3PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTMzLTEzNTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM5NDc8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjY3NDk5MSI+Mzk0Nzwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QWhtZWQsIFQuPC9hdXRob3I+PGF1

dGhvcj5WYW4gZGVyIEpldWdkLCBBLjwvYXV0aG9yPjxhdXRob3I+Qmx1bSwgRC48L2F1dGhvcj48

YXV0aG9yPkdhbGFzLCBNLiBDLjwvYXV0aG9yPjxhdXRob3I+RCZhcG9zO0hvb2dlLCBSLjwvYXV0

aG9yPjxhdXRob3I+QnVlZSwgTC48L2F1dGhvcj48YXV0aG9yPkJhbHNjaHVuLCBELjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkxhYm9yYXRvcnkgb2YgQmlv

bG9naWNhbCBQc3ljaG9sb2d5LCBDYXRob2xpYyBVbml2ZXJzaXR5IG9mIExldXZlbiwgQmVsZ2l1

bS4mI3hEO0luc2VybSwgVU1SODM3LCBMaWxsZSwgRnJhbmNlOyBVbml2ZXJzaXRlIExpbGxlLU5v

cmQgZGUgRnJhbmNlLCBMaWxsZSwgRnJhbmNlOyBVRFNMLCBMaWxsZSwgRnJhbmNlOyBGYWN1bHRl

IGRlIE1lZGVjaW5lLCBJbnN0aXR1dCBkZSBtZWRlY2luZSBwcmVkaWN0aXZlIGV0IHJlY2hlcmNo

ZSB0aGVyYXBldXRpcXVlLCBKZWFuLVBpZXJyZSBBdWJlcnQgUmVzZWFyY2ggQ2VudHJlLCBMaWxs

ZSwgRnJhbmNlLiYjeEQ7TGFib3JhdG9yeSBvZiBCaW9sb2dpY2FsIFBzeWNob2xvZ3ksIENhdGhv

bGljIFVuaXZlcnNpdHkgb2YgTGV1dmVuLCBCZWxnaXVtLiBFbGVjdHJvbmljIGFkZHJlc3M6IERl

dGxlZi5CYWxzY2h1bkBwcHcua3VsZXV2ZW4uYmUuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+Q29nbml0aW9uIGFuZCBoaXBwb2NhbXBhbCBzeW5hcHRpYyBwbGFzdGljaXR5IGluIG1pY2Ug

d2l0aCBhIGhvbW96eWdvdXMgdGF1IGRlbGV0aW9uPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5l

dXJvYmlvbCBBZ2luZzwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxs

LXRpdGxlPk5ldXJvYmlvbCBBZ2luZzwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjI0

NzQtMjQ3ODwvcGFnZXM+PHZvbHVtZT4zNTwvdm9sdW1lPjxudW1iZXI+MTE8L251bWJlcj48ZWRp

dGlvbj4yMDE0LzA2LzExPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9rZXl3

b3JkPjxrZXl3b3JkPipDb2duaXRpb248L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMs

IEFuaW1hbDwva2V5d29yZD48a2V5d29yZD5HZW5lIERlbGV0aW9uPC9rZXl3b3JkPjxrZXl3b3Jk

PkhpcHBvY2FtcHVzLypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SG9tb3p5Z290

ZTwva2V5d29yZD48a2V5d29yZD5Mb25nLVRlcm0gUG90ZW50aWF0aW9uPC9rZXl3b3JkPjxrZXl3

b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgSW5icmVkIEM1N0JMPC9rZXl3b3JkPjxr

ZXl3b3JkPk1pY2UsIEtub2Nrb3V0PC9rZXl3b3JkPjxrZXl3b3JkPk1pY3JvdHVidWxlcy9tZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPipOZXVyb25hbCBQbGFzdGljaXR5PC9rZXl3b3JkPjxr

ZXl3b3JkPlNwYXRpYWwgTGVhcm5pbmc8L2tleXdvcmQ+PGtleXdvcmQ+U3luYXB0aWMgVHJhbnNt

aXNzaW9uPC9rZXl3b3JkPjxrZXl3b3JkPlRhdW9wYXRoaWVzLypwaHlzaW9wYXRob2xvZ3kvKnBz

eWNob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5zLypwaHlzaW9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5D

b2duaXRpb248L2tleXdvcmQ+PGtleXdvcmQ+SGlwcG9jYW1wdXM8L2tleXdvcmQ+PGtleXdvcmQ+

TG9uZy10ZXJtIGRlcHJlc3Npb248L2tleXdvcmQ+PGtleXdvcmQ+TW9ycmlzIHdhdGVyIG1hemU8

L2tleXdvcmQ+PGtleXdvcmQ+U3luYXB0aWMgcGxhc3RpY2l0eTwva2V5d29yZD48a2V5d29yZD5U

YXUga25vY2stb3V0IG1pY2U8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju

PjE1NTgtMTQ5NyAoRWxlY3Ryb25pYykmI3hEOzAxOTctNDU4MCAoTGlua2luZyk8L2lzYm4+PGFj

Y2Vzc2lvbi1udW0+MjQ5MTM4OTU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48

dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI0OTEzODk1PC91cmw+PC9y

ZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2oubmV1

cm9iaW9sYWdpbmcuMjAxNC4wNS4wMDU8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3Jk

PjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlNhbnRhY3J1ejwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+

PFJlY051bT4zOTE4PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zOTE4PC9yZWMtbnVtYmVy

Pjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBm

d3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzY2NzE4NTciPjM5MTg8L2tleT48L2ZvcmVp

Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv

bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNhbnRhY3J1eiwgSy48L2F1dGhvcj48YXV0aG9y

Pkxld2lzLCBKLjwvYXV0aG9yPjxhdXRob3I+U3BpcmVzLCBULjwvYXV0aG9yPjxhdXRob3I+UGF1

bHNvbiwgSi48L2F1dGhvcj48YXV0aG9yPktvdGlsaW5laywgTC48L2F1dGhvcj48YXV0aG9yPklu

Z2Vsc3NvbiwgTS48L2F1dGhvcj48YXV0aG9yPkd1aW1hcmFlcywgQS48L2F1dGhvcj48YXV0aG9y

PkRlVHVyZSwgTS48L2F1dGhvcj48YXV0aG9yPlJhbXNkZW4sIE0uPC9hdXRob3I+PGF1dGhvcj5N

Y0dvd2FuLCBFLjwvYXV0aG9yPjxhdXRob3I+Rm9yc3RlciwgQy48L2F1dGhvcj48YXV0aG9yPll1

ZSwgTS48L2F1dGhvcj48YXV0aG9yPk9ybmUsIEouPC9hdXRob3I+PGF1dGhvcj5KYW51cywgQy48

L2F1dGhvcj48YXV0aG9yPk1hcmlhc2gsIEEuPC9hdXRob3I+PGF1dGhvcj5LdXNrb3dza2ksIE0u

PC9hdXRob3I+PGF1dGhvcj5IeW1hbiwgQi48L2F1dGhvcj48YXV0aG9yPkh1dHRvbiwgTS48L2F1

dGhvcj48YXV0aG9yPkFzaGUsIEsuIEguPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

PjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBMYWJvcmF0b3J5IE1lZGljaW5lIGFuZCBQYXRo

b2xvZ3ksIFVuaXZlcnNpdHkgb2YgTWlubmVzb3RhIE1lZGljYWwgU2Nob29sLCBNaW5uZWFwb2xp

cywgTU4gNTU0NTUsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5UYXUgc3VwcHJl

c3Npb24gaW4gYSBuZXVyb2RlZ2VuZXJhdGl2ZSBtb3VzZSBtb2RlbCBpbXByb3ZlcyBtZW1vcnkg

ZnVuY3Rpb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+U2NpZW5jZTwvc2Vjb25kYXJ5LXRpdGxl

PjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlNjaWVuY2U8L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxwYWdlcz40NzYtODE8L3BhZ2VzPjx2b2x1bWU+MzA5PC92b2x1bWU+PG51bWJl

cj41NzMzPC9udW1iZXI+PGVkaXRpb24+MjAwNS8wNy8xNjwvZWRpdGlvbj48a2V5d29yZHM+PGtl

eXdvcmQ+QWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5B

dHJvcGh5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluLyptZXRhYm9saXNtL3BhdGhvbG9neTwva2V5

d29yZD48a2V5d29yZD5Db2duaXRpb248L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBQcm9ncmVz

c2lvbjwva2V5d29yZD48a2V5d29yZD5Eb3h5Y3ljbGluZS9waGFybWFjb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+SGlwcG9jYW1wdXMvbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk1hemUgTGVhcm5pbmc8L2tleXdvcmQ+PGtleXdv

cmQ+Kk1lbW9yeTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2Us

IFRyYW5zZ2VuaWM8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9kZWdlbmVyYXRpdmUgRGlzZWFzZXMv

bWV0YWJvbGlzbS8qcGF0aG9sb2d5LypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

TmV1cm9maWJyaWxsYXJ5IFRhbmdsZXMvbWV0YWJvbGlzbS8qcGF0aG9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPk5ldXJvbmFsIFBsYXN0aWNpdHk8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9ucy9tZXRh

Ym9saXNtL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5PcmdhbiBTaXplPC9rZXl3b3JkPjxr

ZXl3b3JkPlBob3NwaG9yeWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5STkEsIE1lc3Nlbmdlci9n

ZW5ldGljcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlNvbHViaWxpdHk8L2tleXdvcmQ+

PGtleXdvcmQ+dGF1IFByb3RlaW5zL2NoZW1pc3RyeS9nZW5ldGljcy8qbWV0YWJvbGlzbTwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

SnVsIDE1PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA5NS05MjAzIChFbGVjdHJv

bmljKSYjeEQ7MDAzNi04MDc1IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xNjAyMDcz

NzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNi

aS5ubG0ubmloLmdvdi9wdWJtZWQvMTYwMjA3Mzc8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGN1c3RvbTI+UE1DMTU3NDY0NzwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu

MTEyNi9zY2llbmNlLjExMTM2OTQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48Q2l0ZT48QXV0aG9yPlN5ZG93PC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVjTnVt

PjM5MTk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM5MTk8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjY3MTg3OSI+MzkxOTwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U3lkb3csIEEuPC9hdXRob3I+PGF1dGhvcj5WYW4gZGVyIEpl

dWdkLCBBLjwvYXV0aG9yPjxhdXRob3I+WmhlbmcsIEYuPC9hdXRob3I+PGF1dGhvcj5BaG1lZCwg

VC48L2F1dGhvcj48YXV0aG9yPkJhbHNjaHVuLCBELjwvYXV0aG9yPjxhdXRob3I+UGV0cm92YSwg

Ty48L2F1dGhvcj48YXV0aG9yPkRyZXhsZXIsIEQuPC9hdXRob3I+PGF1dGhvcj5aaG91LCBMLjwv

YXV0aG9yPjxhdXRob3I+UnVuZSwgRy48L2F1dGhvcj48YXV0aG9yPk1hbmRlbGtvdywgRS48L2F1

dGhvcj48YXV0aG9yPkQmYXBvcztIb29nZSwgUi48L2F1dGhvcj48YXV0aG9yPkFsemhlaW1lciwg

Qy48L2F1dGhvcj48YXV0aG9yPk1hbmRlbGtvdywgRS4gTS48L2F1dGhvcj48L2F1dGhvcnM+PC9j

b250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5NYXggUGxhbmNrIFVuaXQgZm9yIFN0cnVjdHVyYWwg

TW9sZWN1bGFyIEJpb2xvZ3ksIGMvbyBERVNZLCAyMjYwNyBIYW1idXJnLCBHZXJtYW55LjwvYXV0

aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRhdS1pbmR1Y2VkIGRlZmVjdHMgaW4gc3luYXB0aWMg

cGxhc3RpY2l0eSwgbGVhcm5pbmcsIGFuZCBtZW1vcnkgYXJlIHJldmVyc2libGUgaW4gdHJhbnNn

ZW5pYyBtaWNlIGFmdGVyIHN3aXRjaGluZyBvZmYgdGhlIHRveGljIFRhdSBtdXRhbnQ8L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+SiBOZXVyb3NjaTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxw

ZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9zY2k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz4yNTExLTI1PC9wYWdlcz48dm9sdW1lPjMxPC92b2x1bWU+PG51bWJlcj43PC9udW1i

ZXI+PGVkaXRpb24+MjAxMS8wMi8xODwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFs

czwva2V5d29yZD48a2V5d29yZD5EaXNlYXNlIE1vZGVscywgQW5pbWFsPC9rZXl3b3JkPjxrZXl3

b3JkPkRveHljeWNsaW5lL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5IYW5kIFN0cmVu

Z3RoL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SGlwcG9jYW1wdXMvcGF0aG9sb2d5L3Vs

dHJhc3RydWN0dXJlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5J

biBWaXRybyBUZWNobmlxdWVzPC9rZXl3b3JkPjxrZXl3b3JkPkxvbmctVGVybSBQb3RlbnRpYXRp

b24vKmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPk1hemUgTGVhcm5pbmcvZHJ1ZyBlZmZlY3Rz

LypwaHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1lbW9yeS9kcnVnIGVmZmVjdHMvKnBoeXNp

b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFu

c2dlbmljPC9rZXl3b3JkPjxrZXl3b3JkPk11dGF0aW9uLypnZW5ldGljczwva2V5d29yZD48a2V5

d29yZD5OZXJ2ZSBUaXNzdWUgUHJvdGVpbnMvZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48

a2V5d29yZD5OZXVyb3BzeWNob2xvZ2ljYWwgVGVzdHM8L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVp

biBTdHJ1Y3R1cmUsIFRlcnRpYXJ5PC9rZXl3b3JkPjxrZXl3b3JkPlNwYWNlIFBlcmNlcHRpb24v

cGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5TeW5hcHNlcy9wYXRob2xvZ3kvdWx0cmFzdHJ1

Y3R1cmU8L2tleXdvcmQ+PGtleXdvcmQ+KlRhdW9wYXRoaWVzL21ldGFib2xpc20vcGF0aG9sb2d5

L3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5UaW1lIEZhY3RvcnM8L2tleXdvcmQ+

PGtleXdvcmQ+dGF1IFByb3RlaW5zLypnZW5ldGljcy9tZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5

d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5GZWIgMTY8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTI5LTI0MDEgKEVsZWN0cm9uaWMpJiN4RDsw

MjcwLTY0NzQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIxMzI1NTE5PC9hY2Nlc3Np

b24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWgu

Z292L3B1Ym1lZC8yMTMyNTUxOTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+MTAuMTUyMy9KTkVVUk9TQ0kuNTI0NS0xMC4yMDExPC9lbGVjdHJvbmlj

LXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BaG1lZDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl

Y051bT4zOTQ3PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTMzLTEzNTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM5NDc8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjY3NDk5MSI+Mzk0Nzwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QWhtZWQsIFQuPC9hdXRob3I+PGF1

dGhvcj5WYW4gZGVyIEpldWdkLCBBLjwvYXV0aG9yPjxhdXRob3I+Qmx1bSwgRC48L2F1dGhvcj48

YXV0aG9yPkdhbGFzLCBNLiBDLjwvYXV0aG9yPjxhdXRob3I+RCZhcG9zO0hvb2dlLCBSLjwvYXV0

aG9yPjxhdXRob3I+QnVlZSwgTC48L2F1dGhvcj48YXV0aG9yPkJhbHNjaHVuLCBELjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkxhYm9yYXRvcnkgb2YgQmlv

bG9naWNhbCBQc3ljaG9sb2d5LCBDYXRob2xpYyBVbml2ZXJzaXR5IG9mIExldXZlbiwgQmVsZ2l1

bS4mI3hEO0luc2VybSwgVU1SODM3LCBMaWxsZSwgRnJhbmNlOyBVbml2ZXJzaXRlIExpbGxlLU5v

cmQgZGUgRnJhbmNlLCBMaWxsZSwgRnJhbmNlOyBVRFNMLCBMaWxsZSwgRnJhbmNlOyBGYWN1bHRl

IGRlIE1lZGVjaW5lLCBJbnN0aXR1dCBkZSBtZWRlY2luZSBwcmVkaWN0aXZlIGV0IHJlY2hlcmNo

ZSB0aGVyYXBldXRpcXVlLCBKZWFuLVBpZXJyZSBBdWJlcnQgUmVzZWFyY2ggQ2VudHJlLCBMaWxs

ZSwgRnJhbmNlLiYjeEQ7TGFib3JhdG9yeSBvZiBCaW9sb2dpY2FsIFBzeWNob2xvZ3ksIENhdGhv

bGljIFVuaXZlcnNpdHkgb2YgTGV1dmVuLCBCZWxnaXVtLiBFbGVjdHJvbmljIGFkZHJlc3M6IERl

dGxlZi5CYWxzY2h1bkBwcHcua3VsZXV2ZW4uYmUuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+Q29nbml0aW9uIGFuZCBoaXBwb2NhbXBhbCBzeW5hcHRpYyBwbGFzdGljaXR5IGluIG1pY2Ug

d2l0aCBhIGhvbW96eWdvdXMgdGF1IGRlbGV0aW9uPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5l

dXJvYmlvbCBBZ2luZzwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxs

LXRpdGxlPk5ldXJvYmlvbCBBZ2luZzwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjI0

NzQtMjQ3ODwvcGFnZXM+PHZvbHVtZT4zNTwvdm9sdW1lPjxudW1iZXI+MTE8L251bWJlcj48ZWRp

dGlvbj4yMDE0LzA2LzExPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9rZXl3

b3JkPjxrZXl3b3JkPipDb2duaXRpb248L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMs

IEFuaW1hbDwva2V5d29yZD48a2V5d29yZD5HZW5lIERlbGV0aW9uPC9rZXl3b3JkPjxrZXl3b3Jk

PkhpcHBvY2FtcHVzLypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SG9tb3p5Z290

ZTwva2V5d29yZD48a2V5d29yZD5Mb25nLVRlcm0gUG90ZW50aWF0aW9uPC9rZXl3b3JkPjxrZXl3

b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgSW5icmVkIEM1N0JMPC9rZXl3b3JkPjxr

ZXl3b3JkPk1pY2UsIEtub2Nrb3V0PC9rZXl3b3JkPjxrZXl3b3JkPk1pY3JvdHVidWxlcy9tZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPipOZXVyb25hbCBQbGFzdGljaXR5PC9rZXl3b3JkPjxr

ZXl3b3JkPlNwYXRpYWwgTGVhcm5pbmc8L2tleXdvcmQ+PGtleXdvcmQ+U3luYXB0aWMgVHJhbnNt

aXNzaW9uPC9rZXl3b3JkPjxrZXl3b3JkPlRhdW9wYXRoaWVzLypwaHlzaW9wYXRob2xvZ3kvKnBz

eWNob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5zLypwaHlzaW9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5D

b2duaXRpb248L2tleXdvcmQ+PGtleXdvcmQ+SGlwcG9jYW1wdXM8L2tleXdvcmQ+PGtleXdvcmQ+

TG9uZy10ZXJtIGRlcHJlc3Npb248L2tleXdvcmQ+PGtleXdvcmQ+TW9ycmlzIHdhdGVyIG1hemU8

L2tleXdvcmQ+PGtleXdvcmQ+U3luYXB0aWMgcGxhc3RpY2l0eTwva2V5d29yZD48a2V5d29yZD5U

YXUga25vY2stb3V0IG1pY2U8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju

PjE1NTgtMTQ5NyAoRWxlY3Ryb25pYykmI3hEOzAxOTctNDU4MCAoTGlua2luZyk8L2lzYm4+PGFj

Y2Vzc2lvbi1udW0+MjQ5MTM4OTU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48

dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI0OTEzODk1PC91cmw+PC9y

ZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2oubmV1

cm9iaW9sYWdpbmcuMjAxNC4wNS4wMDU8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3Jk

PjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlNhbnRhY3J1ejwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+

PFJlY051bT4zOTE4PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zOTE4PC9yZWMtbnVtYmVy

Pjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBm

d3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzY2NzE4NTciPjM5MTg8L2tleT48L2ZvcmVp

Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv

bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNhbnRhY3J1eiwgSy48L2F1dGhvcj48YXV0aG9y

Pkxld2lzLCBKLjwvYXV0aG9yPjxhdXRob3I+U3BpcmVzLCBULjwvYXV0aG9yPjxhdXRob3I+UGF1

bHNvbiwgSi48L2F1dGhvcj48YXV0aG9yPktvdGlsaW5laywgTC48L2F1dGhvcj48YXV0aG9yPklu

Z2Vsc3NvbiwgTS48L2F1dGhvcj48YXV0aG9yPkd1aW1hcmFlcywgQS48L2F1dGhvcj48YXV0aG9y

PkRlVHVyZSwgTS48L2F1dGhvcj48YXV0aG9yPlJhbXNkZW4sIE0uPC9hdXRob3I+PGF1dGhvcj5N

Y0dvd2FuLCBFLjwvYXV0aG9yPjxhdXRob3I+Rm9yc3RlciwgQy48L2F1dGhvcj48YXV0aG9yPll1

ZSwgTS48L2F1dGhvcj48YXV0aG9yPk9ybmUsIEouPC9hdXRob3I+PGF1dGhvcj5KYW51cywgQy48

L2F1dGhvcj48YXV0aG9yPk1hcmlhc2gsIEEuPC9hdXRob3I+PGF1dGhvcj5LdXNrb3dza2ksIE0u

PC9hdXRob3I+PGF1dGhvcj5IeW1hbiwgQi48L2F1dGhvcj48YXV0aG9yPkh1dHRvbiwgTS48L2F1

dGhvcj48YXV0aG9yPkFzaGUsIEsuIEguPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

PjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBMYWJvcmF0b3J5IE1lZGljaW5lIGFuZCBQYXRo

b2xvZ3ksIFVuaXZlcnNpdHkgb2YgTWlubmVzb3RhIE1lZGljYWwgU2Nob29sLCBNaW5uZWFwb2xp

cywgTU4gNTU0NTUsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5UYXUgc3VwcHJl

c3Npb24gaW4gYSBuZXVyb2RlZ2VuZXJhdGl2ZSBtb3VzZSBtb2RlbCBpbXByb3ZlcyBtZW1vcnkg

ZnVuY3Rpb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+U2NpZW5jZTwvc2Vjb25kYXJ5LXRpdGxl

PjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlNjaWVuY2U8L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxwYWdlcz40NzYtODE8L3BhZ2VzPjx2b2x1bWU+MzA5PC92b2x1bWU+PG51bWJl

cj41NzMzPC9udW1iZXI+PGVkaXRpb24+MjAwNS8wNy8xNjwvZWRpdGlvbj48a2V5d29yZHM+PGtl

eXdvcmQ+QWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5B

dHJvcGh5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluLyptZXRhYm9saXNtL3BhdGhvbG9neTwva2V5

d29yZD48a2V5d29yZD5Db2duaXRpb248L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBQcm9ncmVz

c2lvbjwva2V5d29yZD48a2V5d29yZD5Eb3h5Y3ljbGluZS9waGFybWFjb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+SGlwcG9jYW1wdXMvbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk1hemUgTGVhcm5pbmc8L2tleXdvcmQ+PGtleXdv

cmQ+Kk1lbW9yeTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2Us

IFRyYW5zZ2VuaWM8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9kZWdlbmVyYXRpdmUgRGlzZWFzZXMv

bWV0YWJvbGlzbS8qcGF0aG9sb2d5LypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

TmV1cm9maWJyaWxsYXJ5IFRhbmdsZXMvbWV0YWJvbGlzbS8qcGF0aG9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPk5ldXJvbmFsIFBsYXN0aWNpdHk8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9ucy9tZXRh

Ym9saXNtL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5PcmdhbiBTaXplPC9rZXl3b3JkPjxr

ZXl3b3JkPlBob3NwaG9yeWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5STkEsIE1lc3Nlbmdlci9n

ZW5ldGljcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlNvbHViaWxpdHk8L2tleXdvcmQ+

PGtleXdvcmQ+dGF1IFByb3RlaW5zL2NoZW1pc3RyeS9nZW5ldGljcy8qbWV0YWJvbGlzbTwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

SnVsIDE1PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA5NS05MjAzIChFbGVjdHJv

bmljKSYjeEQ7MDAzNi04MDc1IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xNjAyMDcz

NzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNi

aS5ubG0ubmloLmdvdi9wdWJtZWQvMTYwMjA3Mzc8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGN1c3RvbTI+UE1DMTU3NDY0NzwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu

MTEyNi9zY2llbmNlLjExMTM2OTQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48Q2l0ZT48QXV0aG9yPlN5ZG93PC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVjTnVt

PjM5MTk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM5MTk8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjY3MTg3OSI+MzkxOTwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U3lkb3csIEEuPC9hdXRob3I+PGF1dGhvcj5WYW4gZGVyIEpl

dWdkLCBBLjwvYXV0aG9yPjxhdXRob3I+WmhlbmcsIEYuPC9hdXRob3I+PGF1dGhvcj5BaG1lZCwg

VC48L2F1dGhvcj48YXV0aG9yPkJhbHNjaHVuLCBELjwvYXV0aG9yPjxhdXRob3I+UGV0cm92YSwg

Ty48L2F1dGhvcj48YXV0aG9yPkRyZXhsZXIsIEQuPC9hdXRob3I+PGF1dGhvcj5aaG91LCBMLjwv

YXV0aG9yPjxhdXRob3I+UnVuZSwgRy48L2F1dGhvcj48YXV0aG9yPk1hbmRlbGtvdywgRS48L2F1

dGhvcj48YXV0aG9yPkQmYXBvcztIb29nZSwgUi48L2F1dGhvcj48YXV0aG9yPkFsemhlaW1lciwg

Qy48L2F1dGhvcj48YXV0aG9yPk1hbmRlbGtvdywgRS4gTS48L2F1dGhvcj48L2F1dGhvcnM+PC9j

b250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5NYXggUGxhbmNrIFVuaXQgZm9yIFN0cnVjdHVyYWwg

TW9sZWN1bGFyIEJpb2xvZ3ksIGMvbyBERVNZLCAyMjYwNyBIYW1idXJnLCBHZXJtYW55LjwvYXV0

aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRhdS1pbmR1Y2VkIGRlZmVjdHMgaW4gc3luYXB0aWMg

cGxhc3RpY2l0eSwgbGVhcm5pbmcsIGFuZCBtZW1vcnkgYXJlIHJldmVyc2libGUgaW4gdHJhbnNn

ZW5pYyBtaWNlIGFmdGVyIHN3aXRjaGluZyBvZmYgdGhlIHRveGljIFRhdSBtdXRhbnQ8L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+SiBOZXVyb3NjaTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxw

ZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9zY2k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz4yNTExLTI1PC9wYWdlcz48dm9sdW1lPjMxPC92b2x1bWU+PG51bWJlcj43PC9udW1i

ZXI+PGVkaXRpb24+MjAxMS8wMi8xODwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFs

czwva2V5d29yZD48a2V5d29yZD5EaXNlYXNlIE1vZGVscywgQW5pbWFsPC9rZXl3b3JkPjxrZXl3

b3JkPkRveHljeWNsaW5lL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5IYW5kIFN0cmVu

Z3RoL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SGlwcG9jYW1wdXMvcGF0aG9sb2d5L3Vs

dHJhc3RydWN0dXJlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5J

biBWaXRybyBUZWNobmlxdWVzPC9rZXl3b3JkPjxrZXl3b3JkPkxvbmctVGVybSBQb3RlbnRpYXRp

b24vKmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPk1hemUgTGVhcm5pbmcvZHJ1ZyBlZmZlY3Rz

LypwaHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1lbW9yeS9kcnVnIGVmZmVjdHMvKnBoeXNp

b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFu

c2dlbmljPC9rZXl3b3JkPjxrZXl3b3JkPk11dGF0aW9uLypnZW5ldGljczwva2V5d29yZD48a2V5

d29yZD5OZXJ2ZSBUaXNzdWUgUHJvdGVpbnMvZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48

a2V5d29yZD5OZXVyb3BzeWNob2xvZ2ljYWwgVGVzdHM8L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVp

biBTdHJ1Y3R1cmUsIFRlcnRpYXJ5PC9rZXl3b3JkPjxrZXl3b3JkPlNwYWNlIFBlcmNlcHRpb24v

cGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5TeW5hcHNlcy9wYXRob2xvZ3kvdWx0cmFzdHJ1

Y3R1cmU8L2tleXdvcmQ+PGtleXdvcmQ+KlRhdW9wYXRoaWVzL21ldGFib2xpc20vcGF0aG9sb2d5

L3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5UaW1lIEZhY3RvcnM8L2tleXdvcmQ+

PGtleXdvcmQ+dGF1IFByb3RlaW5zLypnZW5ldGljcy9tZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5

d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5GZWIgMTY8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTI5LTI0MDEgKEVsZWN0cm9uaWMpJiN4RDsw

MjcwLTY0NzQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIxMzI1NTE5PC9hY2Nlc3Np

b24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWgu

Z292L3B1Ym1lZC8yMTMyNTUxOTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+MTAuMTUyMy9KTkVVUk9TQ0kuNTI0NS0xMC4yMDExPC9lbGVjdHJvbmlj

LXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 133-135. Currently, PET ligands, peripheral biomarkers, and different therapeutic strategies are available for Tau therapeutic intervention. In addition, prevention and environmental factors may have an effect on Tau pathology and interventions can be used in combination with other treatments (Fig. 1).There are many hypotheses of Tau aggregation. As for APP, Tau has chromosome micro-duplications and deletions important for tauopathies. In addition, specific haplotypes increase the amount of Tau, alternative splicing, conformation, post-translational modification and change in degradation. All these hypotheses open up new therapeutic strategies. New therapies implicate for example to decrease post-translational modifications like phosphorylation. Enhancing Tau dephosphorylation with sodium selenite is another possibility. Other approaches are the modulation of Tau glycosylation, modulation of Tau aggregation (methylene blue derivatives failed in phase?III), stabilization of microtubules and enhancement of Tau proteolysis. Immunotherapy is another very plausible approach. Modulation of alternative splicing may be an approach through gene therapy. Finally, it is important to mention that Tau is not only a microtubule-associated protein, and its role in cells is not completely understood. Tau is bound to the plasma membrane ADDIN EN.CITE <EndNote><Cite><Author>Pooler</Author><Year>2012</Year><RecNum>3929</RecNum><DisplayText><style face="superscript">136</style></DisplayText><record><rec-number>3929</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1536674099">3929</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pooler, A. M.</author><author>Usardi, A.</author><author>Evans, C. J.</author><author>Philpott, K. L.</author><author>Noble, W.</author><author>Hanger, D. P.</author></authors></contributors><auth-address>King&apos;s College London, MRC Centre for Neurodegeneration Research, Department of Neuroscience, Institute of Psychiatry, London, UK. Amy.Pooler@kcl.ac.uk</auth-address><titles><title>Dynamic association of tau with neuronal membranes is regulated by phosphorylation</title><secondary-title>Neurobiol Aging</secondary-title></titles><periodical><full-title>Neurobiol Aging</full-title></periodical><pages>431 e27-38</pages><volume>33</volume><number>2</number><edition>2011/03/11</edition><keywords><keyword>Animals</keyword><keyword>Animals, Newborn</keyword><keyword>Casein Kinase I/*metabolism</keyword><keyword>Cell Membrane/*metabolism</keyword><keyword>Cells, Cultured</keyword><keyword>Glycogen Synthase Kinase 3/*metabolism</keyword><keyword>Neurons/*metabolism</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword><keyword>tau Proteins/*metabolism</keyword></keywords><dates><year>2012</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1558-1497 (Electronic)&#xD;0197-4580 (Linking)</isbn><accession-num>21388709</accession-num><urls><related-urls><url>, it is involved in transduction signaling, especially in brain insulin resistance PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJjaW5pYWs8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFy

PjxSZWNOdW0+MzkzMDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjEzNzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM5MzA8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjY3NDE4NSI+MzkzMDwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWFyY2luaWFrLCBFLjwvYXV0aG9y

PjxhdXRob3I+TGVib3VjaGVyLCBBLjwvYXV0aG9yPjxhdXRob3I+Q2Fyb24sIEUuPC9hdXRob3I+

PGF1dGhvcj5BaG1lZCwgVC48L2F1dGhvcj48YXV0aG9yPlRhaWxsZXV4LCBBLjwvYXV0aG9yPjxh

dXRob3I+RHVtb250LCBKLjwvYXV0aG9yPjxhdXRob3I+SXNzYWQsIFQuPC9hdXRob3I+PGF1dGhv

cj5HZXJoYXJkdCwgRS48L2F1dGhvcj48YXV0aG9yPlBhZ2VzeSwgUC48L2F1dGhvcj48YXV0aG9y

PlZpbGVubywgTS48L2F1dGhvcj48YXV0aG9yPkJvdXJub252aWxsZSwgQy48L2F1dGhvcj48YXV0

aG9yPkhhbWRhbmUsIE0uPC9hdXRob3I+PGF1dGhvcj5CYW50dWJ1bmdpLCBLLjwvYXV0aG9yPjxh

dXRob3I+TGFuY2VsLCBTLjwvYXV0aG9yPjxhdXRob3I+RGVtZXllciwgRC48L2F1dGhvcj48YXV0

aG9yPkVkZGFya2FvdWksIFMuPC9hdXRob3I+PGF1dGhvcj5WYWxsZXosIEUuPC9hdXRob3I+PGF1

dGhvcj5WaWVhdSwgRC48L2F1dGhvcj48YXV0aG9yPkh1bWV6LCBTLjwvYXV0aG9yPjxhdXRob3I+

RmFpdnJlLCBFLjwvYXV0aG9yPjxhdXRob3I+R3Jlbmllci1Cb2xleSwgQi48L2F1dGhvcj48YXV0

aG9yPk91dGVpcm8sIFQuIEYuPC9hdXRob3I+PGF1dGhvcj5TdGFlbHMsIEIuPC9hdXRob3I+PGF1

dGhvcj5BbW91eWVsLCBQLjwvYXV0aG9yPjxhdXRob3I+QmFsc2NodW4sIEQuPC9hdXRob3I+PGF1

dGhvcj5CdWVlLCBMLjwvYXV0aG9yPjxhdXRob3I+Qmx1bSwgRC48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Vbml2ZXJzaXRlIGRlIExpbGxlLCBJbnN0aXR1

dCBOYXRpb25hbCBkZSBsYSBTYW50ZSBldCBkZSBsYSBSZWNoZXJjaGUgTWVkaWNhbGUgKElOU0VS

TSksIENIVSBMaWxsZSwgVU1SLVMgMTE3MiBKUEFyYywgTGlsbGUsIEZyYW5jZS4mI3hEO0xhYkV4

IERJU1RBTFogKERldmVsb3BtZW50IG9mIElubm92YXRpdmUgU3RyYXRlZ2llcyBmb3IgYSBUcmFu

c2Rpc2NpcGxpbmFyeSBhcHByb2FjaCB0byBBTFpoZWltZXImYXBvcztzIGRpc2Vhc2UpLCBMaWxs

ZSwgRnJhbmNlLiYjeEQ7TGFib3JhdG9yeSBvZiBCaW9sb2dpY2FsIFBzeWNob2xvZ3ksIEZhY3Vs

dHkgb2YgUHN5Y2hvbG9neSBhbmQgRWR1Y2F0aW9uYWwgU2NpZW5jZXMsIEtVIExldXZlbiwgTGV1

dmVuLCBCZWxnaXVtLiYjeEQ7TmV1cm9sb2dpY2FsIERpc29yZGVycyBSZXNlYXJjaCBDZW50ZXIs

IFFhdGFyIEJpb21lZGljYWwgUmVzZWFyY2ggSW5zdGl0dXRlLCBIYW1hZCBCaW4gS2hhbGlmYSBV

bml2ZXJzaXR5LCBEb2hhLCBRYXRhci4mI3hEO1VuaXZlcnNpdGUgZGUgTGlsbGUsIElOU0VSTSwg

Q0hVIExpbGxlLCBJbnN0aXR1dCBQYXN0ZXVyIGRlIExpbGxlLCBVMTAxMUVHSUQsIExpbGxlLCBG

cmFuY2UuJiN4RDtVbml2ZXJzaXRlIGRlIExpbGxlLCBJTlNFUk0sIENIVSBMaWxsZSwgSW5zdGl0

dXQgUGFzdGV1ciBkZSBMaWxsZSwgVTExNjcgUklELUFHRSBGYWN0ZXVycyBkZSBSaXNxdWUgZXQg

RGV0ZXJtaW5hbnRzIE1vbGVjdWxhaXJlcyBkZXMgTWFsYWRpZXMgTGllZXMgYXUgVmllaWxsaXNz

ZW1lbnQsIExpbGxlLCBGcmFuY2UuJiN4RDtJTlNFUk0gVTEwMTYsIENOUlMgVU1SODEwNCwgVW5p

dmVyc2l0ZSBQYXJpcyBEZXNjYXJ0ZXMgU29yYm9ubmUgUGFyaXMgQ2l0ZSwgSW5zdGl0dXQgQ29j

aGluLCBQYXJpcywgRnJhbmNlLiYjeEQ7RGVwYXJ0bWVudCBvZiBFeHBlcmltZW50YWwgTmV1cm9k

ZWdlbmVyYXRpb24sIENlbnRlciBmb3IgTmFub3NjYWxlIE1pY3Jvc2NvcHkgYW5kIE1vbGVjdWxh

ciBQaHlzaW9sb2d5IG9mIHRoZSBCcmFpbiwgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRlciBHb2V0

dGluZ2VuLCBHb2V0dGluZ2VuLCBHZXJtYW55LiYjeEQ7VW5pdmVyc2l0ZSBkZSBMaWxsZSwgSW5z

dGl0dXQgTmF0aW9uYWwgZGUgbGEgU2FudGUgZXQgZGUgbGEgUmVjaGVyY2hlIE1lZGljYWxlIChJ

TlNFUk0pLCBDSFUgTGlsbGUsIFVNUi1TIDExNzIgSlBBcmMsIExpbGxlLCBGcmFuY2UgZGF2aWQu

Ymx1bUBpbnNlcm0uZnIuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGF1IGRlbGV0aW9u

IHByb21vdGVzIGJyYWluIGluc3VsaW4gcmVzaXN0YW5jZTwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5KIEV4cCBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MjI1Ny0yMjY5PC9w

YWdlcz48dm9sdW1lPjIxNDwvdm9sdW1lPjxudW1iZXI+ODwvbnVtYmVyPjxlZGl0aW9uPjIwMTcv

MDYvMjg8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdv

cmQ+QnJhaW4vKm1ldGFib2xpc20vcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5Db2duaXRp

dmUgRHlzZnVuY3Rpb24vZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SGFwbG90eXBlczwva2V5

d29yZD48a2V5d29yZD5IaXBwb2NhbXB1cy9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1

bWFuczwva2V5d29yZD48a2V5d29yZD5JbnN1bGluL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+Kkluc3VsaW4gUmVzaXN0YW5jZTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxr

ZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgSW5icmVkIEM1N0JMPC9rZXl3b3Jk

PjxrZXl3b3JkPk1pY2UsIEtub2Nrb3V0PC9rZXl3b3JkPjxrZXl3b3JkPnRhdSBQcm90ZWlucy8q

cGh5c2lvbG9neTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE3PC95ZWFyPjxw

dWItZGF0ZXM+PGRhdGU+QXVnIDc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTQw

LTk1MzggKEVsZWN0cm9uaWMpJiN4RDswMDIyLTEwMDcgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI4NjUyMzAzPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yODY1MjMwMzwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM1NTUxNTcwPC9jdXN0b20yPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4xMDg0L2plbS4yMDE2MTczMTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJjaW5pYWs8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFy

PjxSZWNOdW0+MzkzMDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjEzNzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM5MzA8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjY3NDE4NSI+MzkzMDwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWFyY2luaWFrLCBFLjwvYXV0aG9y

PjxhdXRob3I+TGVib3VjaGVyLCBBLjwvYXV0aG9yPjxhdXRob3I+Q2Fyb24sIEUuPC9hdXRob3I+

PGF1dGhvcj5BaG1lZCwgVC48L2F1dGhvcj48YXV0aG9yPlRhaWxsZXV4LCBBLjwvYXV0aG9yPjxh

dXRob3I+RHVtb250LCBKLjwvYXV0aG9yPjxhdXRob3I+SXNzYWQsIFQuPC9hdXRob3I+PGF1dGhv

cj5HZXJoYXJkdCwgRS48L2F1dGhvcj48YXV0aG9yPlBhZ2VzeSwgUC48L2F1dGhvcj48YXV0aG9y

PlZpbGVubywgTS48L2F1dGhvcj48YXV0aG9yPkJvdXJub252aWxsZSwgQy48L2F1dGhvcj48YXV0

aG9yPkhhbWRhbmUsIE0uPC9hdXRob3I+PGF1dGhvcj5CYW50dWJ1bmdpLCBLLjwvYXV0aG9yPjxh

dXRob3I+TGFuY2VsLCBTLjwvYXV0aG9yPjxhdXRob3I+RGVtZXllciwgRC48L2F1dGhvcj48YXV0

aG9yPkVkZGFya2FvdWksIFMuPC9hdXRob3I+PGF1dGhvcj5WYWxsZXosIEUuPC9hdXRob3I+PGF1

dGhvcj5WaWVhdSwgRC48L2F1dGhvcj48YXV0aG9yPkh1bWV6LCBTLjwvYXV0aG9yPjxhdXRob3I+

RmFpdnJlLCBFLjwvYXV0aG9yPjxhdXRob3I+R3Jlbmllci1Cb2xleSwgQi48L2F1dGhvcj48YXV0

aG9yPk91dGVpcm8sIFQuIEYuPC9hdXRob3I+PGF1dGhvcj5TdGFlbHMsIEIuPC9hdXRob3I+PGF1

dGhvcj5BbW91eWVsLCBQLjwvYXV0aG9yPjxhdXRob3I+QmFsc2NodW4sIEQuPC9hdXRob3I+PGF1

dGhvcj5CdWVlLCBMLjwvYXV0aG9yPjxhdXRob3I+Qmx1bSwgRC48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Vbml2ZXJzaXRlIGRlIExpbGxlLCBJbnN0aXR1

dCBOYXRpb25hbCBkZSBsYSBTYW50ZSBldCBkZSBsYSBSZWNoZXJjaGUgTWVkaWNhbGUgKElOU0VS

TSksIENIVSBMaWxsZSwgVU1SLVMgMTE3MiBKUEFyYywgTGlsbGUsIEZyYW5jZS4mI3hEO0xhYkV4

IERJU1RBTFogKERldmVsb3BtZW50IG9mIElubm92YXRpdmUgU3RyYXRlZ2llcyBmb3IgYSBUcmFu

c2Rpc2NpcGxpbmFyeSBhcHByb2FjaCB0byBBTFpoZWltZXImYXBvcztzIGRpc2Vhc2UpLCBMaWxs

ZSwgRnJhbmNlLiYjeEQ7TGFib3JhdG9yeSBvZiBCaW9sb2dpY2FsIFBzeWNob2xvZ3ksIEZhY3Vs

dHkgb2YgUHN5Y2hvbG9neSBhbmQgRWR1Y2F0aW9uYWwgU2NpZW5jZXMsIEtVIExldXZlbiwgTGV1

dmVuLCBCZWxnaXVtLiYjeEQ7TmV1cm9sb2dpY2FsIERpc29yZGVycyBSZXNlYXJjaCBDZW50ZXIs

IFFhdGFyIEJpb21lZGljYWwgUmVzZWFyY2ggSW5zdGl0dXRlLCBIYW1hZCBCaW4gS2hhbGlmYSBV

bml2ZXJzaXR5LCBEb2hhLCBRYXRhci4mI3hEO1VuaXZlcnNpdGUgZGUgTGlsbGUsIElOU0VSTSwg

Q0hVIExpbGxlLCBJbnN0aXR1dCBQYXN0ZXVyIGRlIExpbGxlLCBVMTAxMUVHSUQsIExpbGxlLCBG

cmFuY2UuJiN4RDtVbml2ZXJzaXRlIGRlIExpbGxlLCBJTlNFUk0sIENIVSBMaWxsZSwgSW5zdGl0

dXQgUGFzdGV1ciBkZSBMaWxsZSwgVTExNjcgUklELUFHRSBGYWN0ZXVycyBkZSBSaXNxdWUgZXQg

RGV0ZXJtaW5hbnRzIE1vbGVjdWxhaXJlcyBkZXMgTWFsYWRpZXMgTGllZXMgYXUgVmllaWxsaXNz

ZW1lbnQsIExpbGxlLCBGcmFuY2UuJiN4RDtJTlNFUk0gVTEwMTYsIENOUlMgVU1SODEwNCwgVW5p

dmVyc2l0ZSBQYXJpcyBEZXNjYXJ0ZXMgU29yYm9ubmUgUGFyaXMgQ2l0ZSwgSW5zdGl0dXQgQ29j

aGluLCBQYXJpcywgRnJhbmNlLiYjeEQ7RGVwYXJ0bWVudCBvZiBFeHBlcmltZW50YWwgTmV1cm9k

ZWdlbmVyYXRpb24sIENlbnRlciBmb3IgTmFub3NjYWxlIE1pY3Jvc2NvcHkgYW5kIE1vbGVjdWxh

ciBQaHlzaW9sb2d5IG9mIHRoZSBCcmFpbiwgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRlciBHb2V0

dGluZ2VuLCBHb2V0dGluZ2VuLCBHZXJtYW55LiYjeEQ7VW5pdmVyc2l0ZSBkZSBMaWxsZSwgSW5z

dGl0dXQgTmF0aW9uYWwgZGUgbGEgU2FudGUgZXQgZGUgbGEgUmVjaGVyY2hlIE1lZGljYWxlIChJ

TlNFUk0pLCBDSFUgTGlsbGUsIFVNUi1TIDExNzIgSlBBcmMsIExpbGxlLCBGcmFuY2UgZGF2aWQu

Ymx1bUBpbnNlcm0uZnIuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGF1IGRlbGV0aW9u

IHByb21vdGVzIGJyYWluIGluc3VsaW4gcmVzaXN0YW5jZTwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5KIEV4cCBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MjI1Ny0yMjY5PC9w

YWdlcz48dm9sdW1lPjIxNDwvdm9sdW1lPjxudW1iZXI+ODwvbnVtYmVyPjxlZGl0aW9uPjIwMTcv

MDYvMjg8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdv

cmQ+QnJhaW4vKm1ldGFib2xpc20vcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5Db2duaXRp

dmUgRHlzZnVuY3Rpb24vZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SGFwbG90eXBlczwva2V5

d29yZD48a2V5d29yZD5IaXBwb2NhbXB1cy9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1

bWFuczwva2V5d29yZD48a2V5d29yZD5JbnN1bGluL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+Kkluc3VsaW4gUmVzaXN0YW5jZTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxr

ZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgSW5icmVkIEM1N0JMPC9rZXl3b3Jk

PjxrZXl3b3JkPk1pY2UsIEtub2Nrb3V0PC9rZXl3b3JkPjxrZXl3b3JkPnRhdSBQcm90ZWlucy8q

cGh5c2lvbG9neTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE3PC95ZWFyPjxw

dWItZGF0ZXM+PGRhdGU+QXVnIDc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTQw

LTk1MzggKEVsZWN0cm9uaWMpJiN4RDswMDIyLTEwMDcgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI4NjUyMzAzPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yODY1MjMwMzwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM1NTUxNTcwPC9jdXN0b20yPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4xMDg0L2plbS4yMDE2MTczMTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 137. It is also present in the nucleus, where it binds DNA, RNA, and is able to change the organization of the chromatin PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gcm9zdDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl

Y051bT4zOTM1PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTM4PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzkzNTwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2Njc0MzAzIj4zOTM1PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Gcm9zdCwgQi48L2F1dGhvcj48YXV0aG9y

PkhlbWJlcmcsIE0uPC9hdXRob3I+PGF1dGhvcj5MZXdpcywgSi48L2F1dGhvcj48YXV0aG9yPkZl

YW55LCBNLiBCLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNz

PkRlcGFydG1lbnQgb2YgUGF0aG9sb2d5LCBCcmlnaGFtIGFuZCBXb21lbiZhcG9zO3MgSG9zcGl0

YWwsIEhhcnZhcmQgTWVkaWNhbCBTY2hvb2wsIEJvc3RvbiwgTWFzc2FjaHVzZXR0cywgVVNBLiYj

eEQ7RGVwYXJ0bWVudCBvZiBPcGh0aGFsbW9sb2d5IGFuZCBQcm9ncmFtIGluIE5ldXJvYmlvbG9n

eSwgQm9zdG9uIENoaWxkcmVuJmFwb3M7cyBIb3NwaXRhbCwgQm9zdG9uLCBNYXNzYWNodXNldHRz

LCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvc2NpZW5jZSBhbmQgQ2VudGVyIGZvciBUcmFu

c2xhdGlvbmFsIFJlc2VhcmNoIGluIE5ldXJvZGVnZW5lcmF0aXZlIERpc2Vhc2UsIFVuaXZlcnNp

dHkgb2YgRmxvcmlkYSwgR2FpbmVzdmlsbGUsIEZsb3JpZGEsIFVTQS48L2F1dGgtYWRkcmVzcz48

dGl0bGVzPjx0aXRsZT5UYXUgcHJvbW90ZXMgbmV1cm9kZWdlbmVyYXRpb24gdGhyb3VnaCBnbG9i

YWwgY2hyb21hdGluIHJlbGF4YXRpb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0IE5ldXJv

c2NpPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjM1Ny02NjwvcGFnZXM+PHZvbHVt

ZT4xNzwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxlZGl0aW9uPjIwMTQvMDEvMjg8L2VkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5k

IG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvZ2VuZXRpY3MvbWV0YWJv

bGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29y

ZD5BbmltYWxzLCBHZW5ldGljYWxseSBNb2RpZmllZDwva2V5d29yZD48a2V5d29yZD5CcmFpbi8q

bWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFu

aW1hbDwva2V5d29yZD48a2V5d29yZD5Ecm9zb3BoaWxhIG1lbGFub2dhc3Rlcjwva2V5d29yZD48

a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SGV0ZXJvY2hyb21hdGluLypnZW5ldGlj

cy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5N

YWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgSW5icmVk

IEM1N0JMPC9rZXl3b3JkPjxrZXl3b3JkPk5lcnZlIERlZ2VuZXJhdGlvbi8qZ2VuZXRpY3MvbWV0

YWJvbGlzbS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+VGF1b3BhdGhpZXMvZ2Vu

ZXRpY3MvKm1ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPnRhdSBQcm90ZWlu

cy9nZW5ldGljcy8qcGh5c2lvbG9neTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDE0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWFyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGlzYm4+MTU0Ni0xNzI2IChFbGVjdHJvbmljKSYjeEQ7MTA5Ny02MjU2IChMaW5raW5nKTwvaXNi

bj48YWNjZXNzaW9uLW51bT4yNDQ2NDA0MTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11

cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjQ0NjQwNDE8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNDAxMjI5NzwvY3VzdG9tMj48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9ubi4zNjM5PC9lbGVjdHJvbmljLXJlc291cmNl

LW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gcm9zdDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl

Y051bT4zOTM1PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTM4PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzkzNTwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2Njc0MzAzIj4zOTM1PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Gcm9zdCwgQi48L2F1dGhvcj48YXV0aG9y

PkhlbWJlcmcsIE0uPC9hdXRob3I+PGF1dGhvcj5MZXdpcywgSi48L2F1dGhvcj48YXV0aG9yPkZl

YW55LCBNLiBCLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNz

PkRlcGFydG1lbnQgb2YgUGF0aG9sb2d5LCBCcmlnaGFtIGFuZCBXb21lbiZhcG9zO3MgSG9zcGl0

YWwsIEhhcnZhcmQgTWVkaWNhbCBTY2hvb2wsIEJvc3RvbiwgTWFzc2FjaHVzZXR0cywgVVNBLiYj

eEQ7RGVwYXJ0bWVudCBvZiBPcGh0aGFsbW9sb2d5IGFuZCBQcm9ncmFtIGluIE5ldXJvYmlvbG9n

eSwgQm9zdG9uIENoaWxkcmVuJmFwb3M7cyBIb3NwaXRhbCwgQm9zdG9uLCBNYXNzYWNodXNldHRz

LCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvc2NpZW5jZSBhbmQgQ2VudGVyIGZvciBUcmFu

c2xhdGlvbmFsIFJlc2VhcmNoIGluIE5ldXJvZGVnZW5lcmF0aXZlIERpc2Vhc2UsIFVuaXZlcnNp

dHkgb2YgRmxvcmlkYSwgR2FpbmVzdmlsbGUsIEZsb3JpZGEsIFVTQS48L2F1dGgtYWRkcmVzcz48

dGl0bGVzPjx0aXRsZT5UYXUgcHJvbW90ZXMgbmV1cm9kZWdlbmVyYXRpb24gdGhyb3VnaCBnbG9i

YWwgY2hyb21hdGluIHJlbGF4YXRpb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0IE5ldXJv

c2NpPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjM1Ny02NjwvcGFnZXM+PHZvbHVt

ZT4xNzwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxlZGl0aW9uPjIwMTQvMDEvMjg8L2VkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5k

IG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvZ2VuZXRpY3MvbWV0YWJv

bGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29y

ZD5BbmltYWxzLCBHZW5ldGljYWxseSBNb2RpZmllZDwva2V5d29yZD48a2V5d29yZD5CcmFpbi8q

bWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFu

aW1hbDwva2V5d29yZD48a2V5d29yZD5Ecm9zb3BoaWxhIG1lbGFub2dhc3Rlcjwva2V5d29yZD48

a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SGV0ZXJvY2hyb21hdGluLypnZW5ldGlj

cy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5N

YWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgSW5icmVk

IEM1N0JMPC9rZXl3b3JkPjxrZXl3b3JkPk5lcnZlIERlZ2VuZXJhdGlvbi8qZ2VuZXRpY3MvbWV0

YWJvbGlzbS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+VGF1b3BhdGhpZXMvZ2Vu

ZXRpY3MvKm1ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPnRhdSBQcm90ZWlu

cy9nZW5ldGljcy8qcGh5c2lvbG9neTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDE0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWFyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGlzYm4+MTU0Ni0xNzI2IChFbGVjdHJvbmljKSYjeEQ7MTA5Ny02MjU2IChMaW5raW5nKTwvaXNi

bj48YWNjZXNzaW9uLW51bT4yNDQ2NDA0MTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11

cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjQ0NjQwNDE8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNDAxMjI5NzwvY3VzdG9tMj48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9ubi4zNjM5PC9lbGVjdHJvbmljLXJlc291cmNl

LW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 138, thus influencing gene expression. It is also involved in synaptic plasticity through interaction with SH3 domains PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZXlub2xkczwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+

PFJlY051bT4zOTQ1PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MTM5PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzk0NTwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2Njc0NTQwIj4zOTQ1PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5SZXlub2xkcywgQy4gSC48L2F1dGhv

cj48YXV0aG9yPkdhcndvb2QsIEMuIEouPC9hdXRob3I+PGF1dGhvcj5XcmF5LCBTLjwvYXV0aG9y

PjxhdXRob3I+UHJpY2UsIEMuPC9hdXRob3I+PGF1dGhvcj5LZWxsaWUsIFMuPC9hdXRob3I+PGF1

dGhvcj5QZXJlcmEsIFQuPC9hdXRob3I+PGF1dGhvcj5admVsZWJpbCwgTS48L2F1dGhvcj48YXV0

aG9yPllhbmcsIEEuPC9hdXRob3I+PGF1dGhvcj5TaGVwcGFyZCwgUC4gVy48L2F1dGhvcj48YXV0

aG9yPlZhcm5kZWxsLCBJLiBNLjwvYXV0aG9yPjxhdXRob3I+SGFuZ2VyLCBELiBQLjwvYXV0aG9y

PjxhdXRob3I+QW5kZXJ0b24sIEIuIEguPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

PjxhdXRoLWFkZHJlc3M+VGhlIE1SQyBDZW50cmUgZm9yIE5ldXJvZGVnZW5lcmF0aW9uIFJlc2Vh

cmNoLCBLaW5nJmFwb3M7cyBDb2xsZWdlIExvbmRvbiwgSW5zdGl0dXRlIG9mIFBzeWNoaWF0cnks

IExvbmRvbiwgVUsuIGgucmV5bm9sZHNAaW9wLmtjbC5hYy51azwvYXV0aC1hZGRyZXNzPjx0aXRs

ZXM+PHRpdGxlPlBob3NwaG9yeWxhdGlvbiByZWd1bGF0ZXMgdGF1IGludGVyYWN0aW9ucyB3aXRo

IFNyYyBob21vbG9neSAzIGRvbWFpbnMgb2YgcGhvc3BoYXRpZHlsaW5vc2l0b2wgMy1raW5hc2Us

IHBob3NwaG9saXBhc2UgQ2dhbW1hMSwgR3JiMiwgYW5kIFNyYyBmYW1pbHkga2luYXNlczwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5KIEJpb2wgQ2hlbTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogQmlvbCBDaGVtPC9mdWxsLXRpdGxlPjwvcGVyaW9k

aWNhbD48cGFnZXM+MTgxNzctODY8L3BhZ2VzPjx2b2x1bWU+MjgzPC92b2x1bWU+PG51bWJlcj4y

NjwvbnVtYmVyPjxlZGl0aW9uPjIwMDgvMDUvMTA8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PkFsemhlaW1lciBEaXNlYXNlL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW1pbm8gQWNp

ZCBTZXF1ZW5jZTwva2V5d29yZD48a2V5d29yZD5HUkIyIEFkYXB0b3IgUHJvdGVpbi8qbWV0YWJv

bGlzbTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TW9sZWN1bGFy

IENvbmZvcm1hdGlvbjwva2V5d29yZD48a2V5d29yZD5Nb2xlY3VsYXIgU2VxdWVuY2UgRGF0YTwv

a2V5d29yZD48a2V5d29yZD5QZXB0aWRlcy9jaGVtaXN0cnk8L2tleXdvcmQ+PGtleXdvcmQ+UGhv

c3BoYXRpZHlsaW5vc2l0b2wgMy1LaW5hc2VzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

PlBob3NwaG9saXBhc2UgQyBnYW1tYS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5QaG9z

cGhvcnlsYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVpbiBCaW5kaW5nPC9rZXl3b3JkPjxr

ZXl3b3JkPlByb3RlaW4gU3RydWN0dXJlLCBUZXJ0aWFyeTwva2V5d29yZD48a2V5d29yZD5zcmMg

SG9tb2xvZ3kgRG9tYWluczwva2V5d29yZD48a2V5d29yZD5zcmMtRmFtaWx5IEtpbmFzZXMvKm1l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5zLypjaGVtaXN0cnk8L2tleXdv

cmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwODwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1

biAyNzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMjEtOTI1OCAoUHJpbnQpJiN4

RDswMDIxLTkyNTggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjE4NDY3MzMyPC9hY2Nl

c3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5u

aWguZ292L3B1Ym1lZC8xODQ2NzMzMjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTA3NC9qYmMuTTcwOTcxNTIwMDwvZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZXlub2xkczwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+

PFJlY051bT4zOTQ1PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MTM5PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzk0NTwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2Njc0NTQwIj4zOTQ1PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5SZXlub2xkcywgQy4gSC48L2F1dGhv

cj48YXV0aG9yPkdhcndvb2QsIEMuIEouPC9hdXRob3I+PGF1dGhvcj5XcmF5LCBTLjwvYXV0aG9y

PjxhdXRob3I+UHJpY2UsIEMuPC9hdXRob3I+PGF1dGhvcj5LZWxsaWUsIFMuPC9hdXRob3I+PGF1

dGhvcj5QZXJlcmEsIFQuPC9hdXRob3I+PGF1dGhvcj5admVsZWJpbCwgTS48L2F1dGhvcj48YXV0

aG9yPllhbmcsIEEuPC9hdXRob3I+PGF1dGhvcj5TaGVwcGFyZCwgUC4gVy48L2F1dGhvcj48YXV0

aG9yPlZhcm5kZWxsLCBJLiBNLjwvYXV0aG9yPjxhdXRob3I+SGFuZ2VyLCBELiBQLjwvYXV0aG9y

PjxhdXRob3I+QW5kZXJ0b24sIEIuIEguPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

PjxhdXRoLWFkZHJlc3M+VGhlIE1SQyBDZW50cmUgZm9yIE5ldXJvZGVnZW5lcmF0aW9uIFJlc2Vh

cmNoLCBLaW5nJmFwb3M7cyBDb2xsZWdlIExvbmRvbiwgSW5zdGl0dXRlIG9mIFBzeWNoaWF0cnks

IExvbmRvbiwgVUsuIGgucmV5bm9sZHNAaW9wLmtjbC5hYy51azwvYXV0aC1hZGRyZXNzPjx0aXRs

ZXM+PHRpdGxlPlBob3NwaG9yeWxhdGlvbiByZWd1bGF0ZXMgdGF1IGludGVyYWN0aW9ucyB3aXRo

IFNyYyBob21vbG9neSAzIGRvbWFpbnMgb2YgcGhvc3BoYXRpZHlsaW5vc2l0b2wgMy1raW5hc2Us

IHBob3NwaG9saXBhc2UgQ2dhbW1hMSwgR3JiMiwgYW5kIFNyYyBmYW1pbHkga2luYXNlczwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5KIEJpb2wgQ2hlbTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogQmlvbCBDaGVtPC9mdWxsLXRpdGxlPjwvcGVyaW9k

aWNhbD48cGFnZXM+MTgxNzctODY8L3BhZ2VzPjx2b2x1bWU+MjgzPC92b2x1bWU+PG51bWJlcj4y

NjwvbnVtYmVyPjxlZGl0aW9uPjIwMDgvMDUvMTA8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PkFsemhlaW1lciBEaXNlYXNlL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW1pbm8gQWNp

ZCBTZXF1ZW5jZTwva2V5d29yZD48a2V5d29yZD5HUkIyIEFkYXB0b3IgUHJvdGVpbi8qbWV0YWJv

bGlzbTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TW9sZWN1bGFy

IENvbmZvcm1hdGlvbjwva2V5d29yZD48a2V5d29yZD5Nb2xlY3VsYXIgU2VxdWVuY2UgRGF0YTwv

a2V5d29yZD48a2V5d29yZD5QZXB0aWRlcy9jaGVtaXN0cnk8L2tleXdvcmQ+PGtleXdvcmQ+UGhv

c3BoYXRpZHlsaW5vc2l0b2wgMy1LaW5hc2VzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

PlBob3NwaG9saXBhc2UgQyBnYW1tYS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5QaG9z

cGhvcnlsYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVpbiBCaW5kaW5nPC9rZXl3b3JkPjxr

ZXl3b3JkPlByb3RlaW4gU3RydWN0dXJlLCBUZXJ0aWFyeTwva2V5d29yZD48a2V5d29yZD5zcmMg

SG9tb2xvZ3kgRG9tYWluczwva2V5d29yZD48a2V5d29yZD5zcmMtRmFtaWx5IEtpbmFzZXMvKm1l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5zLypjaGVtaXN0cnk8L2tleXdv

cmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwODwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1

biAyNzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMjEtOTI1OCAoUHJpbnQpJiN4

RDswMDIxLTkyNTggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjE4NDY3MzMyPC9hY2Nl

c3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5u

aWguZ292L3B1Ym1lZC8xODQ2NzMzMjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTA3NC9qYmMuTTcwOTcxNTIwMDwvZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 139 and mediation of NMDA receptor phosphorylation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5JdHRuZXI8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

ZWNOdW0+MzkzOTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjE0MDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM5Mzk8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjY3NDQ4OCI+MzkzOTwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SXR0bmVyLCBMLiBNLjwvYXV0aG9yPjxh

dXRob3I+S2UsIFkuIEQuPC9hdXRob3I+PGF1dGhvcj5EZWxlcnVlLCBGLjwvYXV0aG9yPjxhdXRo

b3I+QmksIE0uPC9hdXRob3I+PGF1dGhvcj5HbGFkYmFjaCwgQS48L2F1dGhvcj48YXV0aG9yPnZh

biBFZXJzZWwsIEouPC9hdXRob3I+PGF1dGhvcj5Xb2xmaW5nLCBILjwvYXV0aG9yPjxhdXRob3I+

Q2hpZW5nLCBCLiBDLjwvYXV0aG9yPjxhdXRob3I+Q2hyaXN0aWUsIE0uIEouPC9hdXRob3I+PGF1

dGhvcj5OYXBpZXIsIEkuIEEuPC9hdXRob3I+PGF1dGhvcj5FY2tlcnQsIEEuPC9hdXRob3I+PGF1

dGhvcj5TdGF1ZmVuYmllbCwgTS48L2F1dGhvcj48YXV0aG9yPkhhcmRlbWFuLCBFLjwvYXV0aG9y

PjxhdXRob3I+R290eiwgSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgt

YWRkcmVzcz5BbHpoZWltZXImYXBvcztzIGFuZCBQYXJraW5zb24mYXBvcztzIERpc2Vhc2UgTGFi

b3JhdG9yeSwgQnJhaW4gYW5kIE1pbmQgUmVzZWFyY2ggSW5zdGl0dXRlLCBVbml2ZXJzaXR5IG9m

IFN5ZG5leSwgU3lkbmV5IE5TVyAyMDUwLCBBdXN0cmFsaWEuIGxpdHRuZXJAbWVkLnVzeWQuZWR1

LmF1PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+RGVuZHJpdGljIGZ1bmN0aW9uIG9mIHRh

dSBtZWRpYXRlcyBhbXlsb2lkLWJldGEgdG94aWNpdHkgaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNl

YXNlIG1vdXNlIG1vZGVsczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5DZWxsPC9zZWNvbmRhcnkt

dGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2VsbDwvZnVsbC10aXRsZT48

L3BlcmlvZGljYWw+PHBhZ2VzPjM4Ny05NzwvcGFnZXM+PHZvbHVtZT4xNDI8L3ZvbHVtZT48bnVt

YmVyPjM8L251bWJlcj48ZWRpdGlvbj4yMDEwLzA3LzI3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5

d29yZD5BbHpoZWltZXIgRGlzZWFzZS9wYXRob2xvZ3kvKnBoeXNpb3BhdGhvbG9neTwva2V5d29y

ZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvbWV0YWJvbGlzbS90b3hpY2l0eTwva2V5

d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL3BhdGhvbG9neTwv

a2V5d29yZD48a2V5d29yZD5EZW5kcml0ZXMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+

RGlza3MgTGFyZ2UgSG9tb2xvZyA0IFByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+R3VhbnlsYXRl

IEtpbmFzZXM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkludHJh

Y2VsbHVsYXIgU2lnbmFsaW5nIFBlcHRpZGVzIGFuZCBQcm90ZWlucy9tZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPk1lbWJyYW5lIFByb3RlaW5zL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+TWVtb3J5IERpc29yZGVycy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tl

eXdvcmQ+PGtleXdvcmQ+TWljZSwgVHJhbnNnZW5pYzwva2V5d29yZD48a2V5d29yZD5Qcm90by1P

bmNvZ2VuZSBQcm90ZWlucyBjLWZ5bi9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlJlY2Vw

dG9ycywgTi1NZXRoeWwtRC1Bc3BhcnRhdGUvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5T

eW5hcHNlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPnRhdSBQcm90ZWlucy9nZW5ldGlj

cy8qbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEwPC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+QXVnIDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

MDk3LTQxNzIgKEVsZWN0cm9uaWMpJiN4RDswMDkyLTg2NzQgKExpbmtpbmcpPC9pc2JuPjxhY2Nl

c3Npb24tbnVtPjIwNjU1MDk5PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy

bD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMDY1NTA5OTwvdXJsPjwvcmVs

YXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmNlbGwu

MjAxMC4wNi4wMzY8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0Vu

ZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5JdHRuZXI8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

ZWNOdW0+MzkzOTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjE0MDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM5Mzk8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjY3NDQ4OCI+MzkzOTwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SXR0bmVyLCBMLiBNLjwvYXV0aG9yPjxh

dXRob3I+S2UsIFkuIEQuPC9hdXRob3I+PGF1dGhvcj5EZWxlcnVlLCBGLjwvYXV0aG9yPjxhdXRo

b3I+QmksIE0uPC9hdXRob3I+PGF1dGhvcj5HbGFkYmFjaCwgQS48L2F1dGhvcj48YXV0aG9yPnZh

biBFZXJzZWwsIEouPC9hdXRob3I+PGF1dGhvcj5Xb2xmaW5nLCBILjwvYXV0aG9yPjxhdXRob3I+

Q2hpZW5nLCBCLiBDLjwvYXV0aG9yPjxhdXRob3I+Q2hyaXN0aWUsIE0uIEouPC9hdXRob3I+PGF1

dGhvcj5OYXBpZXIsIEkuIEEuPC9hdXRob3I+PGF1dGhvcj5FY2tlcnQsIEEuPC9hdXRob3I+PGF1

dGhvcj5TdGF1ZmVuYmllbCwgTS48L2F1dGhvcj48YXV0aG9yPkhhcmRlbWFuLCBFLjwvYXV0aG9y

PjxhdXRob3I+R290eiwgSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgt

YWRkcmVzcz5BbHpoZWltZXImYXBvcztzIGFuZCBQYXJraW5zb24mYXBvcztzIERpc2Vhc2UgTGFi

b3JhdG9yeSwgQnJhaW4gYW5kIE1pbmQgUmVzZWFyY2ggSW5zdGl0dXRlLCBVbml2ZXJzaXR5IG9m

IFN5ZG5leSwgU3lkbmV5IE5TVyAyMDUwLCBBdXN0cmFsaWEuIGxpdHRuZXJAbWVkLnVzeWQuZWR1

LmF1PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+RGVuZHJpdGljIGZ1bmN0aW9uIG9mIHRh

dSBtZWRpYXRlcyBhbXlsb2lkLWJldGEgdG94aWNpdHkgaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNl

YXNlIG1vdXNlIG1vZGVsczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5DZWxsPC9zZWNvbmRhcnkt

dGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2VsbDwvZnVsbC10aXRsZT48

L3BlcmlvZGljYWw+PHBhZ2VzPjM4Ny05NzwvcGFnZXM+PHZvbHVtZT4xNDI8L3ZvbHVtZT48bnVt

YmVyPjM8L251bWJlcj48ZWRpdGlvbj4yMDEwLzA3LzI3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5

d29yZD5BbHpoZWltZXIgRGlzZWFzZS9wYXRob2xvZ3kvKnBoeXNpb3BhdGhvbG9neTwva2V5d29y

ZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvbWV0YWJvbGlzbS90b3hpY2l0eTwva2V5

d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL3BhdGhvbG9neTwv

a2V5d29yZD48a2V5d29yZD5EZW5kcml0ZXMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+

RGlza3MgTGFyZ2UgSG9tb2xvZyA0IFByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+R3VhbnlsYXRl

IEtpbmFzZXM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkludHJh

Y2VsbHVsYXIgU2lnbmFsaW5nIFBlcHRpZGVzIGFuZCBQcm90ZWlucy9tZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPk1lbWJyYW5lIFByb3RlaW5zL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+TWVtb3J5IERpc29yZGVycy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tl

eXdvcmQ+PGtleXdvcmQ+TWljZSwgVHJhbnNnZW5pYzwva2V5d29yZD48a2V5d29yZD5Qcm90by1P

bmNvZ2VuZSBQcm90ZWlucyBjLWZ5bi9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlJlY2Vw

dG9ycywgTi1NZXRoeWwtRC1Bc3BhcnRhdGUvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5T

eW5hcHNlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPnRhdSBQcm90ZWlucy9nZW5ldGlj

cy8qbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEwPC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+QXVnIDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

MDk3LTQxNzIgKEVsZWN0cm9uaWMpJiN4RDswMDkyLTg2NzQgKExpbmtpbmcpPC9pc2JuPjxhY2Nl

c3Npb24tbnVtPjIwNjU1MDk5PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy

bD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMDY1NTA5OTwvdXJsPjwvcmVs

YXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmNlbGwu

MjAxMC4wNi4wMzY8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0Vu

ZE5vdGU+AG==

ADDIN EN.CITE.DATA 140.The links between Aβ and Tau are still not fully defined. This is one of the main problems for Alzheimer’s disease. For instance, for immunotherapy against Tau, decreasing its amount will improve the symptoms in the mouse models but does not cure the pathology. Thus, the real problem is that we do not have the right model for AD. Takomi Saido in Japan developed APP single copy knock-in mice, which contains the human APP gene without artefacts related to overexpression PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWl0bzwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl

Y051bT4xMzk3PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMzk3PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ1MDAzNDQiPjEzOTc8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNhaXRvLCBULjwvYXV0aG9yPjxhdXRob3I+

TWF0c3ViYSwgWS48L2F1dGhvcj48YXV0aG9yPk1paGlyYSwgTi48L2F1dGhvcj48YXV0aG9yPlRh

a2FubywgSi48L2F1dGhvcj48YXV0aG9yPk5pbHNzb24sIFAuPC9hdXRob3I+PGF1dGhvcj5JdG9o

YXJhLCBTLjwvYXV0aG9yPjxhdXRob3I+SXdhdGEsIE4uPC9hdXRob3I+PGF1dGhvcj5TYWlkbywg

VC4gQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz4xXSBM

YWJvcmF0b3J5IGZvciBQcm90ZW9seXRpYyBOZXVyb3NjaWVuY2UsIFJJS0VOIEJyYWluIFNjaWVu

Y2UgSW5zdGl0dXRlLCBXYWtvLXNoaSwgU2FpdGFtYSwgSmFwYW4uIFsyXSBKYXBhbiBTY2llbmNl

IGFuZCBUZWNobm9sb2d5IEFnZW5jeSwgU2FpdGFtYSwgSmFwYW4uJiN4RDtMYWJvcmF0b3J5IGZv

ciBQcm90ZW9seXRpYyBOZXVyb3NjaWVuY2UsIFJJS0VOIEJyYWluIFNjaWVuY2UgSW5zdGl0dXRl

LCBXYWtvLXNoaSwgU2FpdGFtYSwgSmFwYW4uJiN4RDtMYWJvcmF0b3J5IGZvciBCZWhhdmlvcmFs

IEdlbmV0aWNzLCBSSUtFTiBCcmFpbiBTY2llbmNlIEluc3RpdHV0ZSwgV2Frby1zaGksIFNhaXRh

bWEsIEphcGFuLiYjeEQ7MV0gTGFib3JhdG9yeSBmb3IgUHJvdGVvbHl0aWMgTmV1cm9zY2llbmNl

LCBSSUtFTiBCcmFpbiBTY2llbmNlIEluc3RpdHV0ZSwgV2Frby1zaGksIFNhaXRhbWEsIEphcGFu

LiBbMl0gRGVwYXJ0bWVudCBvZiBNb2xlY3VsYXIgTWVkaWNpbmFsIFNjaWVuY2VzLCBEaXZpc2lv

biBvZiBCaW90ZWNobm9sb2d5LCBOYWdhc2FraSBVbml2ZXJzaXR5IEdyYWR1YXRlIFNjaG9vbCBv

ZiBCaW9tZWRpY2FsIFNjaWVuY2VzLCBOYWdhc2FraSwgSmFwYW4uPC9hdXRoLWFkZHJlc3M+PHRp

dGxlcz48dGl0bGU+U2luZ2xlIEFwcCBrbm9jay1pbiBtb3VzZSBtb2RlbHMgb2YgQWx6aGVpbWVy

JmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5hdCBOZXVyb3NjaTwvc2Vj

b25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz42NjEtMzwvcGFnZXM+PHZvbHVtZT4xNzwvdm9s

dW1lPjxudW1iZXI+NTwvbnVtYmVyPjxlZGl0aW9uPjIwMTQvMDQvMTU8L2VkaXRpb24+PGtleXdv

cmRzPjxrZXl3b3JkPkFnZSBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNl

YXNlLypnZW5ldGljcy9tZXRhYm9saXNtLypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW15

bG9pZCBiZXRhLVByb3RlaW4gUHJlY3Vyc29yLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5B

bmFseXNpcyBvZiBWYXJpYW5jZTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxr

ZXl3b3JkPipEaXNlYXNlIE1vZGVscywgQW5pbWFsPC9rZXl3b3JkPjxrZXl3b3JkPkVuenltZS1M

aW5rZWQgSW1tdW5vc29yYmVudCBBc3NheTwva2V5d29yZD48a2V5d29yZD4qR2VuZSBLbm9jay1J

biBUZWNobmlxdWVzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5N

YXplIExlYXJuaW5nL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48

a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgVHJhbnNn

ZW5pYzwva2V5d29yZD48a2V5d29yZD5NdXRhdGlvbi9nZW5ldGljczwva2V5d29yZD48L2tleXdv

cmRzPjxkYXRlcz48eWVhcj4yMDE0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWF5PC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU0Ni0xNzI2IChFbGVjdHJvbmljKSYjeEQ7MTA5Ny02

MjU2IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNDcyODI2OTwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9w

dWJtZWQvMjQ3MjgyNjk8L3VybD48dXJsPmh0dHBzOi8vd3d3Lm5hdHVyZS5jb20vYXJ0aWNsZXMv

bm4uMzY5Ny5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjEwMzgvbm4uMzY5NzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+

PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWl0bzwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl

Y051bT4xMzk3PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMzk3PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ1MDAzNDQiPjEzOTc8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNhaXRvLCBULjwvYXV0aG9yPjxhdXRob3I+

TWF0c3ViYSwgWS48L2F1dGhvcj48YXV0aG9yPk1paGlyYSwgTi48L2F1dGhvcj48YXV0aG9yPlRh

a2FubywgSi48L2F1dGhvcj48YXV0aG9yPk5pbHNzb24sIFAuPC9hdXRob3I+PGF1dGhvcj5JdG9o

YXJhLCBTLjwvYXV0aG9yPjxhdXRob3I+SXdhdGEsIE4uPC9hdXRob3I+PGF1dGhvcj5TYWlkbywg

VC4gQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz4xXSBM

YWJvcmF0b3J5IGZvciBQcm90ZW9seXRpYyBOZXVyb3NjaWVuY2UsIFJJS0VOIEJyYWluIFNjaWVu

Y2UgSW5zdGl0dXRlLCBXYWtvLXNoaSwgU2FpdGFtYSwgSmFwYW4uIFsyXSBKYXBhbiBTY2llbmNl

IGFuZCBUZWNobm9sb2d5IEFnZW5jeSwgU2FpdGFtYSwgSmFwYW4uJiN4RDtMYWJvcmF0b3J5IGZv

ciBQcm90ZW9seXRpYyBOZXVyb3NjaWVuY2UsIFJJS0VOIEJyYWluIFNjaWVuY2UgSW5zdGl0dXRl

LCBXYWtvLXNoaSwgU2FpdGFtYSwgSmFwYW4uJiN4RDtMYWJvcmF0b3J5IGZvciBCZWhhdmlvcmFs

IEdlbmV0aWNzLCBSSUtFTiBCcmFpbiBTY2llbmNlIEluc3RpdHV0ZSwgV2Frby1zaGksIFNhaXRh

bWEsIEphcGFuLiYjeEQ7MV0gTGFib3JhdG9yeSBmb3IgUHJvdGVvbHl0aWMgTmV1cm9zY2llbmNl

LCBSSUtFTiBCcmFpbiBTY2llbmNlIEluc3RpdHV0ZSwgV2Frby1zaGksIFNhaXRhbWEsIEphcGFu

LiBbMl0gRGVwYXJ0bWVudCBvZiBNb2xlY3VsYXIgTWVkaWNpbmFsIFNjaWVuY2VzLCBEaXZpc2lv

biBvZiBCaW90ZWNobm9sb2d5LCBOYWdhc2FraSBVbml2ZXJzaXR5IEdyYWR1YXRlIFNjaG9vbCBv

ZiBCaW9tZWRpY2FsIFNjaWVuY2VzLCBOYWdhc2FraSwgSmFwYW4uPC9hdXRoLWFkZHJlc3M+PHRp

dGxlcz48dGl0bGU+U2luZ2xlIEFwcCBrbm9jay1pbiBtb3VzZSBtb2RlbHMgb2YgQWx6aGVpbWVy

JmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5hdCBOZXVyb3NjaTwvc2Vj

b25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz42NjEtMzwvcGFnZXM+PHZvbHVtZT4xNzwvdm9s

dW1lPjxudW1iZXI+NTwvbnVtYmVyPjxlZGl0aW9uPjIwMTQvMDQvMTU8L2VkaXRpb24+PGtleXdv

cmRzPjxrZXl3b3JkPkFnZSBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNl

YXNlLypnZW5ldGljcy9tZXRhYm9saXNtLypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW15

bG9pZCBiZXRhLVByb3RlaW4gUHJlY3Vyc29yLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5B

bmFseXNpcyBvZiBWYXJpYW5jZTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxr

ZXl3b3JkPipEaXNlYXNlIE1vZGVscywgQW5pbWFsPC9rZXl3b3JkPjxrZXl3b3JkPkVuenltZS1M

aW5rZWQgSW1tdW5vc29yYmVudCBBc3NheTwva2V5d29yZD48a2V5d29yZD4qR2VuZSBLbm9jay1J

biBUZWNobmlxdWVzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5N

YXplIExlYXJuaW5nL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48

a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgVHJhbnNn

ZW5pYzwva2V5d29yZD48a2V5d29yZD5NdXRhdGlvbi9nZW5ldGljczwva2V5d29yZD48L2tleXdv

cmRzPjxkYXRlcz48eWVhcj4yMDE0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWF5PC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU0Ni0xNzI2IChFbGVjdHJvbmljKSYjeEQ7MTA5Ny02

MjU2IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNDcyODI2OTwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9w

dWJtZWQvMjQ3MjgyNjk8L3VybD48dXJsPmh0dHBzOi8vd3d3Lm5hdHVyZS5jb20vYXJ0aWNsZXMv

bm4uMzY5Ny5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjEwMzgvbm4uMzY5NzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+

PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 41. New Tau knock-in models are currently in development.The presence of Amyloid beta and Tau cannot predict cognitive decline, possibly because of the cognitive reserve. This point out the fact that we have too many therapeutic strategies without knowing the functions of Tau. In order to better target Tau in AD, research needs to focus on understanding brain homeostasis, microbial infections, hormones, about glucose uptake, microglia, insulin, leptin, ghrelin, and other mechanisms not really explored in the field yet. Even for immunotherapy, the mechanisms leading to clearing, or leading the antibody to block extracellular propagation are not understood, simply because we do not know how Tau is transferred from one neuron to another.Synaptic Plasticity and ADNeuroplasticity broadly comprises a spectrum of structural elements: long-term potentiation (LTP) (a cellular correlate of learning and memory), synaptic efficacy and remodeling, synaptogenesis, axonal sprouting, and dendritic remodeling, and neurogenesis. LTP, a model of memory formation, is built on synaptic strengthening which requires activation of pre- and postsynaptic elements. LTP is associated with synaptic dynamics, including formation and removal of synapses and changes in synapse morphology. Neuroplasticity is not only shaped by learning and memory but is also a mediator of responses to neuron attrition and injury (compensatory plasticity). Neuronal systems which play a crucial role in higher brain functions (learning, memory, cognition) such as the hippocampus, neocortical association areas, and cholinergic basal forebrain neurons, retain a high degree of structural plasticity throughout life.The adult central nervous system (CNS) responds to injury with limited - albeit at times effective - restoration of synaptic circuitry. Whether or not compensatory growth reverses cognitive deficits remains a highly debated topic. On the one hand, brain self-reorganization continuously balances synapse formation and removal as well as neurite sprouting and retraction, yet on the other hand, mechanisms that regulate neuronal plasticity might be important in neurodegenerative diseases. It is intriguing that brain regions with the highest degree of structural plasticity take the longest to mature during childhood - the same regions with the highest degree of vulnerability during aging and in AD. An imbalance between dynamic stabilization and destabilization of synapses could underlie failure of plasticity with age and disease. Synaptogenesis declines with developmental age, and adult lesions recapitulate developmental gene expression responses and aging, including AD. If mechanisms controlling developmental plasticity were to be defective and later reactivated (in aging, mild cognitive impairment in early AD) they might contribute to ineffective plasticity responses and actually worsen the plasticity burden of aging and AD ADDIN EN.CITE <EndNote><Cite><Author>Braak</Author><Year>1996</Year><RecNum>1071</RecNum><DisplayText><style face="superscript">141</style></DisplayText><record><rec-number>1071</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865729">1071</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Braak, H.</author><author>Braak, E.</author></authors></contributors><titles><title>Development of Alzheimer-related neurofibrillary changes in the neocortex inversely recapitulates cortical myelogenesis</title><secondary-title>Acta Neuropathologica</secondary-title></titles><periodical><full-title>Acta Neuropathologica</full-title></periodical><pages>197-201</pages><volume>92</volume><number>2</number><dates><year>1996</year><pub-dates><date>1996/07/15</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>0001-6322&#xD;1432-0533</isbn><urls><related-urls><url> loss in the hippocampus and neocortex is a well-established early event and the major structural correlate of cognitive dysfunction in AD. Memory loss in AD may result from the synaptic dysfunction that precedes frank neurodegeneration. Synapse degeneration is believed, to begin with dendritic spines, a primary locus of excitatory synaptic transmission and memory-initiating mechanisms in the mammalian CNS. Loss of spines and their associated molecules is well established for AD brain and transgenic AD mouse models, together with significant decreases in molecules involved in spine signaling and control of filamentous actin. Conceivably, AD dementia may be initiated before spine aberration- triggered synapse degeneration ADDIN EN.CITE <EndNote><Cite><Author>Scheff</Author><Year>2006</Year><RecNum>3284</RecNum><DisplayText><style face="superscript">142</style></DisplayText><record><rec-number>3284</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535635238">3284</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Scheff, S. W.</author><author>Price, D. A.</author><author>Schmitt, F. A.</author><author>Mufson, E. J.</author></authors></contributors><auth-address>Sanders-Brown Center on Aging and the Alzheimer&apos;s Disease Research Center, University of Kentucky College of Medicine, 101 Sanders-Brown, Lexington, KY 40536-0230, USA. sscheff@email.uky.edu</auth-address><titles><title>Hippocampal synaptic loss in early Alzheimer&apos;s disease and mild cognitive impairment</title><secondary-title>Neurobiol Aging</secondary-title></titles><periodical><full-title>Neurobiol Aging</full-title></periodical><pages>1372-84</pages><volume>27</volume><number>10</number><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Alzheimer Disease/*pathology</keyword><keyword>Cognition Disorders/complications/*pathology</keyword><keyword>Female</keyword><keyword>Hippocampus/*pathology</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Nerve Net/*pathology</keyword><keyword>Neural Pathways/*pathology</keyword><keyword>Synapses/*pathology</keyword></keywords><dates><year>2006</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1558-1497 (Electronic)&#xD;0197-4580 (Linking)</isbn><accession-num>16289476</accession-num><urls><related-urls><url> molecules responsible for spine pathology remain unknown, although a role for insoluble A??fibrils has often been considered as a prime suspect. However, in both transgenic mouse AD models and human AD brain, both synapse abnormalities and memory impairments correlate poorly with plaque burden and can occur before plaque formation. Indeed, AD brain and cerebrospinal fluid contain small neurotoxins made up of soluble A??oligomers (A?-derived diffusible ligands or ADDLs). ADDLs are gain-of-function ligands that disrupt, even at nanomolar concentrations, plasticity by binding directly to dendritic spines and interfering with excitatory N-methyl-D-aspartic acid (NMDA) receptor-mediated activation of transcription factors PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LbGVpbjwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl

Y051bT4xMDc3PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTQzLTE0NTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEwNzc8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTcyOSI+MTA3Nzwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+S2xlaW4sIFdpbGxpYW0gTC48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+U3luYXB0aWMgdGFy

Z2V0aW5nIGJ5IEHOsiBvbGlnb21lcnMgKEFERExTKSBhcyBhIGJhc2lzIGZvciBtZW1vcnkgbG9z

cyBpbiBlYXJseSBBbHpoZWltZXLigJlzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+

QWx6aGVpbWVyJmFwb3M7cyAmYW1wOyBEZW1lbnRpYTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwYWdlcz40My01NTwvcGFnZXM+PHZvbHVtZT4yPC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+

PGRhdGVzPjx5ZWFyPjIwMDY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDA2LzAxPC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5FbHNldmllciBCVjwvcHVibGlzaGVyPjxpc2Ju

PjE1NTItNTI2MDwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5v

cmcvMTAuMTAxNi9qLmphbHouMjAwNS4xMS4wMDM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5qYWx6LjIwMDUuMTEuMDAzPC9lbGVj

dHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5MYWNvcjwv

QXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJlY051bT4xMDc4PC9SZWNOdW0+PHJlY29yZD48cmVj

LW51bWJlcj4xMDc4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1p

ZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4

NjU3MjkiPjEwNzg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBB

cnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkxhY29y

LCBQLiBOLjwvYXV0aG9yPjxhdXRob3I+QnVuaWVsLCBNLiBDLjwvYXV0aG9yPjxhdXRob3I+RnVy

bG93LCBQLiBXLjwvYXV0aG9yPjxhdXRob3I+U2FueiBDbGVtZW50ZSwgQS48L2F1dGhvcj48YXV0

aG9yPlZlbGFzY28sIFAuIFQuPC9hdXRob3I+PGF1dGhvcj5Xb29kLCBNLjwvYXV0aG9yPjxhdXRo

b3I+VmlvbGEsIEsuIEwuPC9hdXRob3I+PGF1dGhvcj5LbGVpbiwgVy4gTC48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QcKgIE9saWdvbWVyLUluZHVjZWQg

QWJlcnJhdGlvbnMgaW4gU3luYXBzZSBDb21wb3NpdGlvbiwgU2hhcGUsIGFuZCBEZW5zaXR5IFBy

b3ZpZGUgYSBNb2xlY3VsYXIgQmFzaXMgZm9yIExvc3Mgb2YgQ29ubmVjdGl2aXR5IGluIEFsemhl

aW1lciZhcG9zO3MgRGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Kb3VybmFsIG9mIE5l

dXJvc2NpZW5jZTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz43OTYtODA3PC9wYWdl

cz48dm9sdW1lPjI3PC92b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMDc8

L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDA3LzAxLzI0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0

ZXM+PHB1Ymxpc2hlcj5Tb2NpZXR5IGZvciBOZXVyb3NjaWVuY2U8L3B1Ymxpc2hlcj48aXNibj4w

MjcwLTY0NzQmI3hEOzE1MjktMjQwMTwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL2R4LmRvaS5vcmcvMTAuMTUyMy9qbmV1cm9zY2kuMzUwMS0wNi4yMDA3PC91cmw+PC9yZWxh

dGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTIzL2puZXVyb3Nj

aS4zNTAxLTA2LjIwMDc8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48

Q2l0ZT48QXV0aG9yPldhbmc8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxSZWNOdW0+MTA4MTwv

UmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTA4MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz

PjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVh

diIgdGltZXN0YW1wPSIxNTMyODY1NzI5Ij4xMDgxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10

eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1

dGhvcnM+PGF1dGhvcj5XYW5nLCBIYWktV2VpPC9hdXRob3I+PGF1dGhvcj5QYXN0ZXJuYWssIEpv

c2VwaCBGLjwvYXV0aG9yPjxhdXRob3I+S3VvLCBIZWxlbjwvYXV0aG9yPjxhdXRob3I+UmlzdGlj

LCBIZWxlbjwvYXV0aG9yPjxhdXRob3I+TGFtYmVydCwgTWFyeSBQLjwvYXV0aG9yPjxhdXRob3I+

Q2hyb215LCBCcmV0dDwvYXV0aG9yPjxhdXRob3I+VmlvbGEsIEtpcnN0ZW4gTC48L2F1dGhvcj48

YXV0aG9yPktsZWluLCBXaWxsaWFtIEwuPC9hdXRob3I+PGF1dGhvcj5TdGluZSwgVy4gQmxhaW5l

PC9hdXRob3I+PGF1dGhvcj5LcmFmZnQsIEdyYW50IEEuPC9hdXRob3I+PGF1dGhvcj5Ucm9tbWVy

LCBCYXJiYXJhIEwuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRp

dGxlPlNvbHVibGUgb2xpZ29tZXJzIG9mIM6yIGFteWxvaWQgKDEtNDIpIGluaGliaXQgbG9uZy10

ZXJtIHBvdGVudGlhdGlvbiBidXQgbm90IGxvbmctdGVybSBkZXByZXNzaW9uIGluIHJhdCBkZW50

YXRlIGd5cnVzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkJyYWluIFJlc2VhcmNoPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEzMy0xNDA8L3BhZ2VzPjx2b2x1bWU+OTI0PC92b2x1

bWU+PG51bWJlcj4yPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMDI8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT4yMDAyLzAxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5FbHNldmll

ciBCVjwvcHVibGlzaGVyPjxpc2JuPjAwMDYtODk5MzwvaXNibj48dXJscz48cmVsYXRlZC11cmxz

Pjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAxNi9zMDAwNi04OTkzKDAxKTAzMDU4LXg8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYv

czAwMDYtODk5MygwMSkwMzA1OC14PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48

L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LbGVpbjwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl

Y051bT4xMDc3PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MTQzLTE0NTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEwNzc8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTcyOSI+MTA3Nzwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+S2xlaW4sIFdpbGxpYW0gTC48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+U3luYXB0aWMgdGFy

Z2V0aW5nIGJ5IEHOsiBvbGlnb21lcnMgKEFERExTKSBhcyBhIGJhc2lzIGZvciBtZW1vcnkgbG9z

cyBpbiBlYXJseSBBbHpoZWltZXLigJlzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+

QWx6aGVpbWVyJmFwb3M7cyAmYW1wOyBEZW1lbnRpYTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwYWdlcz40My01NTwvcGFnZXM+PHZvbHVtZT4yPC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+

PGRhdGVzPjx5ZWFyPjIwMDY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDA2LzAxPC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5FbHNldmllciBCVjwvcHVibGlzaGVyPjxpc2Ju

PjE1NTItNTI2MDwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5v

cmcvMTAuMTAxNi9qLmphbHouMjAwNS4xMS4wMDM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5qYWx6LjIwMDUuMTEuMDAzPC9lbGVj

dHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5MYWNvcjwv

QXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJlY051bT4xMDc4PC9SZWNOdW0+PHJlY29yZD48cmVj

LW51bWJlcj4xMDc4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1p

ZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4

NjU3MjkiPjEwNzg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBB

cnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkxhY29y

LCBQLiBOLjwvYXV0aG9yPjxhdXRob3I+QnVuaWVsLCBNLiBDLjwvYXV0aG9yPjxhdXRob3I+RnVy

bG93LCBQLiBXLjwvYXV0aG9yPjxhdXRob3I+U2FueiBDbGVtZW50ZSwgQS48L2F1dGhvcj48YXV0

aG9yPlZlbGFzY28sIFAuIFQuPC9hdXRob3I+PGF1dGhvcj5Xb29kLCBNLjwvYXV0aG9yPjxhdXRo

b3I+VmlvbGEsIEsuIEwuPC9hdXRob3I+PGF1dGhvcj5LbGVpbiwgVy4gTC48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QcKgIE9saWdvbWVyLUluZHVjZWQg

QWJlcnJhdGlvbnMgaW4gU3luYXBzZSBDb21wb3NpdGlvbiwgU2hhcGUsIGFuZCBEZW5zaXR5IFBy

b3ZpZGUgYSBNb2xlY3VsYXIgQmFzaXMgZm9yIExvc3Mgb2YgQ29ubmVjdGl2aXR5IGluIEFsemhl

aW1lciZhcG9zO3MgRGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Kb3VybmFsIG9mIE5l

dXJvc2NpZW5jZTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz43OTYtODA3PC9wYWdl

cz48dm9sdW1lPjI3PC92b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMDc8

L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDA3LzAxLzI0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0

ZXM+PHB1Ymxpc2hlcj5Tb2NpZXR5IGZvciBOZXVyb3NjaWVuY2U8L3B1Ymxpc2hlcj48aXNibj4w

MjcwLTY0NzQmI3hEOzE1MjktMjQwMTwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL2R4LmRvaS5vcmcvMTAuMTUyMy9qbmV1cm9zY2kuMzUwMS0wNi4yMDA3PC91cmw+PC9yZWxh

dGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTIzL2puZXVyb3Nj

aS4zNTAxLTA2LjIwMDc8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48

Q2l0ZT48QXV0aG9yPldhbmc8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxSZWNOdW0+MTA4MTwv

UmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTA4MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz

PjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVh

diIgdGltZXN0YW1wPSIxNTMyODY1NzI5Ij4xMDgxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10

eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1

dGhvcnM+PGF1dGhvcj5XYW5nLCBIYWktV2VpPC9hdXRob3I+PGF1dGhvcj5QYXN0ZXJuYWssIEpv

c2VwaCBGLjwvYXV0aG9yPjxhdXRob3I+S3VvLCBIZWxlbjwvYXV0aG9yPjxhdXRob3I+UmlzdGlj

LCBIZWxlbjwvYXV0aG9yPjxhdXRob3I+TGFtYmVydCwgTWFyeSBQLjwvYXV0aG9yPjxhdXRob3I+

Q2hyb215LCBCcmV0dDwvYXV0aG9yPjxhdXRob3I+VmlvbGEsIEtpcnN0ZW4gTC48L2F1dGhvcj48

YXV0aG9yPktsZWluLCBXaWxsaWFtIEwuPC9hdXRob3I+PGF1dGhvcj5TdGluZSwgVy4gQmxhaW5l

PC9hdXRob3I+PGF1dGhvcj5LcmFmZnQsIEdyYW50IEEuPC9hdXRob3I+PGF1dGhvcj5Ucm9tbWVy

LCBCYXJiYXJhIEwuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRp

dGxlPlNvbHVibGUgb2xpZ29tZXJzIG9mIM6yIGFteWxvaWQgKDEtNDIpIGluaGliaXQgbG9uZy10

ZXJtIHBvdGVudGlhdGlvbiBidXQgbm90IGxvbmctdGVybSBkZXByZXNzaW9uIGluIHJhdCBkZW50

YXRlIGd5cnVzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkJyYWluIFJlc2VhcmNoPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEzMy0xNDA8L3BhZ2VzPjx2b2x1bWU+OTI0PC92b2x1

bWU+PG51bWJlcj4yPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMDI8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT4yMDAyLzAxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5FbHNldmll

ciBCVjwvcHVibGlzaGVyPjxpc2JuPjAwMDYtODk5MzwvaXNibj48dXJscz48cmVsYXRlZC11cmxz

Pjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAxNi9zMDAwNi04OTkzKDAxKTAzMDU4LXg8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYv

czAwMDYtODk5MygwMSkwMzA1OC14PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48

L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 143-145 (See Fig. 2).Figure 2. Dendritic spine and AD: mechanisms causing spine degeneration. Impaired synaptic plasticity is an early events in Alzheimer disease (AD). Synaptic plasticity is accompanied by morphological adaptations of dendritic spines, such as changes in the number and shape of spines (structural plasticity). A fundamental mechanism for modification of synaptic strength is insertion (activation) or removal (inactivation) of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) at the postsynaptic membrane. Such adaptation occurs within minutes, yet may also extend over longer times. Aβ1–42 over-activates NMDAR/calmodulin (CaM)/calcineurin/glycogen synthase kinase-3β (GSK-3β). Calcineurin, a calcium-sensitive phosphatase, regulates synaptic plasticity and is required for AMPARs internalization and long-term depression. Aβ oligomer-induced AMPARs endocytosis and spine loss is prevented by calcineurin inhibition. Therefore, inhibition of calcineurin could be a therapeutic strategies for combating early stage AD impairment. Diabetes has been linked to impairment in episodic memory. Non-diabetic persons with mild forms of impaired glucose tolerance may also show cognitive impairments. Among non-diabetic, non-demented middle-aged/elderly individuals, decreased peripheral glucose regulation is associated with a lower overall general cognitive performance, memory impairment, and hippocampal atrophy. Metabolic substrate delivery may influence brain structure and function. As such, improving lifetime management of blood sugar may be beneficial in improving memory in old age and possibly even reduce the risk of hippocampal damage and development of AD.Insulin has metabolic, neurotrophic and neuromodulatory actions in the brain ADDIN EN.CITE <EndNote><Cite><Author>Blazquez</Author><Year>2014</Year><RecNum>1095</RecNum><DisplayText><style face="superscript">146</style></DisplayText><record><rec-number>1095</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865796">1095</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Blazquez, E.</author><author>Velazquez, E.</author><author>Hurtado-Carneiro, V.</author><author>Ruiz-Albusac, J. M.</author></authors></contributors><auth-address>Departamento de Bioquimica y Biologia Molecular III, Facultad de Medicina, Universidad Complutense , Madrid , Spain ; The Center for Biomedical Research in Diabetes and Associated Metabolic Disorders (CIBERDEM) , Madrid , Spain ; Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos (IdiSSC) , Madrid , Spain.</auth-address><titles><title>Insulin in the brain: its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer&apos;s disease</title><secondary-title>Front Endocrinol (Lausanne)</secondary-title></titles><pages>161</pages><volume>5</volume><keywords><keyword>Alzheimer&apos;s disease</keyword><keyword>biological actions</keyword><keyword>brain</keyword><keyword>central insulin resistance</keyword><keyword>insulin</keyword><keyword>pathophysiological implications</keyword><keyword>receptors</keyword><keyword>type 2 diabetes</keyword></keywords><dates><year>2014</year></dates><isbn>1664-2392 (Print)&#xD;1664-2392 (Linking)</isbn><accession-num>25346723</accession-num><urls><related-urls><url>. Insulin receptors on central neurons are mainly synaptic and are components of postsynaptic densities, suggesting a role for insulin in learning and memory. Insulin resistance, characteristic of Type II diabetes, is associated with a higher prevalence of AD and neuroinflammation. It is not uncommon for AD patients to have abnormal cerebrospinal fluid insulin levels, suggesting an altered insulin processing. Insulin also regulates the phosphorylation of Tau, a major component of neurofibrillary tangles seen in AD brain ADDIN EN.CITE <EndNote><Cite><Author>Dyer</Author><Year>2016</Year><RecNum>1074</RecNum><DisplayText><style face="superscript">147</style></DisplayText><record><rec-number>1074</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865729">1074</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dyer, Adam H.</author><author>Vahdatpour, Cyrus</author><author>Sanfeliu, Albert</author><author>Tropea, Daniela</author></authors></contributors><titles><title>The role of Insulin-Like Growth Factor 1 (IGF-1) in brain development, maturation and neuroplasticity</title><secondary-title>Neuroscience</secondary-title></titles><periodical><full-title>Neuroscience</full-title></periodical><pages>89-99</pages><volume>325</volume><dates><year>2016</year><pub-dates><date>2016/06</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>0306-4522</isbn><urls><related-urls><url>. Moreover, insulin has been found to aggregate in human AD brains, particularly in Tau-tangle positive neurons ADDIN EN.CITE <EndNote><Cite><Author>Rodriguez-Rodriguez</Author><Year>2017</Year><RecNum>1005</RecNum><DisplayText><style face="superscript">148</style></DisplayText><record><rec-number>1005</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865640">1005</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rodriguez-Rodriguez, Patricia</author><author>Sandebring-Matton, Anna</author><author>Merino-Serrais, Paula</author><author>Parrado-Fernandez, Cristina</author><author>Rabano, Alberto</author><author>Winblad, Bengt</author><author>?vila, Jesús</author><author>Ferrer, Isidre</author><author>Cedazo-Minguez, Angel</author></authors></contributors><titles><title>Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons</title><secondary-title>Brain</secondary-title></titles><periodical><full-title>Brain</full-title></periodical><pages>3269-3285</pages><volume>140</volume><number>12</number><dates><year>2017</year><pub-dates><date>2017/10/13</date></pub-dates></dates><publisher>Oxford University Press (OUP)</publisher><isbn>0006-8950&#xD;1460-2156</isbn><urls><related-urls><url>. Endosomes are major sorting stations in the endocytic process, directing proteins and lipids to multiple destinations including the cell surface, Golgi complex, and lysosomes. Bi-directional protein trafficking in postsynaptic membranes is a key mechanism underlying various forms of synaptic plasticity. AMPA receptor sorting occurs early in endosomes and is regulated by synaptic activity and AMPA/NMDA receptor activation. Endocytosis and exocytosis serve important roles in LTP and long-term depression at hippocampal synapses. Blocking exocytosis prevents LTP induction, whereas blocking endocytosis prevents induction of long-term depression. Spine expansion is driven by recycling endosomes that reside locally at the spines themselves, positing that agents stimulating endocytosis and dendritic spine structure could promote synaptic plasticity ADDIN EN.CITE <EndNote><Cite><Author>Esteves?da?Silva</Author><Year>2015</Year><RecNum>1075</RecNum><DisplayText><style face="superscript">149</style></DisplayText><record><rec-number>1075</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865729">1075</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Esteves?da?Silva, Marta</author><author>Adrian, Max</author><author>Sch?tzle, Philipp</author><author>Lipka, Joanna</author><author>Watanabe, Takuya</author><author>Cho, Sukhee</author><author>Futai, Kensuke</author><author>Wierenga, Corette?J</author><author>Kapitein, Lukas?C</author><author>Hoogenraad, Casper?C</author></authors></contributors><titles><title>Positioning of AMPA Receptor-Containing Endosomes Regulates Synapse Architecture</title><secondary-title>Cell Reports</secondary-title></titles><pages>933-943</pages><volume>13</volume><number>5</number><dates><year>2015</year><pub-dates><date>2015/11</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>2211-1247</isbn><urls><related-urls><url> play a critical role in synapse formation and plasticity. For example, the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) pathway mediates the synaptogenic action of neurotrophic factors. This pathway may participate in long-term synaptic plasticity by regulating transcriptional factor activity following nuclear translocation. MAPKs are present and active in synaptic terminals, suggesting functions in distinct subcellular compartments during short- and long-term plasticity, by phosphorylating synaptic targets. Cyclin-dependent kinase 5 displays multi-faceted roles in synaptic plasticity: dendritic spine formation, ion channel conductance, protein expression, and transcription in postsynaptic neurons. It has been implicated also in phosphorylating numerous substrates relevant to synaptic plasticity ADDIN EN.CITE <EndNote><Cite><Author>Angelo</Author><Year>2006</Year><RecNum>1067</RecNum><DisplayText><style face="superscript">150</style></DisplayText><record><rec-number>1067</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865729">1067</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Angelo, Marco</author><author>Plattner, Florian</author><author>Giese, K. Peter</author></authors></contributors><titles><title>Cyclin-dependent kinase 5 in synaptic plasticity, learning and memory</title><secondary-title>Journal of Neurochemistry</secondary-title></titles><pages>353-370</pages><volume>99</volume><number>2</number><dates><year>2006</year><pub-dates><date>2006/10</date></pub-dates></dates><publisher>Wiley</publisher><isbn>0022-3042&#xD;1471-4159</isbn><urls><related-urls><url> memory formation involves complex biochemical cascades leading to changes in gene expression, in part based on epigenetic mechanisms that remodel chromatin. Chromatin remodeling contributes to the regulation of gene expression and neuronal function, especially in terms of memory and synaptic plasticity. Erk regulates histone phosphorylation in hippocampal CA1 neurons. Mitogen- and stress-activated protein kinase-1 (MSK1), a nuclear kinase downstream of MAPK/Erk and p38/MAPK is an important histone kinase. Mice lacking MSK1 have deficits in multiple hippocampus-dependent tasks ADDIN EN.CITE <EndNote><Cite><Author>Brami-Cherrier</Author><Year>2009</Year><RecNum>1072</RecNum><DisplayText><style face="superscript">151</style></DisplayText><record><rec-number>1072</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865729">1072</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Brami-Cherrier, Karen</author><author>Roze, Emmanuel</author><author>Girault, Jean-Antoine</author><author>Betuing, Sandrine</author><author>Caboche, Jocelyne</author></authors></contributors><titles><title>Role of the ERK/MSK1 signalling pathway in chromatin remodelling and brain responses to drugs of abuse</title><secondary-title>Journal of Neurochemistry</secondary-title></titles><pages>1323-1335</pages><volume>108</volume><number>6</number><dates><year>2009</year><pub-dates><date>2009/03</date></pub-dates></dates><publisher>Wiley</publisher><isbn>0022-3042&#xD;1471-4159</isbn><urls><related-urls><url> adhesion molecules of the immunoglobulin and cadherin super families engage in cell migration, axonal growth and guidance, and synapse formation. The neural cell adhesion molecule (NCAM), a membrane-associated glycoprotein expressed on the surface of neurons and glia, plays a key role in nervous system development and synaptic plasticity in the context of learning and memory consolidation. Enreptin, a peptide agonist of NCAM has neuroprotective and memory-enhancing properties. Besides NCAM, the cell adhesion molecule N-cadherin participates in activity-mediated spine stabilization, presenting another mechanism whereby spine dynamics and stability are regulated by activity in central neurons. Synaptic cell adhesion molecules not only interact with Aβ (which affects their expression and synaptic localization) but can also regulate Aβ production by interacting with key enzymes involved in Aβ formation. Aβ-dependent changes in synaptic adhesion affect, in turn, synapse function and integrity, suggesting that alterations in synaptic adhesion play key roles in disrupting neuronal networks in AD ADDIN EN.CITE <EndNote><Cite><Author>Leshchyns’ka</Author><Year>2016</Year><RecNum>1079</RecNum><DisplayText><style face="superscript">152</style></DisplayText><record><rec-number>1079</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865729">1079</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Leshchyns’ka, Iryna</author><author>Sytnyk, Vladimir</author></authors></contributors><titles><title>Synaptic Cell Adhesion Molecules in Alzheimer’s Disease</title><secondary-title>Neural Plasticity</secondary-title></titles><pages>1-9</pages><volume>2016</volume><dates><year>2016</year></dates><publisher>Hindawi Limited</publisher><isbn>2090-5904&#xD;1687-5443</isbn><urls><related-urls><url> neurotrophins, a gene family of polypeptide neurotrophic factors, not only promote neuronal cell survival but also regulate synapse formation and synaptic plasticity. Nerve growth factor (NGF), a member of the neurotrophin family, promotes the synaptic function of cholinergic basal forebrain neurons, which provide input for cognitive functions such as memory. The regenerative effects of NGF on these cholinergic neurons in AD preclinical studies have stimulated an interest in the targeted delivery of NGF as a potential AD therapy. Recently a small clinical trial inserting encapsulated NGF-producing cells in AD patients has shown safety and tolerability increasing cholinergic markers in CSF PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FeWpvbGZzZG90dGlyPC9BdXRob3I+PFllYXI+MjAxNjwv

WWVhcj48UmVjTnVtPjQ2NDE8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVy

c2NyaXB0Ij4xNTM8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40NjQx

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDM5MjA5MjYiPjQ2NDE8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkV5am9sZnNkb3R0aXIsIEgu

PC9hdXRob3I+PGF1dGhvcj5Fcmlrc2RvdHRlciwgTS48L2F1dGhvcj48YXV0aG9yPkxpbmRlcm90

aCwgQi48L2F1dGhvcj48YXV0aG9yPkxpbmQsIEcuPC9hdXRob3I+PGF1dGhvcj5KdWxpdXNzb24s

IEIuPC9hdXRob3I+PGF1dGhvcj5LdXNrLCBQLjwvYXV0aG9yPjxhdXRob3I+QWxta3Zpc3QsIE8u

PC9hdXRob3I+PGF1dGhvcj5BbmRyZWFzZW4sIE4uPC9hdXRob3I+PGF1dGhvcj5CbGVubm93LCBL

LjwvYXV0aG9yPjxhdXRob3I+RmVycmVpcmEsIEQuPC9hdXRob3I+PGF1dGhvcj5XZXN0bWFuLCBF

LjwvYXV0aG9yPjxhdXRob3I+TmVubmVzbW8sIEkuPC9hdXRob3I+PGF1dGhvcj5LYXJhbWksIEEu

PC9hdXRob3I+PGF1dGhvcj5EYXJyZWgtU2hvcmksIFQuPC9hdXRob3I+PGF1dGhvcj5LYWRpciwg

QS48L2F1dGhvcj48YXV0aG9yPk5vcmRiZXJnLCBBLjwvYXV0aG9yPjxhdXRob3I+U3VuZHN0cm9t

LCBFLjwvYXV0aG9yPjxhdXRob3I+V2FobHVuZCwgTC4gTy48L2F1dGhvcj48YXV0aG9yPldhbGws

IEEuPC9hdXRob3I+PGF1dGhvcj5XaWJlcmcsIE0uPC9hdXRob3I+PGF1dGhvcj5XaW5ibGFkLCBC

LjwvYXV0aG9yPjxhdXRob3I+U2VpZ2VyLCBBLjwvYXV0aG9yPjxhdXRob3I+V2FobGJlcmcsIEwu

PC9hdXRob3I+PGF1dGhvcj5BbG1xdmlzdCwgUC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli

dXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2ll

bmNlcyBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCAxNzEgNzcsIFN0b2NraG9s

bSwgU3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBHZXJpYXRyaWNzLCBLYXJvbGluc2thIFVuaXZl

cnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCAxNzEgNzYsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7

RGVwYXJ0bWVudCBvZiBDbGluaWNhbCBOZXVyb3NjaWVuY2UsIEthcm9saW5za2EgSW5zdGl0dXRl

dCwgMTcxIDc3LCBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9zdXJn

ZXJ5LCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwgU29sbmEsIEJ1aWxkaW5nIFIzOjAy

LCAxNzEgNzYsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7TnNHZW5lIEluYy4sIDIyNSBDaGFwbWFu

IFN0cmVldCwgUHJvdmlkZW5jZSwgUkksIDAyOTA1LTQ1MzMsIFVTQS4mI3hEO0NsaW5pY2FsIE5l

dXJvY2hlbWlzdHJ5IExhYm9yYXRvcnksIERlcGFydG1lbnQgb2YgQ2xpbmljYWwgTmV1cm9zY2ll

bmNlLCBVbml2ZXJzaXR5IG9mIEdvdGhlbmJ1cmcsIDQxMzQ1LCBHb3RoZW5idXJnLCBTd2VkZW4u

JiN4RDtEZXBhcnRtZW50IG9mIExhYm9yYXRvcnkgTWVkaWNpbmUsIFNlY3Rpb24gb2YgUGF0aG9s

b2d5LCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIDE3MSA3NiwgU3RvY2tob2xtLCBT

d2VkZW4uJiN4RDtTdGlmdGVsc2VuIFN0b2NraG9sbXMgU2p1a2hlbSwgTWFyaWViZXJnc2dhdGFu

IDIyLCAxMTIgMzUsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBTdXJnaWNh

bCBTY2llbmNlcywgU2VjdGlvbiBvZiBOdWNsZWFyIE1lZGljaW5lIGFuZCBQRVQsIFVwcHNhbGEg

VW5pdmVyc2l0eSBIb3NwaXRhbCwgNzUxODUsIFVwcHNhbGEsIFN3ZWRlbi4mI3hEO0RlcGFydG1l

bnQgb2YgQ2xpbmljYWwgU2NpZW5jZSwgSW50ZXJ2ZW50aW9uIGFuZCBUZWNobm9sb2d5LCBEaXZp

c2lvbiBvZiBNZWRpY2FsIEltYWdpbmcgYW5kIFRlY2hub2xvZ3ksIEthcm9saW5za2EgSW5zdGl0

dXRldCwgMTcxIDc3LCBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0RlcGFydG1lbnQgb2YgUmFkaW9s

b2d5LCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIDE3MSA3NiwgU3RvY2tob2xtLCBT

d2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIENsaW5pY2FsIE5ldXJvc2NpZW5jZSwgS2Fyb2xpbnNr

YSBJbnN0aXR1dGV0LCAxNzEgNzcsIFN0b2NraG9sbSwgU3dlZGVuLiBwZXIuYWxtcXZpc3RAa2ku

c2UuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvc3VyZ2VyeSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5

IEhvc3BpdGFsIFNvbG5hLCBCdWlsZGluZyBSMzowMiwgMTcxIDc2LCBTdG9ja2hvbG0sIFN3ZWRl

bi4gcGVyLmFsbXF2aXN0QGtpLnNlLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRhcmdl

dGVkIGRlbGl2ZXJ5IG9mIG5lcnZlIGdyb3d0aCBmYWN0b3IgdG8gdGhlIGNob2xpbmVyZ2ljIGJh

c2FsIGZvcmVicmFpbiBvZiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgcGF0aWVudHM6IGFwcGxp

Y2F0aW9uIG9mIGEgc2Vjb25kLWdlbmVyYXRpb24gZW5jYXBzdWxhdGVkIGNlbGwgYmlvZGVsaXZl

cnkgZGV2aWNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFsemhlaW1lcnMgUmVzIFRoZXI8L3Nl

Y29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbHpoZWltZXJz

IFJlcyBUaGVyPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzA8L3BhZ2VzPjx2b2x1

bWU+ODwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxlZGl0aW9uPjIwMTYvMDcvMDk8L2VkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPkFjZXR5bGNob2xpbmVzdGVyYXNlL21ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9j

ZXJlYnJvc3BpbmFsIGZsdWlkL2RpYWdub3N0aWMgaW1hZ2luZy8qZHJ1ZyB0aGVyYXB5PC9rZXl3

b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9jZXJlYnJvc3BpbmFsIGZsdWlkPC9r

ZXl3b3JkPjxrZXl3b3JkPkJhc2FsIEZvcmVicmFpbi9kaWFnbm9zdGljIGltYWdpbmcvKmRydWcg

ZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5DYXBzdWxlczwva2V5d29yZD48a2V5d29yZD5DZWxs

IExpbmU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGluZSBPLUFjZXR5bHRyYW5zZmVyYXNlL2NlcmVi

cm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+Q29nbml0aW9uIERpc29yZGVycy9ldGlv

bG9neTwva2V5d29yZD48a2V5d29yZD5Db2hvcnQgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5E

b3NlLVJlc3BvbnNlIFJlbGF0aW9uc2hpcCwgRHJ1Zzwva2V5d29yZD48a2V5d29yZD4qRHJ1ZyBE

ZWxpdmVyeSBTeXN0ZW1zPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29y

ZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUg

QWdlZDwva2V5d29yZD48a2V5d29yZD5OZXJ2ZSBHcm93dGggRmFjdG9yLyphZG1pbmlzdHJhdGlv

biAmYW1wOyBkb3NhZ2U8L2tleXdvcmQ+PGtleXdvcmQ+TmVydmUgVGlzc3VlIFByb3RlaW5zL2Nl

cmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+UGVwdGlkZSBGcmFnbWVudHMvY2Vy

ZWJyb3NwaW5hbCBmbHVpZDwva2V5d29yZD48a2V5d29yZD5UcmVhdG1lbnQgT3V0Y29tZTwva2V5

d29yZD48a2V5d29yZD50YXUgUHJvdGVpbnMvY2VyZWJyb3NwaW5hbCBmbHVpZDwva2V5d29yZD48

a2V5d29yZD4qQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPipFbmNh

cHN1bGF0ZWQgY2VsbCBiaW9kZWxpdmVyeTwva2V5d29yZD48a2V5d29yZD4qTmVydmUgZ3Jvd3Ro

IGZhY3Rvcjwva2V5d29yZD48a2V5d29yZD4qUmVnZW5lcmF0aXZlIG1lZGljaW5lPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWwg

NzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE3NTgtOTE5MyAoRWxlY3Ryb25pYyk8

L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjczODk0MDI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0

ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI3Mzg5NDAy

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQ5MzYwMjA8L2N1c3RvbTI+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExODYvczEzMTk1LTAxNi0wMTk1LTk8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FeWpvbGZzZG90dGlyPC9BdXRob3I+PFllYXI+MjAxNjwv

WWVhcj48UmVjTnVtPjQ2NDE8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVy

c2NyaXB0Ij4xNTM8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40NjQx

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDM5MjA5MjYiPjQ2NDE8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkV5am9sZnNkb3R0aXIsIEgu

PC9hdXRob3I+PGF1dGhvcj5Fcmlrc2RvdHRlciwgTS48L2F1dGhvcj48YXV0aG9yPkxpbmRlcm90

aCwgQi48L2F1dGhvcj48YXV0aG9yPkxpbmQsIEcuPC9hdXRob3I+PGF1dGhvcj5KdWxpdXNzb24s

IEIuPC9hdXRob3I+PGF1dGhvcj5LdXNrLCBQLjwvYXV0aG9yPjxhdXRob3I+QWxta3Zpc3QsIE8u

PC9hdXRob3I+PGF1dGhvcj5BbmRyZWFzZW4sIE4uPC9hdXRob3I+PGF1dGhvcj5CbGVubm93LCBL

LjwvYXV0aG9yPjxhdXRob3I+RmVycmVpcmEsIEQuPC9hdXRob3I+PGF1dGhvcj5XZXN0bWFuLCBF

LjwvYXV0aG9yPjxhdXRob3I+TmVubmVzbW8sIEkuPC9hdXRob3I+PGF1dGhvcj5LYXJhbWksIEEu

PC9hdXRob3I+PGF1dGhvcj5EYXJyZWgtU2hvcmksIFQuPC9hdXRob3I+PGF1dGhvcj5LYWRpciwg

QS48L2F1dGhvcj48YXV0aG9yPk5vcmRiZXJnLCBBLjwvYXV0aG9yPjxhdXRob3I+U3VuZHN0cm9t

LCBFLjwvYXV0aG9yPjxhdXRob3I+V2FobHVuZCwgTC4gTy48L2F1dGhvcj48YXV0aG9yPldhbGws

IEEuPC9hdXRob3I+PGF1dGhvcj5XaWJlcmcsIE0uPC9hdXRob3I+PGF1dGhvcj5XaW5ibGFkLCBC

LjwvYXV0aG9yPjxhdXRob3I+U2VpZ2VyLCBBLjwvYXV0aG9yPjxhdXRob3I+V2FobGJlcmcsIEwu

PC9hdXRob3I+PGF1dGhvcj5BbG1xdmlzdCwgUC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli

dXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2ll

bmNlcyBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCAxNzEgNzcsIFN0b2NraG9s

bSwgU3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBHZXJpYXRyaWNzLCBLYXJvbGluc2thIFVuaXZl

cnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCAxNzEgNzYsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7

RGVwYXJ0bWVudCBvZiBDbGluaWNhbCBOZXVyb3NjaWVuY2UsIEthcm9saW5za2EgSW5zdGl0dXRl

dCwgMTcxIDc3LCBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9zdXJn

ZXJ5LCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwgU29sbmEsIEJ1aWxkaW5nIFIzOjAy

LCAxNzEgNzYsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7TnNHZW5lIEluYy4sIDIyNSBDaGFwbWFu

IFN0cmVldCwgUHJvdmlkZW5jZSwgUkksIDAyOTA1LTQ1MzMsIFVTQS4mI3hEO0NsaW5pY2FsIE5l

dXJvY2hlbWlzdHJ5IExhYm9yYXRvcnksIERlcGFydG1lbnQgb2YgQ2xpbmljYWwgTmV1cm9zY2ll

bmNlLCBVbml2ZXJzaXR5IG9mIEdvdGhlbmJ1cmcsIDQxMzQ1LCBHb3RoZW5idXJnLCBTd2VkZW4u

JiN4RDtEZXBhcnRtZW50IG9mIExhYm9yYXRvcnkgTWVkaWNpbmUsIFNlY3Rpb24gb2YgUGF0aG9s

b2d5LCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIDE3MSA3NiwgU3RvY2tob2xtLCBT

d2VkZW4uJiN4RDtTdGlmdGVsc2VuIFN0b2NraG9sbXMgU2p1a2hlbSwgTWFyaWViZXJnc2dhdGFu

IDIyLCAxMTIgMzUsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBTdXJnaWNh

bCBTY2llbmNlcywgU2VjdGlvbiBvZiBOdWNsZWFyIE1lZGljaW5lIGFuZCBQRVQsIFVwcHNhbGEg

VW5pdmVyc2l0eSBIb3NwaXRhbCwgNzUxODUsIFVwcHNhbGEsIFN3ZWRlbi4mI3hEO0RlcGFydG1l

bnQgb2YgQ2xpbmljYWwgU2NpZW5jZSwgSW50ZXJ2ZW50aW9uIGFuZCBUZWNobm9sb2d5LCBEaXZp

c2lvbiBvZiBNZWRpY2FsIEltYWdpbmcgYW5kIFRlY2hub2xvZ3ksIEthcm9saW5za2EgSW5zdGl0

dXRldCwgMTcxIDc3LCBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0RlcGFydG1lbnQgb2YgUmFkaW9s

b2d5LCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIDE3MSA3NiwgU3RvY2tob2xtLCBT

d2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIENsaW5pY2FsIE5ldXJvc2NpZW5jZSwgS2Fyb2xpbnNr

YSBJbnN0aXR1dGV0LCAxNzEgNzcsIFN0b2NraG9sbSwgU3dlZGVuLiBwZXIuYWxtcXZpc3RAa2ku

c2UuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvc3VyZ2VyeSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5

IEhvc3BpdGFsIFNvbG5hLCBCdWlsZGluZyBSMzowMiwgMTcxIDc2LCBTdG9ja2hvbG0sIFN3ZWRl

bi4gcGVyLmFsbXF2aXN0QGtpLnNlLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRhcmdl

dGVkIGRlbGl2ZXJ5IG9mIG5lcnZlIGdyb3d0aCBmYWN0b3IgdG8gdGhlIGNob2xpbmVyZ2ljIGJh

c2FsIGZvcmVicmFpbiBvZiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgcGF0aWVudHM6IGFwcGxp

Y2F0aW9uIG9mIGEgc2Vjb25kLWdlbmVyYXRpb24gZW5jYXBzdWxhdGVkIGNlbGwgYmlvZGVsaXZl

cnkgZGV2aWNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFsemhlaW1lcnMgUmVzIFRoZXI8L3Nl

Y29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbHpoZWltZXJz

IFJlcyBUaGVyPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzA8L3BhZ2VzPjx2b2x1

bWU+ODwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxlZGl0aW9uPjIwMTYvMDcvMDk8L2VkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPkFjZXR5bGNob2xpbmVzdGVyYXNlL21ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9j

ZXJlYnJvc3BpbmFsIGZsdWlkL2RpYWdub3N0aWMgaW1hZ2luZy8qZHJ1ZyB0aGVyYXB5PC9rZXl3

b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9jZXJlYnJvc3BpbmFsIGZsdWlkPC9r

ZXl3b3JkPjxrZXl3b3JkPkJhc2FsIEZvcmVicmFpbi9kaWFnbm9zdGljIGltYWdpbmcvKmRydWcg

ZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5DYXBzdWxlczwva2V5d29yZD48a2V5d29yZD5DZWxs

IExpbmU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGluZSBPLUFjZXR5bHRyYW5zZmVyYXNlL2NlcmVi

cm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+Q29nbml0aW9uIERpc29yZGVycy9ldGlv

bG9neTwva2V5d29yZD48a2V5d29yZD5Db2hvcnQgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5E

b3NlLVJlc3BvbnNlIFJlbGF0aW9uc2hpcCwgRHJ1Zzwva2V5d29yZD48a2V5d29yZD4qRHJ1ZyBE

ZWxpdmVyeSBTeXN0ZW1zPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29y

ZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUg

QWdlZDwva2V5d29yZD48a2V5d29yZD5OZXJ2ZSBHcm93dGggRmFjdG9yLyphZG1pbmlzdHJhdGlv

biAmYW1wOyBkb3NhZ2U8L2tleXdvcmQ+PGtleXdvcmQ+TmVydmUgVGlzc3VlIFByb3RlaW5zL2Nl

cmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+UGVwdGlkZSBGcmFnbWVudHMvY2Vy

ZWJyb3NwaW5hbCBmbHVpZDwva2V5d29yZD48a2V5d29yZD5UcmVhdG1lbnQgT3V0Y29tZTwva2V5

d29yZD48a2V5d29yZD50YXUgUHJvdGVpbnMvY2VyZWJyb3NwaW5hbCBmbHVpZDwva2V5d29yZD48

a2V5d29yZD4qQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPipFbmNh

cHN1bGF0ZWQgY2VsbCBiaW9kZWxpdmVyeTwva2V5d29yZD48a2V5d29yZD4qTmVydmUgZ3Jvd3Ro

IGZhY3Rvcjwva2V5d29yZD48a2V5d29yZD4qUmVnZW5lcmF0aXZlIG1lZGljaW5lPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWwg

NzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE3NTgtOTE5MyAoRWxlY3Ryb25pYyk8

L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjczODk0MDI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0

ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI3Mzg5NDAy

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQ5MzYwMjA8L2N1c3RvbTI+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExODYvczEzMTk1LTAxNi0wMTk1LTk8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 153. Long-term exposure of hippocampal neurons to brain-derived neurotrophic factor (BDNF, another neurotrophin with structural similarity to NGF) modulates synaptic transmission and plasticity and effects structural changes of dendrites, spines, and presynaptic terminals. This BDNF exposure also affects the synaptic proteome, either by acting on protein synthesis machinery and/or by regulating protein degradation ADDIN EN.CITE <EndNote><Cite><Author>Bothwell</Author><Year>2014</Year><RecNum>1070</RecNum><DisplayText><style face="superscript">154</style></DisplayText><record><rec-number>1070</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865729">1070</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Bothwell, M.</author></authors></contributors><titles><title>NGF, BDNF, NT3, and NT4</title><secondary-title>Neurotrophic Factors</secondary-title></titles><pages>3-15</pages><dates><year>2014</year></dates><publisher>Springer Berlin Heidelberg</publisher><isbn>0171-2004&#xD;1865-0325&#xD;9783642451058&#xD;9783642451065</isbn><urls><related-urls><url> guide the migration of neuronal somata and axons, promote survival and differentiation of neurons and insulate and nourish neurons. Glial processes ensheath most CNS synapses and promote synapse formation and function, and secrete proteins (e.g. thrombospondins) that promote CNS synaptogenesis. Complement pathway components C1q and C3 may play a role in synaptic elimination, being upregulated in neurons exposed to astrocytes. Loss of progranulin (an endogenous antagonist of tumor necrosis factor alpha (TNF- α)) occurs in patients with frontotemporal dementia and causes lysosomal defects and excessive complement production, which triggers selective synaptic pruning by microglia and behavioral defects that can be recovered by blocking complement activation ADDIN EN.CITE <EndNote><Cite><Author>Miyamoto</Author><Year>2016</Year><RecNum>1080</RecNum><DisplayText><style face="superscript">155</style></DisplayText><record><rec-number>1080</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865729">1080</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Miyamoto, Akiko</author><author>Wake, Hiroaki</author><author>Ishikawa, Ayako Wendy</author><author>Eto, Kei</author><author>Shibata, Keisuke</author><author>Murakoshi, Hideji</author><author>Koizumi, Schuichi</author><author>Moorhouse, Andrew J.</author><author>Yoshimura, Yumiko</author><author>Nabekura, Junichi</author></authors></contributors><titles><title>Microglia contact induces synapse formation in developing somatosensory cortex</title><secondary-title>Nature Communications</secondary-title></titles><pages>12540</pages><volume>7</volume><dates><year>2016</year><pub-dates><date>2016/08/25</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>2041-1723</isbn><urls><related-urls><url>β-Estradiol (E2) promotes dendritic outgrowth, spinogenesis, and synaptogenesis in several discrete loci within the developing and adult brain. In particular, hippocampal E2 modulates memory-related synaptic plasticity not only slowly (genomically via classical nuclear receptors) but also rapidly (non-genomically via synapse-localized or extranuclear receptors) ADDIN EN.CITE <EndNote><Cite><Author>Haraguchi</Author><Year>2011</Year><RecNum>1076</RecNum><DisplayText><style face="superscript">156</style></DisplayText><record><rec-number>1076</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865729">1076</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Haraguchi, Shogo</author><author>Sasahara, Katsunori</author><author>Shikimi, Hanako</author><author>Honda, Shin-ichiro</author><author>Harada, Nobuhiro</author><author>Tsutsui, Kazuyoshi</author></authors></contributors><titles><title>Estradiol Promotes Purkinje Dendritic Growth, Spinogenesis, and Synaptogenesis During Neonatal Life by Inducing the Expression of BDNF</title><secondary-title>The Cerebellum</secondary-title></titles><pages>416-417</pages><volume>11</volume><number>2</number><dates><year>2011</year><pub-dates><date>2011/12/24</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>1473-4222&#xD;1473-4230</isbn><urls><related-urls><url>. Nanomolar concentrations of E2 bring about rapid changes in hippocampal neuron spine density and morphology. Astrocytes release glutamate in response to PGE2, which then activates glutamate receptors on neighboring neurons to modulate dendritic spine density ADDIN EN.CITE <EndNote><Cite><Author>Dave</Author><Year>2010</Year><RecNum>1073</RecNum><DisplayText><style face="superscript">157</style></DisplayText><record><rec-number>1073</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865729">1073</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dave, Kathleen A.</author><author>Platel, Jean-Claude</author><author>Huang, Frank</author><author>Tian, David</author><author>Stamboulian-Platel, Severine</author><author>Bordey, Angélique</author></authors></contributors><titles><title>Prostaglandin E2 induces glutamate release from subventricular zone astrocytes</title><secondary-title>Neuron Glia Biology</secondary-title></titles><pages>201-207</pages><volume>6</volume><number>03</number><dates><year>2010</year><pub-dates><date>2010/08</date></pub-dates></dates><publisher>Cambridge University Press (CUP)</publisher><isbn>1740-925X&#xD;1741-0533</isbn><urls><related-urls><url> is recognized to have an inflammatory component characterized by astrogliosis, microgliosis, cytokine elevation, and changes in acute phase proteins. Levels of TNF-?, a cytokine likely to play a central role in the self-propagation of neuroinflammation is increased in the brain and plasma of AD patients. TNF-??alters synaptic transmission in rat hippocampal slices, and TNF-??released by glia controls synaptic strength. From a mechanistic point of view, synaptic scaling might be invoked, having been suggested as a key component in the synaptic dysfunction of AD. Synaptic scaling involves uniform adjustments in the strength of all synaptic connections for a neuron in response to changes in the neuron’s electrical activity and is a homeostatic mechanism which serves to optimize functioning of neural networks. As glial TNF-??can regulate synaptic scaling, synaptic dysregulation caused by excess TNF-??may contribute to cognitive and behavioural deficits in AD ADDIN EN.CITE <EndNote><Cite><Author>Batti</Author><Year>2010</Year><RecNum>1068</RecNum><DisplayText><style face="superscript">158</style></DisplayText><record><rec-number>1068</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865729">1068</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Batti, Laura</author><author>O&apos;Connor, John J.</author></authors></contributors><titles><title>Tumor necrosis factor-α impairs the recovery of synaptic transmission from hypoxia in rat hippocampal slices</title><secondary-title>Journal of Neuroimmunology</secondary-title></titles><pages>21-27</pages><volume>218</volume><number>1-2</number><dates><year>2010</year><pub-dates><date>2010/01</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>0165-5728</isbn><urls><related-urls><url> summary, the dendritic spine is a primary locus of excitatory synaptic transmission in the mammalian CNS, and contains neurotransmitter receptors, organelles, and signalling systems essential for synaptic function and plasticity. Numerous disorders of the CNS, including AD, are associated with abnormal dendritic spines. A number of factors can impinge on synaptic plasticity and spine dysfunction, including Aβ, impaired glucose tolerance, lipid metabolism, steroids, kinase signalling cascades, cell adhesion molecules, neurotrophic factors, astrocytes, and inflammation. Understanding the cellular and molecular substrates underlying these age- and/or cognitive capabilities may lead to effective treatments for both age-associated memory impairment and for other, more severe cognitive impairments, in particular AD.Epigenetics and ADEpigenetics involves heritable changes in gene function not caused by mutations in DNA sequence ADDIN EN.CITE <EndNote><Cite><Author>Dupont</Author><Year>2009</Year><RecNum>1034</RecNum><DisplayText><style face="superscript">159</style></DisplayText><record><rec-number>1034</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865679">1034</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dupont, Cathérine</author><author>Armant, D.</author><author>Brenner, Carol</author></authors></contributors><titles><title>Epigenetics: Definition, Mechanisms and Clinical Perspective</title><secondary-title>Seminars in Reproductive Medicine</secondary-title></titles><pages>351-357</pages><volume>27</volume><number>05</number><dates><year>2009</year><pub-dates><date>2009/08/26</date></pub-dates></dates><publisher>Georg Thieme Verlag KG</publisher><isbn>1526-8004&#xD;1526-4564</isbn><urls><related-urls><url>. Such changes may relate to chromosomal ones that affect gene activity and expression, as well as heritable phenotypic changes that do not derive from genome modification. These effects on cellular and physiological phenotypic traits could be driven by external or environmental factors, or be part of a normal developmental program. Numerous CNS physiological functions (neural stem cell fate determination, neural plasticity, and learning and memory) have significant epigenetic components. This is the case also for neurodegenerative diseases. For example, in Alzheimer disease (AD), both genetic and non- genetic factors contribute to disease etiopathology. While over 250 gene mutations have been related to familial AD, less than 5% of AD cases are gene-related.At least three systems including DNA methylation, histone modification and non-coding RNA (ncRNA)-associated gene silencing are thought to initiate and sustain epigenetic change. More than likely non-genetic factors, probably triggered by environmental factors, are causative factors of late-onset AD. Many CNS pathologies, including AD are associated with dysregulation of DNA methylation, histone modifications (deacetylation, phosphorylation, ubiquitylation and SUMOylation), and ncRNAs ADDIN EN.CITE <EndNote><Cite><Author>Rogers</Author><Year>2011</Year><RecNum>1035</RecNum><DisplayText><style face="superscript">160</style></DisplayText><record><rec-number>1035</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865679">1035</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rogers, Joseph</author><author>Mastroeni, Diego</author><author>Grover, Andrew</author><author>Delvaux, Elaine</author><author>Whiteside, Charisse</author><author>Coleman, Paul D.</author></authors></contributors><titles><title>The epigenetics of Alzheimer&apos;s disease — additional considerations</title><secondary-title>Neurobiology of Aging</secondary-title></titles><pages>1196-1197</pages><volume>32</volume><number>7</number><dates><year>2011</year><pub-dates><date>2011/07</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>0197-4580</isbn><urls><related-urls><url>. Histone phosphorylation, in particular, appears to be part of a complex interplay between other epigenetic markers, such as histone acetylation and methylation, and DNA methylation.Indeed, histone phosphorylation increases pro-inflammatory gene activation ADDIN EN.CITE <EndNote><Cite><Author>Neal</Author><Year>2018</Year><RecNum>1036</RecNum><DisplayText><style face="superscript">161</style></DisplayText><record><rec-number>1036</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865679">1036</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Neal, Matthew</author><author>Richardson, Jason R.</author></authors></contributors><titles><title>Epigenetic regulation of astrocyte function in neuroinflammation and neurodegeneration</title><secondary-title>Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease</secondary-title></titles><pages>432-443</pages><volume>1864</volume><number>2</number><dates><year>2018</year><pub-dates><date>2018/02</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>0925-4439</isbn><urls><related-urls><url>. A number of proteins involved in AD pathology (amyloid precursor protein (APP), Tau, β-site amyloid precursor protein cleaving enzyme 1 (BACE1), glycogen synthase kinase-3β and c-Jun N- terminal kinase) are SUMO (Small Ubiquitin-like Modifier) targets ADDIN EN.CITE <EndNote><Cite><Author>Feligioni</Author><Year>2013</Year><RecNum>1037</RecNum><DisplayText><style face="superscript">162</style></DisplayText><record><rec-number>1037</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865679">1037</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Feligioni, Marco</author><author>Nisticò, Robert</author></authors></contributors><titles><title>SUMO: a (Oxidative) Stressed Protein</title><secondary-title>NeuroMolecular Medicine</secondary-title></titles><pages>707-719</pages><volume>15</volume><number>4</number><dates><year>2013</year><pub-dates><date>2013/09/20</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>1535-1084&#xD;1559-1174</isbn><urls><related-urls><url>. Furthermore, AD patients have altered levels of SUMOylation and SUMO-related protein expression ADDIN EN.CITE <EndNote><Cite><Author>Li</Author><Year>2006</Year><RecNum>1038</RecNum><DisplayText><style face="superscript">163</style></DisplayText><record><rec-number>1038</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865679">1038</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Li, Tianwei</author><author>Santockyte, Rasa</author><author>Shen, Rong-Fong</author><author>Tekle, Ephrem</author><author>Wang, Guanghui</author><author>Yang, David C. H.</author><author>Chock, P. Boon</author></authors></contributors><titles><title>Expression of SUMO-2/3 Induced Senescence through p53- and pRB-mediated Pathways</title><secondary-title>Journal of Biological Chemistry</secondary-title></titles><pages>36221-36227</pages><volume>281</volume><number>47</number><dates><year>2006</year><pub-dates><date>2006/09/29</date></pub-dates></dates><publisher>American Society for Biochemistry &amp; Molecular Biology (ASBMB)</publisher><isbn>0021-9258&#xD;1083-351X</isbn><urls><related-urls><url> the classes of ncRNA, microRNAs (miRNAs) are highly expressed in CNS neurons, where they play a major role in neuron differentiation, synaptogenesis, and plasticity. MicroRNAs impact higher cognitive functions, as their functional impairment is involved in the etiology of neurological diseases, including AD ADDIN EN.CITE <EndNote><Cite><Author>Fiore</Author><Year>2011</Year><RecNum>1039</RecNum><DisplayText><style face="superscript">164</style></DisplayText><record><rec-number>1039</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865679">1039</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Fiore, Roberto</author><author>Khudayberdiev, Sharof</author><author>Saba, Reuben</author><author>Schratt, Gerhard</author></authors></contributors><titles><title>MicroRNA Function in the Nervous System</title><secondary-title>Progress in Molecular Biology and Translational Science</secondary-title></titles><pages>47-100</pages><dates><year>2011</year></dates><publisher>Elsevier</publisher><isbn>1877-1173&#xD;9780124157958</isbn><urls><related-urls><url>. A growing body of evidence points to alterations in the miRNA network as active contributors to AD disease processes ADDIN EN.CITE <EndNote><Cite><Author>Putteeraj</Author><Year>2018</Year><RecNum>1040</RecNum><DisplayText><style face="superscript">165</style></DisplayText><record><rec-number>1040</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865679">1040</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Putteeraj, Manish</author><author>Fairuz, Yahaya Mohamad</author><author>Teoh, Seong Lin</author></authors></contributors><titles><title>MicroRNA Dysregulation in Alzheimer&apos;s Disease</title><secondary-title>CNS &amp; Neurological Disorders - Drug Targets</secondary-title></titles><volume>16</volume><number>9</number><dates><year>2018</year><pub-dates><date>2018/01/19</date></pub-dates></dates><publisher>Bentham Science Publishers Ltd.</publisher><isbn>1871-5273</isbn><urls><related-urls><url>. Alterations in the miRNA network contribute to AD disease pathogenesis by: (i) regulating expression of APP and other enzymes involved in Aβ processing, in particular BACE1. (ii) Neurofibrillary tangles in AD brain are composed mainly of hyperphosphorylated Tau, whose state of phosphorylation represents a fine balance between kinases and phosphatases, processes that may be regulated by miRNAs; (iii) regulation of lipid metabolism ADDIN EN.CITE <EndNote><Cite><Author>Goedeke</Author><Year>2014</Year><RecNum>1041</RecNum><DisplayText><style face="superscript">166</style></DisplayText><record><rec-number>1041</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865679">1041</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Goedeke, Leigh</author><author>Fernández-Hernando, Carlos</author></authors></contributors><titles><title>microRNAs: A connection between cholesterol metabolism and neurodegeneration</title><secondary-title>Neurobiology of Disease</secondary-title></titles><pages>48-53</pages><volume>72</volume><dates><year>2014</year><pub-dates><date>2014/12</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>0969-9961</isbn><urls><related-urls><url>; and (iv) neuroinflammation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZW5la2E8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS

ZWNOdW0+MTA0MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjE2Nzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEwNDI8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY3OSI+MTA0Mjwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SGVuZWthLCBNaWNoYWVsIFQuPC9hdXRo

b3I+PGF1dGhvcj5DYXJzb24sIE1vbmljYSBKLjwvYXV0aG9yPjxhdXRob3I+S2hvdXJ5LCBKb3Nl

cGggRWw8L2F1dGhvcj48YXV0aG9yPkxhbmRyZXRoLCBHYXJ5IEUuPC9hdXRob3I+PGF1dGhvcj5C

cm9zc2Vyb24sIEZyZWRlcmljPC9hdXRob3I+PGF1dGhvcj5GZWluc3RlaW4sIERvdWdsYXMgTC48

L2F1dGhvcj48YXV0aG9yPkphY29icywgQW5kcmVhcyBILjwvYXV0aG9yPjxhdXRob3I+V3lzcy1D

b3JheSwgVG9ueTwvYXV0aG9yPjxhdXRob3I+Vml0b3JpY2EsIEphdmllcjwvYXV0aG9yPjxhdXRo

b3I+UmFuc29ob2ZmLCBSaWNoYXJkIE0uPC9hdXRob3I+PGF1dGhvcj5IZXJydXAsIEthcmw8L2F1

dGhvcj48YXV0aG9yPkZyYXV0c2NoeSwgU2FsbHkgQS48L2F1dGhvcj48YXV0aG9yPkZpbnNlbiwg

QmVudGU8L2F1dGhvcj48YXV0aG9yPkJyb3duLCBHdXkgQy48L2F1dGhvcj48YXV0aG9yPlZlcmto

cmF0c2t5LCBBbGV4ZWk8L2F1dGhvcj48YXV0aG9yPllhbWFuYWthLCBLb2ppPC9hdXRob3I+PGF1

dGhvcj5Lb2lzdGluYWhvLCBKYXJpPC9hdXRob3I+PGF1dGhvcj5MYXR6LCBFaWNrZTwvYXV0aG9y

PjxhdXRob3I+SGFsbGUsIEFubmV0dDwvYXV0aG9yPjxhdXRob3I+UGV0em9sZCwgR2Fib3IgQy48

L2F1dGhvcj48YXV0aG9yPlRvd24sIFRlcnJlbmNlPC9hdXRob3I+PGF1dGhvcj5Nb3JnYW4sIERh

dmU8L2F1dGhvcj48YXV0aG9yPlNoaW5vaGFyYSwgTWFyaSBMLjwvYXV0aG9yPjxhdXRob3I+UGVy

cnksIFYuIEh1Z2g8L2F1dGhvcj48YXV0aG9yPkhvbG1lcywgQ2xpdmU8L2F1dGhvcj48YXV0aG9y

PkJhemFuLCBOaWNvbGFzIEcuPC9hdXRob3I+PGF1dGhvcj5Ccm9va3MsIERhdmlkIEouPC9hdXRo

b3I+PGF1dGhvcj5IdW5vdCwgU3TDqXBoYW5lPC9hdXRob3I+PGF1dGhvcj5Kb3NlcGgsIEJlcnRy

YW5kPC9hdXRob3I+PGF1dGhvcj5EZWlnZW5kZXNjaCwgTmlrb2xhdXM8L2F1dGhvcj48YXV0aG9y

PkdhcmFzY2h1aywgT2xnYTwvYXV0aG9yPjxhdXRob3I+Qm9kZGVrZSwgRXJpazwvYXV0aG9yPjxh

dXRob3I+RGluYXJlbGxvLCBDaGFybGVzIEEuPC9hdXRob3I+PGF1dGhvcj5CcmVpdG5lciwgSm9o

biBDLjwvYXV0aG9yPjxhdXRob3I+Q29sZSwgR3JlZyBNLjwvYXV0aG9yPjxhdXRob3I+R29sZW5i

b2NrLCBEb3VnbGFzIFQuPC9hdXRob3I+PGF1dGhvcj5LdW1tZXIsIE1hcmt1cyBQLjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5OZXVyb2luZmxhbW1hdGlv

biBpbiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+VGhl

IExhbmNldCBOZXVyb2xvZ3k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+Mzg4LTQw

NTwvcGFnZXM+PHZvbHVtZT4xNDwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxkYXRlcz48eWVh

cj4yMDE1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxNS8wNDwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxwdWJsaXNoZXI+RWxzZXZpZXIgQlY8L3B1Ymxpc2hlcj48aXNibj4xNDc0LTQ0MjI8

L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjEwMTYv

czE0NzQtNDQyMigxNSk3MDAxNi01PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJv

bmljLXJlc291cmNlLW51bT4xMC4xMDE2L3MxNDc0LTQ0MjIoMTUpNzAwMTYtNTwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZW5la2E8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS

ZWNOdW0+MTA0MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjE2Nzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEwNDI8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY3OSI+MTA0Mjwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SGVuZWthLCBNaWNoYWVsIFQuPC9hdXRo

b3I+PGF1dGhvcj5DYXJzb24sIE1vbmljYSBKLjwvYXV0aG9yPjxhdXRob3I+S2hvdXJ5LCBKb3Nl

cGggRWw8L2F1dGhvcj48YXV0aG9yPkxhbmRyZXRoLCBHYXJ5IEUuPC9hdXRob3I+PGF1dGhvcj5C

cm9zc2Vyb24sIEZyZWRlcmljPC9hdXRob3I+PGF1dGhvcj5GZWluc3RlaW4sIERvdWdsYXMgTC48

L2F1dGhvcj48YXV0aG9yPkphY29icywgQW5kcmVhcyBILjwvYXV0aG9yPjxhdXRob3I+V3lzcy1D

b3JheSwgVG9ueTwvYXV0aG9yPjxhdXRob3I+Vml0b3JpY2EsIEphdmllcjwvYXV0aG9yPjxhdXRo

b3I+UmFuc29ob2ZmLCBSaWNoYXJkIE0uPC9hdXRob3I+PGF1dGhvcj5IZXJydXAsIEthcmw8L2F1

dGhvcj48YXV0aG9yPkZyYXV0c2NoeSwgU2FsbHkgQS48L2F1dGhvcj48YXV0aG9yPkZpbnNlbiwg

QmVudGU8L2F1dGhvcj48YXV0aG9yPkJyb3duLCBHdXkgQy48L2F1dGhvcj48YXV0aG9yPlZlcmto

cmF0c2t5LCBBbGV4ZWk8L2F1dGhvcj48YXV0aG9yPllhbWFuYWthLCBLb2ppPC9hdXRob3I+PGF1

dGhvcj5Lb2lzdGluYWhvLCBKYXJpPC9hdXRob3I+PGF1dGhvcj5MYXR6LCBFaWNrZTwvYXV0aG9y

PjxhdXRob3I+SGFsbGUsIEFubmV0dDwvYXV0aG9yPjxhdXRob3I+UGV0em9sZCwgR2Fib3IgQy48

L2F1dGhvcj48YXV0aG9yPlRvd24sIFRlcnJlbmNlPC9hdXRob3I+PGF1dGhvcj5Nb3JnYW4sIERh

dmU8L2F1dGhvcj48YXV0aG9yPlNoaW5vaGFyYSwgTWFyaSBMLjwvYXV0aG9yPjxhdXRob3I+UGVy

cnksIFYuIEh1Z2g8L2F1dGhvcj48YXV0aG9yPkhvbG1lcywgQ2xpdmU8L2F1dGhvcj48YXV0aG9y

PkJhemFuLCBOaWNvbGFzIEcuPC9hdXRob3I+PGF1dGhvcj5Ccm9va3MsIERhdmlkIEouPC9hdXRo

b3I+PGF1dGhvcj5IdW5vdCwgU3TDqXBoYW5lPC9hdXRob3I+PGF1dGhvcj5Kb3NlcGgsIEJlcnRy

YW5kPC9hdXRob3I+PGF1dGhvcj5EZWlnZW5kZXNjaCwgTmlrb2xhdXM8L2F1dGhvcj48YXV0aG9y

PkdhcmFzY2h1aywgT2xnYTwvYXV0aG9yPjxhdXRob3I+Qm9kZGVrZSwgRXJpazwvYXV0aG9yPjxh

dXRob3I+RGluYXJlbGxvLCBDaGFybGVzIEEuPC9hdXRob3I+PGF1dGhvcj5CcmVpdG5lciwgSm9o

biBDLjwvYXV0aG9yPjxhdXRob3I+Q29sZSwgR3JlZyBNLjwvYXV0aG9yPjxhdXRob3I+R29sZW5i

b2NrLCBEb3VnbGFzIFQuPC9hdXRob3I+PGF1dGhvcj5LdW1tZXIsIE1hcmt1cyBQLjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5OZXVyb2luZmxhbW1hdGlv

biBpbiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+VGhl

IExhbmNldCBOZXVyb2xvZ3k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+Mzg4LTQw

NTwvcGFnZXM+PHZvbHVtZT4xNDwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxkYXRlcz48eWVh

cj4yMDE1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxNS8wNDwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxwdWJsaXNoZXI+RWxzZXZpZXIgQlY8L3B1Ymxpc2hlcj48aXNibj4xNDc0LTQ0MjI8

L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjEwMTYv

czE0NzQtNDQyMigxNSk3MDAxNi01PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJv

bmljLXJlc291cmNlLW51bT4xMC4xMDE2L3MxNDc0LTQ0MjIoMTUpNzAwMTYtNTwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 167.Understanding epigenetic dysregulation in AD could contribute to our view of the origin and progression of AD and, possibly, the development of efficacious therapeutics. However, one caveat with epigenetic studies is the issue of causality. Yet, given the failure of AD clinical trials to date, focus is now shifting to diagnose AD at as early a stage as possible, even before onset of cognitive decline. Despite the inherent difficulties, timely disease detection offers a multitude of benefits, not the least of which are opportunities for early intervention and better management of symptoms. miRNAs have emerged as potential candidates for reliable biomarkers of early-stage AD, being present in biofluids and displaying high stability in terms of storage/handling. Moreover, ncRNAs, miRNAs – and especially long ncRNAs - as therapeutic targets are only beginning to be considered. Even so, these transcripts represent potential targets for two reasons: (i) long ncRNA expression seems to be rather cell- and tissue-specific; (ii) the sequence-specific function of long ncRNA can be advantageous in designing specific therapies.Blood-Brain Barrier (BBB) targetsBlood Brain Barrier BBB is a multicellular vascular structure that separates the central nervous system (CNS) from the peripheral blood circulation. The core anatomical element of the BBB is the cerebral blood vessel formed by endothelial cells (ECs). Mural cells represented by pericytes and astrocytes sit on the abluminal surface of the microvascular endothelial tube. Astrocytes interact with neurons and microglia. Both pericytes and astrocytes interact with ECs and maintain the sealing of interendothelial tight and adherent junctions, loss of leukocyte adhesion molecules and inhibition of transcytosis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PYmVybWVpZXI8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFy

PjxSZWNOdW0+MTE1NDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjE2OC0xNzE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMTU0

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU5MTgiPjExNTQ8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iR2VuZXJpYyI+MTM8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5PYmVybWVpZXIsIEJpcmdpdDwvYXV0aG9y

PjxhdXRob3I+VmVybWEsIEFqYXk8L2F1dGhvcj48YXV0aG9yPlJhbnNvaG9mZiwgUmljaGFyZCBN

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5UaGUgYmxv

b2TigJNicmFpbiBiYXJyaWVyPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkhhbmRib29rIG9mIENs

aW5pY2FsIE5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4zOS01OTwv

cGFnZXM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2aWVy

PC9wdWJsaXNoZXI+PGlzYm4+MDA3Mi05NzUyJiN4RDs5NzgwNDQ0NjM0MzIwPC9pc2JuPjx1cmxz

PjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2I5NzgtMC00NDQt

NjM0MzItMC4wMDAwMy03PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4xMDE2L2I5NzgtMC00NDQtNjM0MzItMC4wMDAwMy03PC9lbGVjdHJvbmlj

LXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5EYW5lbWFuPC9BdXRo

b3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVtPjExNTU8L1JlY051bT48cmVjb3JkPjxyZWMtbnVt

YmVyPjExNTU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJm

d2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTkx

OCI+MTE1NTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj

bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RGFuZW1hbiwg

UmljaGFyZDwvYXV0aG9yPjxhdXRob3I+UHJhdCwgQWxleGFuZHJlPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlRoZSBCbG9vZOKAk0JyYWluIEJhcnJpZXI8

L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Q29sZCBTcHJpbmcgSGFyYm9yIFBlcnNwZWN0aXZlcyBp

biBCaW9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0

bGU+Q29sZCBTcHJpbmcgSGFyYm9yIFBlcnNwZWN0aXZlcyBpbiBCaW9sb2d5PC9mdWxsLXRpdGxl

PjwvcGVyaW9kaWNhbD48cGFnZXM+YTAyMDQxMjwvcGFnZXM+PHZvbHVtZT43PC92b2x1bWU+PG51

bWJlcj4xPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4y

MDE1LzAxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5Db2xkIFNwcmluZyBI

YXJib3IgTGFib3JhdG9yeTwvcHVibGlzaGVyPjxpc2JuPjE5NDMtMDI2NDwvaXNibj48dXJscz48

cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTEwMS9jc2hwZXJzcGVjdC5h

MDIwNDEyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4xMTAxL2NzaHBlcnNwZWN0LmEwMjA0MTI8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwv

cmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlN3ZWVuZXk8L0F1dGhvcj48WWVhcj4yMDE2PC9Z

ZWFyPjxSZWNOdW0+MTE1NjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTE1NjwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyODY1OTE4Ij4xMTU2PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Td2VlbmV5LCBNZWxhbmllIEQuPC9hdXRo

b3I+PGF1dGhvcj5BeXlhZHVyYWksIFNoaXZhPC9hdXRob3I+PGF1dGhvcj5abG9rb3ZpYywgQmVy

aXNsYXYgVi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+

UGVyaWN5dGVzIG9mIHRoZSBuZXVyb3Zhc2N1bGFyIHVuaXQ6IGtleSBmdW5jdGlvbnMgYW5kIHNp

Z25hbGluZyBwYXRod2F5czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OYXR1cmUgTmV1cm9zY2ll

bmNlPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjc3MS03ODM8L3BhZ2VzPjx2b2x1

bWU+MTk8L3ZvbHVtZT48bnVtYmVyPjY8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48

cHViLWRhdGVzPjxkYXRlPjIwMTYvMDUvMjY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVi

bGlzaGVyPlNwcmluZ2VyIE5hdHVyZTwvcHVibGlzaGVyPjxpc2JuPjEwOTctNjI1NiYjeEQ7MTU0

Ni0xNzI2PC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8x

MC4xMDM4L25uLjQyODg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjEwLjEwMzgvbm4uNDI4ODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNv

cmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Q2hlc2xvdzwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+

PFJlY051bT4xMTU3PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4xMTU3PC9yZWMtbnVtYmVy

Pjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBm

d3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU5MTgiPjExNTc8L2tleT48L2ZvcmVp

Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv

bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkNoZXNsb3csIExhcmE8L2F1dGhvcj48YXV0aG9y

PkFsdmFyZXosIEpvcmdlIEl2w6FuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0

aXRsZXM+PHRpdGxlPkdsaWFsLWVuZG90aGVsaWFsIGNyb3NzdGFsayByZWd1bGF0ZXMgYmxvb2Ti

gJNicmFpbiBiYXJyaWVyIGZ1bmN0aW9uPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkN1cnJlbnQg

T3BpbmlvbiBpbiBQaGFybWFjb2xvZ3k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+

MzktNDY8L3BhZ2VzPjx2b2x1bWU+MjY8L3ZvbHVtZT48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48

cHViLWRhdGVzPjxkYXRlPjIwMTYvMDI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlz

aGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MTQ3MS00ODkyPC9pc2JuPjx1cmxzPjxy

ZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2ouY29waC4yMDE1LjA5

LjAxMDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

MTAuMTAxNi9qLmNvcGguMjAxNS4wOS4wMTA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVj

b3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PYmVybWVpZXI8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFy

PjxSZWNOdW0+MTE1NDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjE2OC0xNzE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMTU0

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU5MTgiPjExNTQ8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iR2VuZXJpYyI+MTM8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5PYmVybWVpZXIsIEJpcmdpdDwvYXV0aG9y

PjxhdXRob3I+VmVybWEsIEFqYXk8L2F1dGhvcj48YXV0aG9yPlJhbnNvaG9mZiwgUmljaGFyZCBN

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5UaGUgYmxv

b2TigJNicmFpbiBiYXJyaWVyPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkhhbmRib29rIG9mIENs

aW5pY2FsIE5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4zOS01OTwv

cGFnZXM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2aWVy

PC9wdWJsaXNoZXI+PGlzYm4+MDA3Mi05NzUyJiN4RDs5NzgwNDQ0NjM0MzIwPC9pc2JuPjx1cmxz

PjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2I5NzgtMC00NDQt

NjM0MzItMC4wMDAwMy03PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4xMDE2L2I5NzgtMC00NDQtNjM0MzItMC4wMDAwMy03PC9lbGVjdHJvbmlj

LXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5EYW5lbWFuPC9BdXRo

b3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVtPjExNTU8L1JlY051bT48cmVjb3JkPjxyZWMtbnVt

YmVyPjExNTU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJm

d2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTkx

OCI+MTE1NTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj

bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RGFuZW1hbiwg

UmljaGFyZDwvYXV0aG9yPjxhdXRob3I+UHJhdCwgQWxleGFuZHJlPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlRoZSBCbG9vZOKAk0JyYWluIEJhcnJpZXI8

L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Q29sZCBTcHJpbmcgSGFyYm9yIFBlcnNwZWN0aXZlcyBp

biBCaW9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0

bGU+Q29sZCBTcHJpbmcgSGFyYm9yIFBlcnNwZWN0aXZlcyBpbiBCaW9sb2d5PC9mdWxsLXRpdGxl

PjwvcGVyaW9kaWNhbD48cGFnZXM+YTAyMDQxMjwvcGFnZXM+PHZvbHVtZT43PC92b2x1bWU+PG51

bWJlcj4xPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4y

MDE1LzAxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5Db2xkIFNwcmluZyBI

YXJib3IgTGFib3JhdG9yeTwvcHVibGlzaGVyPjxpc2JuPjE5NDMtMDI2NDwvaXNibj48dXJscz48

cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTEwMS9jc2hwZXJzcGVjdC5h

MDIwNDEyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4xMTAxL2NzaHBlcnNwZWN0LmEwMjA0MTI8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwv

cmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlN3ZWVuZXk8L0F1dGhvcj48WWVhcj4yMDE2PC9Z

ZWFyPjxSZWNOdW0+MTE1NjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTE1NjwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyODY1OTE4Ij4xMTU2PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Td2VlbmV5LCBNZWxhbmllIEQuPC9hdXRo

b3I+PGF1dGhvcj5BeXlhZHVyYWksIFNoaXZhPC9hdXRob3I+PGF1dGhvcj5abG9rb3ZpYywgQmVy

aXNsYXYgVi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+

UGVyaWN5dGVzIG9mIHRoZSBuZXVyb3Zhc2N1bGFyIHVuaXQ6IGtleSBmdW5jdGlvbnMgYW5kIHNp

Z25hbGluZyBwYXRod2F5czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OYXR1cmUgTmV1cm9zY2ll

bmNlPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjc3MS03ODM8L3BhZ2VzPjx2b2x1

bWU+MTk8L3ZvbHVtZT48bnVtYmVyPjY8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48

cHViLWRhdGVzPjxkYXRlPjIwMTYvMDUvMjY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVi

bGlzaGVyPlNwcmluZ2VyIE5hdHVyZTwvcHVibGlzaGVyPjxpc2JuPjEwOTctNjI1NiYjeEQ7MTU0

Ni0xNzI2PC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8x

MC4xMDM4L25uLjQyODg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjEwLjEwMzgvbm4uNDI4ODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNv

cmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Q2hlc2xvdzwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+

PFJlY051bT4xMTU3PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4xMTU3PC9yZWMtbnVtYmVy

Pjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBm

d3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU5MTgiPjExNTc8L2tleT48L2ZvcmVp

Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv

bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkNoZXNsb3csIExhcmE8L2F1dGhvcj48YXV0aG9y

PkFsdmFyZXosIEpvcmdlIEl2w6FuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0

aXRsZXM+PHRpdGxlPkdsaWFsLWVuZG90aGVsaWFsIGNyb3NzdGFsayByZWd1bGF0ZXMgYmxvb2Ti

gJNicmFpbiBiYXJyaWVyIGZ1bmN0aW9uPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkN1cnJlbnQg

T3BpbmlvbiBpbiBQaGFybWFjb2xvZ3k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+

MzktNDY8L3BhZ2VzPjx2b2x1bWU+MjY8L3ZvbHVtZT48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48

cHViLWRhdGVzPjxkYXRlPjIwMTYvMDI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlz

aGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MTQ3MS00ODkyPC9pc2JuPjx1cmxzPjxy

ZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2ouY29waC4yMDE1LjA5

LjAxMDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

MTAuMTAxNi9qLmNvcGguMjAxNS4wOS4wMTA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVj

b3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 168-171. The vascular tube is surrounded by two basement membranes, the endothelial vascular basement membrane corresponded to an extracellular matrix secreted by the ECs and pericytes, and the parenchymal basement membrane primarily secreted by astrocytic processes that extend toward the vasculature. The molecular components of these basement membranes also contribute to the complexity of the barrier ADDIN EN.CITE <EndNote><Cite><Author>Zhao</Author><Year>2015</Year><RecNum>1158</RecNum><DisplayText><style face="superscript">172</style></DisplayText><record><rec-number>1158</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1158</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zhao, Zhen</author><author>Nelson, Amy R.</author><author>Betsholtz, Christer</author><author>Zlokovic, Berislav V.</author></authors></contributors><titles><title>Establishment and Dysfunction of the Blood-Brain Barrier</title><secondary-title>Cell</secondary-title></titles><periodical><full-title>Cell</full-title></periodical><pages>1064-1078</pages><volume>163</volume><number>5</number><dates><year>2015</year><pub-dates><date>2015/11</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>0092-8674</isbn><urls><related-urls><url> these complex cellular interactions which correspond to the neurovascular unit instead of BBB, endothelial cells express different types of transporters and receptors among which some are involved in the efflux and influx of the amyloid peptide ADDIN EN.CITE <EndNote><Cite><Author>Mahringer</Author><Year>2016</Year><RecNum>1160</RecNum><DisplayText><style face="superscript">173,174</style></DisplayText><record><rec-number>1160</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1160</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mahringer, Anne</author><author>Fricker, Gert</author></authors></contributors><titles><title>ABC transporters at the blood–brain barrier</title><secondary-title>Expert Opinion on Drug Metabolism &amp; Toxicology</secondary-title></titles><pages>499-508</pages><volume>12</volume><number>5</number><dates><year>2016</year><pub-dates><date>2016/04/04</date></pub-dates></dates><publisher>Informa Healthcare</publisher><isbn>1742-5255&#xD;1744-7607</isbn><urls><related-urls><url> app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1159</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zlokovic, Berislav V.</author></authors></contributors><titles><title>Neurovascular pathways to neurodegeneration in Alzheimer&apos;s disease and other disorders</title><secondary-title>Nature Reviews Neuroscience</secondary-title></titles><pages>723-738</pages><volume>12</volume><number>12</number><dates><year>2011</year><pub-dates><date>2011/11/03</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>1471-003X&#xD;1471-0048</isbn><urls><related-urls><url>. Beyond barrier function, influx and efflux are actively regulated at the blood-brain interface. Moreover, recent research have uncovered different transcription factors involved in phenotype change (zonation) along the vessels of the BBB PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYW5sYW5kZXdpamNrPC9BdXRob3I+PFllYXI+MjAxODwv

WWVhcj48UmVjTnVtPjQ2NDM8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVy

c2NyaXB0Ij4xNzU8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40NjQz

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDM5MzY1NDUiPjQ2NDM8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlZhbmxhbmRld2lqY2ssIE0u

PC9hdXRob3I+PGF1dGhvcj5IZSwgTC48L2F1dGhvcj48YXV0aG9yPk1hZSwgTS4gQS48L2F1dGhv

cj48YXV0aG9yPkFuZHJhZSwgSi48L2F1dGhvcj48YXV0aG9yPkFuZG8sIEsuPC9hdXRob3I+PGF1

dGhvcj5EZWwgR2F1ZGlvLCBGLjwvYXV0aG9yPjxhdXRob3I+TmFoYXIsIEsuPC9hdXRob3I+PGF1

dGhvcj5MZWJvdXZpZXIsIFQuPC9hdXRob3I+PGF1dGhvcj5MYXZpbmEsIEIuPC9hdXRob3I+PGF1

dGhvcj5Hb3V2ZWlhLCBMLjwvYXV0aG9yPjxhdXRob3I+U3VuLCBZLjwvYXV0aG9yPjxhdXRob3I+

UmFzY2hwZXJnZXIsIEUuPC9hdXRob3I+PGF1dGhvcj5SYXNhbmVuLCBNLjwvYXV0aG9yPjxhdXRo

b3I+WmFyYiwgWS48L2F1dGhvcj48YXV0aG9yPk1vY2hpenVraSwgTi48L2F1dGhvcj48YXV0aG9y

PktlbGxlciwgQS48L2F1dGhvcj48YXV0aG9yPkxlbmRhaGwsIFUuPC9hdXRob3I+PGF1dGhvcj5C

ZXRzaG9sdHosIEMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJl

c3M+S2Fyb2xpbnNrYSBJbnN0aXR1dGV0L0FzdHJhWmVuZWNhIEludGVncmF0ZWQgQ2FyZGlvIE1l

dGFib2xpYyBDZW50cmUgKEtJL0FaIElDTUMpLCBCbGlja2FnYW5nZW4gNiwgU0UtMTQxIDU3IEh1

ZGRpbmdlLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIEltbXVub2xvZ3ksIEdlbmV0aWNzIGFu

ZCBQYXRob2xvZ3ksIFJ1ZGJlY2sgTGFib3JhdG9yeSwgVXBwc2FsYSBVbml2ZXJzaXR5LCBEYWcg

SGFtbWFyc2tqb2xkcyB2YWcgMjAsIFNFLTc1MSA4NSBVcHBzYWxhLCBTd2VkZW4uJiN4RDtEZXBh

cnRtZW50IG9mIE5ldXJvc3VyZ2VyeSwgVGlhbmppbiBNZWRpY2FsIFVuaXZlcnNpdHkgR2VuZXJh

bCBIb3NwaXRhbCwgVGlhbmppbiBOZXVyb2xvZ2ljYWwgSW5zdGl0dXRlLCBLZXkgTGFib3JhdG9y

eSBvZiBQb3N0LU5ldXJvaW5qdXJ5IE5ldXJvLVJlcGFpciBhbmQgUmVnZW5lcmF0aW9uIGluIENl

bnRyYWwgTmVydm91cyBTeXN0ZW0sIE1pbmlzdHJ5IG9mIEVkdWNhdGlvbiBhbmQgVGlhbmppbiBD

aXR5LCBUaWFuamluIDMwMDA1MiwgQ2hpbmEuJiN4RDtEZXBhcnRtZW50IG9mIENlbGwgYW5kIE1v

bGVjdWxhciBCaW9sb2d5LCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFZvbiBFdWxlcnMgdmFnIDMs

IFNFLTE3MSA3NyBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0luc2VybSBVMTE3MSwgVW5pdmVyc2l0

eSBvZiBMaWxsZSwgQ0hVLCBNZW1vcnkgQ2VudGVyLCBEaXN0YWx6LCBGLTU5MDAwIExpbGxlLCBG

cmFuY2UuJiN4RDtEZXBhcnRtZW50IG9mIEJpb2luZm9ybWF0aWNzLCBaaG9uZ3l1YW4gVW5pb24g

R2VuZXRpYyBUZWNobm9sb2d5IENvLiwgTHRkLiwgTm8uNDUsIHRoZSA5dGggRWFzdCBSb2FkLCBU

aWFuamluIEFpcnBvcnQgRWNvbm9taWMgQXJlYSwgVGlhbmppbiAzMDAzMDQsIENoaW5hLiYjeEQ7

V2lodXJpIFJlc2VhcmNoIEluc3RpdHV0ZSBhbmQgVHJhbnNsYXRpb25hbCBDYW5jZXIgQmlvbG9n

eSBQcm9ncmFtLCBCaW9tZWRpY3VtIEhlbHNpbmtpLCBVbml2ZXJzaXR5IG9mIEhlbHNpbmtpLCBI

YWFydG1hbmlua2F0dSA4LCBQLk8uIEJveCA2MywgRkktMDAwMTQgSGVsc2lua2ksIEZpbmxhbmQu

JiN4RDtEaXZpc2lvbiBvZiBOZXVyb3N1cmdlcnksIFp1cmljaCBVbml2ZXJzaXR5IEhvc3BpdGFs

LCBadXJpY2ggVW5pdmVyc2l0eSwgWnVyaWNoLCBDSC04MDkxLCBTd2l0emVybGFuZC4mI3hEO0Rl

cGFydG1lbnQgb2YgQ2VsbCBCaW9sb2d5LCBOYXRpb25hbCBDZXJlYnJhbCBhbmQgQ2FyZGlvdmFz

Y3VsYXIgQ2VudGVyIFJlc2VhcmNoIEluc3RpdHV0ZSwgU3VpdGEsIE9zYWthLCBKYXBhbi4mI3hE

O0FNRUQtQ1JFU1QsIE5hdGlvbmFsIENlcmVicmFsIGFuZCBDYXJkaW92YXNjdWxhciBDZW50ZXIs

IFN1aXRhLCBPc2FrYSwgSmFwYW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QSBtb2xl

Y3VsYXIgYXRsYXMgb2YgY2VsbCB0eXBlcyBhbmQgem9uYXRpb24gaW4gdGhlIGJyYWluIHZhc2N1

bGF0dXJlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5hdHVyZTwvc2Vjb25kYXJ5LXRpdGxlPjwv

dGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5hdHVyZTwvZnVsbC10aXRsZT48L3Blcmlv

ZGljYWw+PHBhZ2VzPjQ3NS00ODA8L3BhZ2VzPjx2b2x1bWU+NTU0PC92b2x1bWU+PG51bWJlcj43

NjkzPC9udW1iZXI+PGVkaXRpb24+MjAxOC8wMi8xNTwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdv

cmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BcnRlcmllcy9jeXRvbG9neTwva2V5d29yZD48

a2V5d29yZD5BcnRlcmlvbGVzL2N5dG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJsb29kIFZlc3Nl

bHMvKmN5dG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluLypibG9vZCBzdXBwbHkvKmN5dG9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNhcGlsbGFyaWVzL2N5dG9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPkVuZG90aGVsaWFsIENlbGxzLypjbGFzc2lmaWNhdGlvbjwva2V5d29yZD48a2V5d29yZD5G

ZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+Rmlicm9ibGFzdHMvY2xhc3NpZmljYXRpb248L2tleXdv

cmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3Jk

Pk15b2N5dGVzLCBTbW9vdGggTXVzY2xlL2NsYXNzaWZpY2F0aW9uPC9rZXl3b3JkPjxrZXl3b3Jk

Pk9yZ2FuIFNwZWNpZmljaXR5PC9rZXl3b3JkPjxrZXl3b3JkPlBlcmljeXRlcy9jbGFzc2lmaWNh

dGlvbjwva2V5d29yZD48a2V5d29yZD5TaW5nbGUtQ2VsbCBBbmFseXNpczwva2V5d29yZD48a2V5

d29yZD5UcmFuc2NyaXB0b21lPC9rZXl3b3JkPjxrZXl3b3JkPlZlaW5zL2N5dG9sb2d5PC9rZXl3

b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5G

ZWIgMjI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDc2LTQ2ODcgKEVsZWN0cm9u

aWMpJiN4RDswMDI4LTA4MzYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5NDQzOTY1

PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3B1Ym1lZC8yOTQ0Mzk2NTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9uYXR1cmUyNTczOTwvZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYW5sYW5kZXdpamNrPC9BdXRob3I+PFllYXI+MjAxODwv

WWVhcj48UmVjTnVtPjQ2NDM8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVy

c2NyaXB0Ij4xNzU8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40NjQz

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDM5MzY1NDUiPjQ2NDM8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlZhbmxhbmRld2lqY2ssIE0u

PC9hdXRob3I+PGF1dGhvcj5IZSwgTC48L2F1dGhvcj48YXV0aG9yPk1hZSwgTS4gQS48L2F1dGhv

cj48YXV0aG9yPkFuZHJhZSwgSi48L2F1dGhvcj48YXV0aG9yPkFuZG8sIEsuPC9hdXRob3I+PGF1

dGhvcj5EZWwgR2F1ZGlvLCBGLjwvYXV0aG9yPjxhdXRob3I+TmFoYXIsIEsuPC9hdXRob3I+PGF1

dGhvcj5MZWJvdXZpZXIsIFQuPC9hdXRob3I+PGF1dGhvcj5MYXZpbmEsIEIuPC9hdXRob3I+PGF1

dGhvcj5Hb3V2ZWlhLCBMLjwvYXV0aG9yPjxhdXRob3I+U3VuLCBZLjwvYXV0aG9yPjxhdXRob3I+

UmFzY2hwZXJnZXIsIEUuPC9hdXRob3I+PGF1dGhvcj5SYXNhbmVuLCBNLjwvYXV0aG9yPjxhdXRo

b3I+WmFyYiwgWS48L2F1dGhvcj48YXV0aG9yPk1vY2hpenVraSwgTi48L2F1dGhvcj48YXV0aG9y

PktlbGxlciwgQS48L2F1dGhvcj48YXV0aG9yPkxlbmRhaGwsIFUuPC9hdXRob3I+PGF1dGhvcj5C

ZXRzaG9sdHosIEMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJl

c3M+S2Fyb2xpbnNrYSBJbnN0aXR1dGV0L0FzdHJhWmVuZWNhIEludGVncmF0ZWQgQ2FyZGlvIE1l

dGFib2xpYyBDZW50cmUgKEtJL0FaIElDTUMpLCBCbGlja2FnYW5nZW4gNiwgU0UtMTQxIDU3IEh1

ZGRpbmdlLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIEltbXVub2xvZ3ksIEdlbmV0aWNzIGFu

ZCBQYXRob2xvZ3ksIFJ1ZGJlY2sgTGFib3JhdG9yeSwgVXBwc2FsYSBVbml2ZXJzaXR5LCBEYWcg

SGFtbWFyc2tqb2xkcyB2YWcgMjAsIFNFLTc1MSA4NSBVcHBzYWxhLCBTd2VkZW4uJiN4RDtEZXBh

cnRtZW50IG9mIE5ldXJvc3VyZ2VyeSwgVGlhbmppbiBNZWRpY2FsIFVuaXZlcnNpdHkgR2VuZXJh

bCBIb3NwaXRhbCwgVGlhbmppbiBOZXVyb2xvZ2ljYWwgSW5zdGl0dXRlLCBLZXkgTGFib3JhdG9y

eSBvZiBQb3N0LU5ldXJvaW5qdXJ5IE5ldXJvLVJlcGFpciBhbmQgUmVnZW5lcmF0aW9uIGluIENl

bnRyYWwgTmVydm91cyBTeXN0ZW0sIE1pbmlzdHJ5IG9mIEVkdWNhdGlvbiBhbmQgVGlhbmppbiBD

aXR5LCBUaWFuamluIDMwMDA1MiwgQ2hpbmEuJiN4RDtEZXBhcnRtZW50IG9mIENlbGwgYW5kIE1v

bGVjdWxhciBCaW9sb2d5LCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFZvbiBFdWxlcnMgdmFnIDMs

IFNFLTE3MSA3NyBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0luc2VybSBVMTE3MSwgVW5pdmVyc2l0

eSBvZiBMaWxsZSwgQ0hVLCBNZW1vcnkgQ2VudGVyLCBEaXN0YWx6LCBGLTU5MDAwIExpbGxlLCBG

cmFuY2UuJiN4RDtEZXBhcnRtZW50IG9mIEJpb2luZm9ybWF0aWNzLCBaaG9uZ3l1YW4gVW5pb24g

R2VuZXRpYyBUZWNobm9sb2d5IENvLiwgTHRkLiwgTm8uNDUsIHRoZSA5dGggRWFzdCBSb2FkLCBU

aWFuamluIEFpcnBvcnQgRWNvbm9taWMgQXJlYSwgVGlhbmppbiAzMDAzMDQsIENoaW5hLiYjeEQ7

V2lodXJpIFJlc2VhcmNoIEluc3RpdHV0ZSBhbmQgVHJhbnNsYXRpb25hbCBDYW5jZXIgQmlvbG9n

eSBQcm9ncmFtLCBCaW9tZWRpY3VtIEhlbHNpbmtpLCBVbml2ZXJzaXR5IG9mIEhlbHNpbmtpLCBI

YWFydG1hbmlua2F0dSA4LCBQLk8uIEJveCA2MywgRkktMDAwMTQgSGVsc2lua2ksIEZpbmxhbmQu

JiN4RDtEaXZpc2lvbiBvZiBOZXVyb3N1cmdlcnksIFp1cmljaCBVbml2ZXJzaXR5IEhvc3BpdGFs

LCBadXJpY2ggVW5pdmVyc2l0eSwgWnVyaWNoLCBDSC04MDkxLCBTd2l0emVybGFuZC4mI3hEO0Rl

cGFydG1lbnQgb2YgQ2VsbCBCaW9sb2d5LCBOYXRpb25hbCBDZXJlYnJhbCBhbmQgQ2FyZGlvdmFz

Y3VsYXIgQ2VudGVyIFJlc2VhcmNoIEluc3RpdHV0ZSwgU3VpdGEsIE9zYWthLCBKYXBhbi4mI3hE

O0FNRUQtQ1JFU1QsIE5hdGlvbmFsIENlcmVicmFsIGFuZCBDYXJkaW92YXNjdWxhciBDZW50ZXIs

IFN1aXRhLCBPc2FrYSwgSmFwYW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QSBtb2xl

Y3VsYXIgYXRsYXMgb2YgY2VsbCB0eXBlcyBhbmQgem9uYXRpb24gaW4gdGhlIGJyYWluIHZhc2N1

bGF0dXJlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5hdHVyZTwvc2Vjb25kYXJ5LXRpdGxlPjwv

dGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5hdHVyZTwvZnVsbC10aXRsZT48L3Blcmlv

ZGljYWw+PHBhZ2VzPjQ3NS00ODA8L3BhZ2VzPjx2b2x1bWU+NTU0PC92b2x1bWU+PG51bWJlcj43

NjkzPC9udW1iZXI+PGVkaXRpb24+MjAxOC8wMi8xNTwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdv

cmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BcnRlcmllcy9jeXRvbG9neTwva2V5d29yZD48

a2V5d29yZD5BcnRlcmlvbGVzL2N5dG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJsb29kIFZlc3Nl

bHMvKmN5dG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluLypibG9vZCBzdXBwbHkvKmN5dG9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNhcGlsbGFyaWVzL2N5dG9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPkVuZG90aGVsaWFsIENlbGxzLypjbGFzc2lmaWNhdGlvbjwva2V5d29yZD48a2V5d29yZD5G

ZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+Rmlicm9ibGFzdHMvY2xhc3NpZmljYXRpb248L2tleXdv

cmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3Jk

Pk15b2N5dGVzLCBTbW9vdGggTXVzY2xlL2NsYXNzaWZpY2F0aW9uPC9rZXl3b3JkPjxrZXl3b3Jk

Pk9yZ2FuIFNwZWNpZmljaXR5PC9rZXl3b3JkPjxrZXl3b3JkPlBlcmljeXRlcy9jbGFzc2lmaWNh

dGlvbjwva2V5d29yZD48a2V5d29yZD5TaW5nbGUtQ2VsbCBBbmFseXNpczwva2V5d29yZD48a2V5

d29yZD5UcmFuc2NyaXB0b21lPC9rZXl3b3JkPjxrZXl3b3JkPlZlaW5zL2N5dG9sb2d5PC9rZXl3

b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5G

ZWIgMjI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDc2LTQ2ODcgKEVsZWN0cm9u

aWMpJiN4RDswMDI4LTA4MzYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5NDQzOTY1

PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3B1Ym1lZC8yOTQ0Mzk2NTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9uYXR1cmUyNTczOTwvZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 175. The BBB maintains an environment that allows neurons to function properly by tightly controlling the passage of molecules and ions, instantaneously delivering nutrients and oxygen according to current neuronal needs, and by protecting the brain from toxins and pathogens.In conclusion, we now know that the cellular and molecular complexity of the BBB explains that the dysfunction of a cellular or molecular actor can disrupt its dynamics, although the precise process is unclear ADDIN EN.CITE <EndNote><Cite><Author>Erd?</Author><Year>2016</Year><RecNum>1161</RecNum><DisplayText><style face="superscript">176</style></DisplayText><record><rec-number>1161</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1161</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Erd?, Franciska</author><author>Denes, László</author><author>de Lange, Elizabeth</author></authors></contributors><titles><title>Age-associated physiological and pathological changes at the blood–brain barrier: A review</title><secondary-title>Journal of Cerebral Blood Flow &amp; Metabolism</secondary-title></titles><pages>4-24</pages><volume>37</volume><number>1</number><dates><year>2016</year><pub-dates><date>2016/11/13</date></pub-dates></dates><publisher>SAGE Publications</publisher><isbn>0271-678X&#xD;1559-7016</isbn><urls><related-urls><url>. Recently, it has been shown that pericytes control white-matter structure and function, which has implications for the pathogenesis and treatment of human white-matter disease associated with small-vessel disease ADDIN EN.CITE <EndNote><Cite><Author>Montagne</Author><Year>2016</Year><RecNum>1164</RecNum><DisplayText><style face="superscript">177</style></DisplayText><record><rec-number>1164</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1164</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Montagne, Axel</author><author>Nation, Daniel A.</author><author>Pa, Judy</author><author>Sweeney, Melanie D.</author><author>Toga, Arthur W.</author><author>Zlokovic, Berislav V.</author></authors></contributors><titles><title>Brain imaging of neurovascular dysfunction in Alzheimer’s disease</title><secondary-title>Acta Neuropathologica</secondary-title></titles><periodical><full-title>Acta Neuropathologica</full-title></periodical><pages>687-707</pages><volume>131</volume><number>5</number><dates><year>2016</year><pub-dates><date>2016/04/01</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>0001-6322&#xD;1432-0533</isbn><urls><related-urls><url> Barrier in ADSeveral impairments of the neurovascular unit have been described in Alzheimer's disease (AD), but the time-point at which they occur during disease pathogenesis remains unclear because they are too often seen in post-mortem brains. However, for the past 3 years, medical imaging has demonstrated the early BBB disruption in the hippocampus even before the onset of hippocampal atrophy ADDIN EN.CITE <EndNote><Cite><Author>van de Haar</Author><Year>2016</Year><RecNum>1163</RecNum><DisplayText><style face="superscript">178</style></DisplayText><record><rec-number>1163</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1163</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>van de Haar, Harm J.</author><author>Burgmans, Saartje</author><author>Jansen, Jacobus F. A.</author><author>van Osch, Matthias J. P.</author><author>van Buchem, Mark A.</author><author>Muller, Majon</author><author>Hofman, Paul A. M.</author><author>Verhey, Frans R. J.</author><author>Backes, Walter H.</author></authors></contributors><titles><title>Blood-Brain Barrier Leakage in Patients with Early Alzheimer Disease</title><secondary-title>Radiology</secondary-title></titles><pages>527-535</pages><volume>281</volume><number>2</number><dates><year>2016</year><pub-dates><date>2016/11</date></pub-dates></dates><publisher>Radiological Society of North America (RSNA)</publisher><isbn>0033-8419&#xD;1527-1315</isbn><urls><related-urls><url>. In addition, many studies indicated cerebral microbleeds (micro hemorrhages) in AD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Td2VlbmV5PC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48

UmVjTnVtPjExNjU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4xNzksMTgwPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTE2NTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyODY1OTE4Ij4xMTY1PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Td2VlbmV5LCBNZWxhbmllIEQu

PC9hdXRob3I+PGF1dGhvcj5TYWdhcmUsIEFiaGF5IFAuPC9hdXRob3I+PGF1dGhvcj5abG9rb3Zp

YywgQmVyaXNsYXYgVi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48

dGl0bGU+Qmxvb2TigJNicmFpbiBiYXJyaWVyIGJyZWFrZG93biBpbiBBbHpoZWltZXIgZGlzZWFz

ZSBhbmQgb3RoZXIgbmV1cm9kZWdlbmVyYXRpdmUgZGlzb3JkZXJzPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPk5hdHVyZSBSZXZpZXdzIE5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwYWdlcz4xMzMtMTUwPC9wYWdlcz48dm9sdW1lPjE0PC92b2x1bWU+PG51bWJlcj4zPC9udW1i

ZXI+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDE4LzAxLzI5PC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5TcHJpbmdlciBOYXR1cmU8L3B1Ymxp

c2hlcj48aXNibj4xNzU5LTQ3NTgmI3hEOzE3NTktNDc2NjwvaXNibj48dXJscz48cmVsYXRlZC11

cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAzOC9ucm5ldXJvbC4yMDE3LjE4ODwvdXJs

PjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9u

cm5ldXJvbC4yMDE3LjE4ODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRl

PjxDaXRlPjxBdXRob3I+UG9saWFrb3ZhPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVjTnVt

PjExNjY8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjExNjY8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTkxOCI+MTE2Njwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+UG9saWFrb3ZhLCBULjwvYXV0aG9yPjxhdXRob3I+TGV2aW4s

IE8uPC9hdXRob3I+PGF1dGhvcj5BcmFibGluc2tpeSwgQS48L2F1dGhvcj48YXV0aG9yPlZhc2Vu

aW5hLCBFLjwvYXV0aG9yPjxhdXRob3I+WmVyciwgSS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+Q2VyZWJyYWwgbWljcm9ibGVlZHMgaW4gZWFybHkgQWx6

aGVpbWVy4oCZcyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkpvdXJuYWwgb2YgTmV1

cm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjE5NjEtMTk2ODwvcGFnZXM+

PHZvbHVtZT4yNjM8L3ZvbHVtZT48bnVtYmVyPjEwPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTY8

L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDE2LzA3LzA3PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0

ZXM+PHB1Ymxpc2hlcj5TcHJpbmdlciBOYXR1cmU8L3B1Ymxpc2hlcj48aXNibj4wMzQwLTUzNTQm

I3hEOzE0MzItMTQ1OTwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRv

aS5vcmcvMTAuMTAwNy9zMDA0MTUtMDE2LTgyMjAtMjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMDA0MTUtMDE2LTgyMjAtMjwvZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Td2VlbmV5PC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48

UmVjTnVtPjExNjU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4xNzksMTgwPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTE2NTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyODY1OTE4Ij4xMTY1PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Td2VlbmV5LCBNZWxhbmllIEQu

PC9hdXRob3I+PGF1dGhvcj5TYWdhcmUsIEFiaGF5IFAuPC9hdXRob3I+PGF1dGhvcj5abG9rb3Zp

YywgQmVyaXNsYXYgVi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48

dGl0bGU+Qmxvb2TigJNicmFpbiBiYXJyaWVyIGJyZWFrZG93biBpbiBBbHpoZWltZXIgZGlzZWFz

ZSBhbmQgb3RoZXIgbmV1cm9kZWdlbmVyYXRpdmUgZGlzb3JkZXJzPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPk5hdHVyZSBSZXZpZXdzIE5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwYWdlcz4xMzMtMTUwPC9wYWdlcz48dm9sdW1lPjE0PC92b2x1bWU+PG51bWJlcj4zPC9udW1i

ZXI+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDE4LzAxLzI5PC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5TcHJpbmdlciBOYXR1cmU8L3B1Ymxp

c2hlcj48aXNibj4xNzU5LTQ3NTgmI3hEOzE3NTktNDc2NjwvaXNibj48dXJscz48cmVsYXRlZC11

cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAzOC9ucm5ldXJvbC4yMDE3LjE4ODwvdXJs

PjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9u

cm5ldXJvbC4yMDE3LjE4ODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRl

PjxDaXRlPjxBdXRob3I+UG9saWFrb3ZhPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVjTnVt

PjExNjY8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjExNjY8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTkxOCI+MTE2Njwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+UG9saWFrb3ZhLCBULjwvYXV0aG9yPjxhdXRob3I+TGV2aW4s

IE8uPC9hdXRob3I+PGF1dGhvcj5BcmFibGluc2tpeSwgQS48L2F1dGhvcj48YXV0aG9yPlZhc2Vu

aW5hLCBFLjwvYXV0aG9yPjxhdXRob3I+WmVyciwgSS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+Q2VyZWJyYWwgbWljcm9ibGVlZHMgaW4gZWFybHkgQWx6

aGVpbWVy4oCZcyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkpvdXJuYWwgb2YgTmV1

cm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjE5NjEtMTk2ODwvcGFnZXM+

PHZvbHVtZT4yNjM8L3ZvbHVtZT48bnVtYmVyPjEwPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTY8

L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDE2LzA3LzA3PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0

ZXM+PHB1Ymxpc2hlcj5TcHJpbmdlciBOYXR1cmU8L3B1Ymxpc2hlcj48aXNibj4wMzQwLTUzNTQm

I3hEOzE0MzItMTQ1OTwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRv

aS5vcmcvMTAuMTAwNy9zMDA0MTUtMDE2LTgyMjAtMjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMDA0MTUtMDE2LTgyMjAtMjwvZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 179,180. Compared with controls, BBB P-glycoprotein activity was significantly lower in the parietotemporal, frontal, and posterior cingulate cortices and hippocampus of mild AD subjects by PET-scan ADDIN EN.CITE <EndNote><Cite><Author>Deo</Author><Year>2014</Year><RecNum>1167</RecNum><DisplayText><style face="superscript">181</style></DisplayText><record><rec-number>1167</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1167</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Deo, A. K.</author><author>Borson, S.</author><author>Link, J. M.</author><author>Domino, K.</author><author>Eary, J. F.</author><author>Ke, B.</author><author>Richards, T. L.</author><author>Mankoff, D. A.</author><author>Minoshima, S.</author><author>O&apos;Sullivan, F.</author><author>Eyal, S.</author><author>Hsiao, P.</author><author>Maravilla, K.</author><author>Unadkat, J. D.</author></authors></contributors><titles><title>Activity of P-Glycoprotein, a ?-Amyloid Transporter at the Blood-Brain Barrier, Is Compromised in Patients with Mild Alzheimer Disease</title><secondary-title>Journal of Nuclear Medicine</secondary-title></titles><pages>1106-1111</pages><volume>55</volume><number>7</number><dates><year>2014</year><pub-dates><date>2014/05/19</date></pub-dates></dates><publisher>Society of Nuclear Medicine</publisher><isbn>0161-5505</isbn><urls><related-urls><url>. Besides, many morphological and functional changes in brain vasculature in AD were observed: thinning of microvessels, referred to as atrophic or string vessels; twisted or tortuous vessels and fragmented vessels ADDIN EN.CITE <EndNote><Cite><Author>Bailey</Author><Year>2004</Year><RecNum>1168</RecNum><DisplayText><style face="superscript">182</style></DisplayText><record><rec-number>1168</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1168</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bailey, Thomasina L.</author><author>Rivara, Claire B.</author><author>Rocher, Anne B.</author><author>Hof, Patrick R.</author></authors></contributors><titles><title>The nature and effects of cortical microvascular pathology in aging and Alzheimer&apos;s disease</title><secondary-title>Neurological Research</secondary-title></titles><pages>573-578</pages><volume>26</volume><number>5</number><dates><year>2004</year><pub-dates><date>2004/07</date></pub-dates></dates><publisher>Informa UK Limited</publisher><isbn>0161-6412&#xD;1743-1328</isbn><urls><related-urls><url>; thickening and vacuolization of the vascular basement membrane with increase of collagen IV ADDIN EN.CITE <EndNote><Cite><Author>Lepelletier</Author><Year>2015</Year><RecNum>1169</RecNum><DisplayText><style face="superscript">183</style></DisplayText><record><rec-number>1169</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1169</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lepelletier, F. X.</author><author>Mann, D. M. A.</author><author>Robinson, A. C.</author><author>Pinteaux, E.</author><author>Boutin, H.</author></authors></contributors><titles><title>Early changes in extracellular matrix in Alzheimer&apos;s disease</title><secondary-title>Neuropathology and Applied Neurobiology</secondary-title></titles><pages>167-182</pages><volume>43</volume><number>2</number><dates><year>2015</year><pub-dates><date>2015/11/30</date></pub-dates></dates><publisher>Wiley</publisher><isbn>0305-1846</isbn><urls><related-urls><url>; leakage and accumulation of circulating plasma proteins with direct neurotoxic properties and erythrocyte-derived hemoglobin in brain ADDIN EN.CITE <EndNote><Cite><Author>Zlokovic</Author><Year>2011</Year><RecNum>1159</RecNum><DisplayText><style face="superscript">174</style></DisplayText><record><rec-number>1159</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1159</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zlokovic, Berislav V.</author></authors></contributors><titles><title>Neurovascular pathways to neurodegeneration in Alzheimer&apos;s disease and other disorders</title><secondary-title>Nature Reviews Neuroscience</secondary-title></titles><pages>723-738</pages><volume>12</volume><number>12</number><dates><year>2011</year><pub-dates><date>2011/11/03</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>1471-003X&#xD;1471-0048</isbn><urls><related-urls><url>. Additional changes include also pericyte loss ADDIN EN.CITE <EndNote><Cite><Author>Halliday</Author><Year>2015</Year><RecNum>1170</RecNum><DisplayText><style face="superscript">184</style></DisplayText><record><rec-number>1170</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1170</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Halliday, Matthew R.</author><author>Rege, Sanket V.</author><author>Ma, Qingyi</author><author>Zhao, Zhen</author><author>Miller, Carol A.</author><author>Winkler, Ethan A.</author><author>Zlokovic, Berislav V.</author></authors></contributors><titles><title>Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease</title><secondary-title>Journal of Cerebral Blood Flow &amp; Metabolism</secondary-title></titles><pages>216-227</pages><volume>36</volume><number>1</number><dates><year>2015</year><pub-dates><date>2015/03/11</date></pub-dates></dates><publisher>SAGE Publications</publisher><isbn>0271-678X&#xD;1559-7016</isbn><urls><related-urls><url>, astromicrogliosis, many molecular changes directly impacting the clearance of the amyloid peptide (decrease of GLUT-1, LRP-1, P-gp and increase RAGE) ADDIN EN.CITE <EndNote><Cite><Author>Sweeney</Author><Year>2018</Year><RecNum>1165</RecNum><DisplayText><style face="superscript">179</style></DisplayText><record><rec-number>1165</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1165</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sweeney, Melanie D.</author><author>Sagare, Abhay P.</author><author>Zlokovic, Berislav V.</author></authors></contributors><titles><title>Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders</title><secondary-title>Nature Reviews Neurology</secondary-title></titles><pages>133-150</pages><volume>14</volume><number>3</number><dates><year>2018</year><pub-dates><date>2018/01/29</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>1759-4758&#xD;1759-4766</isbn><urls><related-urls><url>, hypoperfusion and permeability failure ADDIN EN.CITE <EndNote><Cite><Author>Nelson</Author><Year>2016</Year><RecNum>1171</RecNum><DisplayText><style face="superscript">185</style></DisplayText><record><rec-number>1171</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1171</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nelson, Amy R.</author><author>Sweeney, Melanie D.</author><author>Sagare, Abhay P.</author><author>Zlokovic, Berislav V.</author></authors></contributors><titles><title>Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer&apos;s disease</title><secondary-title>Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease</secondary-title></titles><pages>887-900</pages><volume>1862</volume><number>5</number><dates><year>2016</year><pub-dates><date>2016/05</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>0925-4439</isbn><urls><related-urls><url> impact in AD brainIn 1988, Rogers et al. highlighted in AD brain class II major histocompatibility complex (MHC) antigens necessary for T cell binding and antigen presentation ADDIN EN.CITE <EndNote><Cite><Author>Rogers</Author><Year>1988</Year><RecNum>1172</RecNum><DisplayText><style face="superscript">186</style></DisplayText><record><rec-number>1172</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1172</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rogers, Joseph</author><author>Luber-Narod, Judith</author><author>Styren, Scot D.</author><author>Civin, W. Harold</author></authors></contributors><titles><title>Expression of immune system-associated antigens by cells of the human central nervous system: Relationship to the pathology of Alzheimer&apos;s disease</title><secondary-title>Neurobiology of Aging</secondary-title></titles><pages>339-349</pages><volume>9</volume><dates><year>1988</year><pub-dates><date>1988/01</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>0197-4580</isbn><urls><related-urls><url>(88)80079-4</url></related-urls></urls><electronic-resource-num>10.1016/s0197-4580(88)80079-4</electronic-resource-num></record></Cite></EndNote>186. Furthermore, Togo et al. showed that the number of T cells was increased in the majority of AD cases compared with non-AD degenerative dementias and controls ADDIN EN.CITE <EndNote><Cite><Author>Togo</Author><Year>2002</Year><RecNum>1173</RecNum><DisplayText><style face="superscript">187</style></DisplayText><record><rec-number>1173</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1173</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Togo, Takashi</author><author>Akiyama, Haruhiko</author><author>Iseki, Eizo</author><author>Kondo, Hiromi</author><author>Ikeda, Kenji</author><author>Kato, Masanori</author><author>Oda, Tatsuro</author><author>Tsuchiya, Kuniaki</author><author>Kosaka, Kenji</author></authors></contributors><titles><title>Occurrence of T cells in the brain of Alzheimer&apos;s disease and other neurological diseases</title><secondary-title>Journal of Neuroimmunology</secondary-title></titles><pages>83-92</pages><volume>124</volume><number>1-2</number><dates><year>2002</year><pub-dates><date>2002/03</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>0165-5728</isbn><urls><related-urls><url>(01)00496-9</url></related-urls></urls><electronic-resource-num>10.1016/s0165-5728(01)00496-9</electronic-resource-num></record></Cite></EndNote>187. In order to get to the brain, T lymphocytes can pass through two main barriers: the BBB and the blood-cerebrospinal fluid barrier (BCSFB). In AD, the proportion of cells that pass through these two gateways is unknown, but the inflammatory environment remains a suitable condition for their transmigration. At the BBB, many mediators are involved in this AD process such as VCAM-1, the endothelial CX3CR1 receptor, the RAGE receptor, the CCR5 chemokine and the TNF-? produced by A?-activated microglia ADDIN EN.CITE <EndNote><Cite><Author>Mietelska-Porowska</Author><Year>2017</Year><RecNum>1174</RecNum><DisplayText><style face="superscript">188</style></DisplayText><record><rec-number>1174</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1174</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mietelska-Porowska, Anna</author><author>Wojda, Urszula</author></authors></contributors><titles><title>T Lymphocytes and Inflammatory Mediators in the Interplay between Brain and Blood in Alzheimer’s Disease: Potential Pools of New Biomarkers</title><secondary-title>Journal of Immunology Research</secondary-title></titles><pages>1-17</pages><volume>2017</volume><dates><year>2017</year></dates><publisher>Hindawi Limited</publisher><isbn>2314-8861&#xD;2314-7156</isbn><urls><related-urls><url>. BCSFB is also a selective barrier that restricts the passage of molecules and cells, including circulating immune cells, from the stromal compartment into the brain parenchyma and plays an essential role in immune surveillance and the maintenance of homeostasis and repair processes in the brain ADDIN EN.CITE <EndNote><Cite><Author>Baruch</Author><Year>2013</Year><RecNum>1175</RecNum><DisplayText><style face="superscript">189</style></DisplayText><record><rec-number>1175</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1175</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Baruch, Kuti</author><author>Schwartz, Michal</author></authors></contributors><titles><title>CNS-specific T cells shape brain function via the choroid plexus</title><secondary-title>Brain, Behavior, and Immunity</secondary-title></titles><pages>11-16</pages><volume>34</volume><dates><year>2013</year><pub-dates><date>2013/11</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>0889-1591</isbn><urls><related-urls><url>. Of note, higher proportion of activated CD8+ T cells in the CSF of patients correlated with clinical and structural markers of the pathology ADDIN EN.CITE <EndNote><Cite><Author>Lueg</Author><Year>2015</Year><RecNum>1176</RecNum><DisplayText><style face="superscript">190</style></DisplayText><record><rec-number>1176</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1176</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lueg, Gero</author><author>Gross, Catharina C.</author><author>Lohmann, Hubertus</author><author>Johnen, Andreas</author><author>Kemmling, Andre</author><author>Deppe, Michael</author><author>Groger, Julia</author><author>Minnerup, Jens</author><author>Wiendl, Heinz</author><author>Meuth, Sven G.</author><author>Duning, Thomas</author></authors></contributors><titles><title>Clinical relevance of specific T-cell activation in the blood and cerebrospinal fluid of patients with mild Alzheimer&apos;s disease</title><secondary-title>Neurobiology of Aging</secondary-title></titles><pages>81-89</pages><volume>36</volume><number>1</number><dates><year>2015</year><pub-dates><date>2015/01</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>0197-4580</isbn><urls><related-urls><url>. In AD, many mediators are increased, including cytokines and their receptors (TNF-?, IL-6, IL-8), chemokines (CCL11, CXCL8, CCL2) and integrins (ICAM-1, VCAM-1 and P-selectin), leading to the damage of tight junctions of BCSFB and modulating immune cell migration to the CSF ADDIN EN.CITE <EndNote><Cite><Author>Mietelska-Porowska</Author><Year>2017</Year><RecNum>1174</RecNum><DisplayText><style face="superscript">188</style></DisplayText><record><rec-number>1174</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1174</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mietelska-Porowska, Anna</author><author>Wojda, Urszula</author></authors></contributors><titles><title>T Lymphocytes and Inflammatory Mediators in the Interplay between Brain and Blood in Alzheimer’s Disease: Potential Pools of New Biomarkers</title><secondary-title>Journal of Immunology Research</secondary-title></titles><pages>1-17</pages><volume>2017</volume><dates><year>2017</year></dates><publisher>Hindawi Limited</publisher><isbn>2314-8861&#xD;2314-7156</isbn><urls><related-urls><url> these cells have been identified in the post-mortem AD brain, no information on their transmigration in relation to the degree of severity of the disease is available and their protective or pathogenic role in AD is debated ADDIN EN.CITE <EndNote><Cite><Author>McManus</Author><Year>2015</Year><RecNum>1177</RecNum><DisplayText><style face="superscript">191,192</style></DisplayText><record><rec-number>1177</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1177</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McManus, Róisín M.</author><author>Mills, Kingston H. G.</author><author>Lynch, Marina A.</author></authors></contributors><titles><title>T Cells—Protective or Pathogenic in Alzheimer’s Disease?</title><secondary-title>Journal of Neuroimmune Pharmacology</secondary-title></titles><pages>547-560</pages><volume>10</volume><number>4</number><dates><year>2015</year><pub-dates><date>2015/05/10</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>1557-1890&#xD;1557-1904</isbn><urls><related-urls><url> app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1178</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bryson, Karen J.</author><author>Lynch, Marina A.</author></authors></contributors><titles><title>Linking T cells to Alzheimer&apos;s disease: from neurodegeneration to neurorepair</title><secondary-title>Current Opinion in Pharmacology</secondary-title></titles><pages>67-73</pages><volume>26</volume><dates><year>2016</year><pub-dates><date>2016/02</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>1471-4892</isbn><urls><related-urls><url>. The active vaccination strategy led to a fatal encephalopathy and the authors highlighted the presence of T cells in the brain with a strong inflammatory response ADDIN EN.CITE <EndNote><Cite><Author>Schenk</Author><Year>2002</Year><RecNum>1179</RecNum><DisplayText><style face="superscript">193</style></DisplayText><record><rec-number>1179</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1179</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schenk, Dale</author></authors></contributors><titles><title>Amyloid-β immunotherapy for Alzheimer&apos;s disease: the end of the beginning</title><secondary-title>Nature Reviews Neuroscience</secondary-title></titles><pages>824-828</pages><volume>3</volume><number>10</number><dates><year>2002</year><pub-dates><date>2002/10</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>1471-003X&#xD;1471-0048</isbn><urls><related-urls><url>. Many studies support the deleterious role of T cells in particular Th1 cells producing interferon-γ by participating in the inflammatory response and Tau-triggered spatial memory deficits in experimental models of AD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ccnlzb248L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

ZWNOdW0+MTE3ODwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjE5MiwxOTQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMTc4PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU5MTgiPjExNzg8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJyeXNvbiwgS2FyZW4gSi48L2F1

dGhvcj48YXV0aG9yPkx5bmNoLCBNYXJpbmEgQS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli

dXRvcnM+PHRpdGxlcz48dGl0bGU+TGlua2luZyBUIGNlbGxzIHRvIEFsemhlaW1lciZhcG9zO3Mg

ZGlzZWFzZTogZnJvbSBuZXVyb2RlZ2VuZXJhdGlvbiB0byBuZXVyb3JlcGFpcjwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5DdXJyZW50IE9waW5pb24gaW4gUGhhcm1hY29sb2d5PC9zZWNvbmRhcnkt

dGl0bGU+PC90aXRsZXM+PHBhZ2VzPjY3LTczPC9wYWdlcz48dm9sdW1lPjI2PC92b2x1bWU+PGRh

dGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDE2LzAyPC9kYXRlPjwvcHVi

LWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5FbHNldmllciBCVjwvcHVibGlzaGVyPjxpc2JuPjE0

NzEtNDg5MjwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcv

MTAuMTAxNi9qLmNvcGguMjAxNS4xMC4wMDM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5jb3BoLjIwMTUuMTAuMDAzPC9lbGVjdHJv

bmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5MYXVyZW50PC9B

dXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVjTnVtPjExODA8L1JlY051bT48cmVjb3JkPjxyZWMt

bnVtYmVyPjExODA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk

PSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2

NTkxOCI+MTE4MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFy

dGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TGF1cmVu

dCwgQ3lyaWw8L2F1dGhvcj48YXV0aG9yPkRvcm90aMOpZSwgR3VpbGxhdW1lPC9hdXRob3I+PGF1

dGhvcj5IdW5vdCwgU3TDqXBoYW5lPC9hdXRob3I+PGF1dGhvcj5NYXJ0aW4sIEVsb2RpZTwvYXV0

aG9yPjxhdXRob3I+TW9ubmV0LCBZYW5uPC9hdXRob3I+PGF1dGhvcj5EdWNoYW1wLCBNYXJpZTwv

YXV0aG9yPjxhdXRob3I+RG9uZywgWXVhbjwvYXV0aG9yPjxhdXRob3I+TMOpZ2Vyb24sIEZyYW7D

p29pcy1QaWVycmU8L2F1dGhvcj48YXV0aG9yPkxlYm91Y2hlciwgQW50b2luZTwvYXV0aG9yPjxh

dXRob3I+QnVybm91ZiwgU3lsdmllPC9hdXRob3I+PGF1dGhvcj5GYWl2cmUsIEVtaWxpZTwvYXV0

aG9yPjxhdXRob3I+Q2FydmFsaG8sIEvDqXZpbjwvYXV0aG9yPjxhdXRob3I+Q2FpbGxpZXJleiwg

UmFwaGHDq2xsZTwvYXV0aG9yPjxhdXRob3I+Wm9tbWVyLCBOYWTDqGdlPC9hdXRob3I+PGF1dGhv

cj5EZW1leWVyLCBEb21pbmlxdWU8L2F1dGhvcj48YXV0aG9yPkpvdXksIE5hdGhhbGllPC9hdXRo

b3I+PGF1dGhvcj5TYXpkb3ZpdGNoLCBWZXJvbmlxdWU8L2F1dGhvcj48YXV0aG9yPlNjaHJhZW4t

TWFzY2hrZSwgU3VzYW5uYTwvYXV0aG9yPjxhdXRob3I+RGVsYXJhc3NlLCBDw6ljaWxlPC9hdXRo

b3I+PGF1dGhvcj5CdcOpZSwgTHVjPC9hdXRob3I+PGF1dGhvcj5CbHVtLCBEYXZpZDwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5IaXBwb2NhbXBhbCBUIGNl

bGwgaW5maWx0cmF0aW9uIHByb21vdGVzIG5ldXJvaW5mbGFtbWF0aW9uIGFuZCBjb2duaXRpdmUg

ZGVjbGluZSBpbiBhIG1vdXNlIG1vZGVsIG9mIHRhdW9wYXRoeTwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5CcmFpbjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRp

dGxlPkJyYWluPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTg0LTIwMDwvcGFnZXM+

PHZvbHVtZT4xNDA8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMTEvMDU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48cHVibGlzaGVyPk94Zm9yZCBVbml2ZXJzaXR5IFByZXNzIChPVVApPC9wdWJsaXNoZXI+PGlz

Ym4+MDAwNi04OTUwJiN4RDsxNDYwLTIxNTY8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJs

Pmh0dHA6Ly9keC5kb2kub3JnLzEwLjEwOTMvYnJhaW4vYXd3MjcwPC91cmw+PC9yZWxhdGVkLXVy

bHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDkzL2JyYWluL2F3dzI3MDwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ccnlzb248L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

ZWNOdW0+MTE3ODwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjE5MiwxOTQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMTc4PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU5MTgiPjExNzg8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJyeXNvbiwgS2FyZW4gSi48L2F1

dGhvcj48YXV0aG9yPkx5bmNoLCBNYXJpbmEgQS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli

dXRvcnM+PHRpdGxlcz48dGl0bGU+TGlua2luZyBUIGNlbGxzIHRvIEFsemhlaW1lciZhcG9zO3Mg

ZGlzZWFzZTogZnJvbSBuZXVyb2RlZ2VuZXJhdGlvbiB0byBuZXVyb3JlcGFpcjwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5DdXJyZW50IE9waW5pb24gaW4gUGhhcm1hY29sb2d5PC9zZWNvbmRhcnkt

dGl0bGU+PC90aXRsZXM+PHBhZ2VzPjY3LTczPC9wYWdlcz48dm9sdW1lPjI2PC92b2x1bWU+PGRh

dGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDE2LzAyPC9kYXRlPjwvcHVi

LWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5FbHNldmllciBCVjwvcHVibGlzaGVyPjxpc2JuPjE0

NzEtNDg5MjwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcv

MTAuMTAxNi9qLmNvcGguMjAxNS4xMC4wMDM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5jb3BoLjIwMTUuMTAuMDAzPC9lbGVjdHJv

bmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5MYXVyZW50PC9B

dXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVjTnVtPjExODA8L1JlY051bT48cmVjb3JkPjxyZWMt

bnVtYmVyPjExODA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk

PSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2

NTkxOCI+MTE4MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFy

dGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TGF1cmVu

dCwgQ3lyaWw8L2F1dGhvcj48YXV0aG9yPkRvcm90aMOpZSwgR3VpbGxhdW1lPC9hdXRob3I+PGF1

dGhvcj5IdW5vdCwgU3TDqXBoYW5lPC9hdXRob3I+PGF1dGhvcj5NYXJ0aW4sIEVsb2RpZTwvYXV0

aG9yPjxhdXRob3I+TW9ubmV0LCBZYW5uPC9hdXRob3I+PGF1dGhvcj5EdWNoYW1wLCBNYXJpZTwv

YXV0aG9yPjxhdXRob3I+RG9uZywgWXVhbjwvYXV0aG9yPjxhdXRob3I+TMOpZ2Vyb24sIEZyYW7D

p29pcy1QaWVycmU8L2F1dGhvcj48YXV0aG9yPkxlYm91Y2hlciwgQW50b2luZTwvYXV0aG9yPjxh

dXRob3I+QnVybm91ZiwgU3lsdmllPC9hdXRob3I+PGF1dGhvcj5GYWl2cmUsIEVtaWxpZTwvYXV0

aG9yPjxhdXRob3I+Q2FydmFsaG8sIEvDqXZpbjwvYXV0aG9yPjxhdXRob3I+Q2FpbGxpZXJleiwg

UmFwaGHDq2xsZTwvYXV0aG9yPjxhdXRob3I+Wm9tbWVyLCBOYWTDqGdlPC9hdXRob3I+PGF1dGhv

cj5EZW1leWVyLCBEb21pbmlxdWU8L2F1dGhvcj48YXV0aG9yPkpvdXksIE5hdGhhbGllPC9hdXRo

b3I+PGF1dGhvcj5TYXpkb3ZpdGNoLCBWZXJvbmlxdWU8L2F1dGhvcj48YXV0aG9yPlNjaHJhZW4t

TWFzY2hrZSwgU3VzYW5uYTwvYXV0aG9yPjxhdXRob3I+RGVsYXJhc3NlLCBDw6ljaWxlPC9hdXRo

b3I+PGF1dGhvcj5CdcOpZSwgTHVjPC9hdXRob3I+PGF1dGhvcj5CbHVtLCBEYXZpZDwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5IaXBwb2NhbXBhbCBUIGNl

bGwgaW5maWx0cmF0aW9uIHByb21vdGVzIG5ldXJvaW5mbGFtbWF0aW9uIGFuZCBjb2duaXRpdmUg

ZGVjbGluZSBpbiBhIG1vdXNlIG1vZGVsIG9mIHRhdW9wYXRoeTwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5CcmFpbjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRp

dGxlPkJyYWluPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTg0LTIwMDwvcGFnZXM+

PHZvbHVtZT4xNDA8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMTEvMDU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48cHVibGlzaGVyPk94Zm9yZCBVbml2ZXJzaXR5IFByZXNzIChPVVApPC9wdWJsaXNoZXI+PGlz

Ym4+MDAwNi04OTUwJiN4RDsxNDYwLTIxNTY8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJs

Pmh0dHA6Ly9keC5kb2kub3JnLzEwLjEwOTMvYnJhaW4vYXd3MjcwPC91cmw+PC9yZWxhdGVkLXVy

bHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDkzL2JyYWluL2F3dzI3MDwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 192,194. Others on the contrary, from experimental work, showed that Th2 cells elicited by a vaccine program in mice ADDIN EN.CITE <EndNote><Cite><Author>Xing</Author><Year>2012</Year><RecNum>1181</RecNum><DisplayText><style face="superscript">195</style></DisplayText><record><rec-number>1181</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1181</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Xing, Xiaona</author><author>Sha, Sha</author><author>Li, Yu</author><author>Zong, Lixia</author><author>Jiang, Tongzi</author><author>Cao, Yunpeng</author></authors></contributors><titles><title>Immunization with a new DNA vaccine for Alzheimer&apos;s disease elicited Th2 immune response in BALB/c mice by in vivo electroporation</title><secondary-title>Journal of the Neurological Sciences</secondary-title></titles><pages>17-21</pages><volume>313</volume><number>1-2</number><dates><year>2012</year><pub-dates><date>2012/02</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>0022-510X</isbn><urls><related-urls><url> or GFP-positive monocytes injected in the bone marrow of mice ADDIN EN.CITE <EndNote><Cite><Author>Simard</Author><Year>2006</Year><RecNum>1182</RecNum><DisplayText><style face="superscript">196</style></DisplayText><record><rec-number>1182</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1182</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Simard, Alain R.</author><author>Soulet, Denis</author><author>Gowing, Genevieve</author><author>Julien, Jean-Pierre</author><author>Rivest, Serge</author></authors></contributors><titles><title>Bone Marrow-Derived Microglia Play a Critical Role in Restricting Senile Plaque Formation in Alzheimer&apos;s Disease</title><secondary-title>Neuron</secondary-title></titles><periodical><full-title>Neuron</full-title></periodical><pages>489-502</pages><volume>49</volume><number>4</number><dates><year>2006</year><pub-dates><date>2006/02</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>0896-6273</isbn><urls><related-urls><url> or CD4+-T lymphocytes during vaccine experiments in mice ADDIN EN.CITE <EndNote><Cite><Author>Fisher</Author><Year>2010</Year><RecNum>1183</RecNum><DisplayText><style face="superscript">197</style></DisplayText><record><rec-number>1183</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1183</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fisher, Yair</author><author>Nemirovsky, Anna</author><author>Baron, Rona</author><author>Monsonego, Alon</author></authors></contributors><titles><title>T Cells Specifically Targeted to Amyloid Plaques Enhance Plaque Clearance in a Mouse Model of Alzheimer&apos;s Disease</title><secondary-title>PLoS ONE</secondary-title></titles><periodical><full-title>PLoS One</full-title></periodical><pages>e10830</pages><volume>5</volume><number>5</number><dates><year>2010</year><pub-dates><date>2010/05/26</date></pub-dates></dates><publisher>Public Library of Science (PLoS)</publisher><isbn>1932-6203</isbn><urls><related-urls><url>, led to amyloid peptide clearance. In addition, early transient depletion of regulatory T cells accelerated the onset of cognitive deficits, reduced recruitment of microglia towards amyloid deposits and altered disease-related gene expression profile in AD mice. Conversely, amplification of regulatory T cells through peripheral low-dose IL-2 treatment increased numbers of plaque-associated microglia and restored cognitive functions in AD mice ADDIN EN.CITE <EndNote><Cite><Author>Dansokho</Author><Year>2016</Year><RecNum>1184</RecNum><DisplayText><style face="superscript">198</style></DisplayText><record><rec-number>1184</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1184</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dansokho, Cira</author><author>Ait Ahmed, Dylla</author><author>Aid, Saba</author><author>Toly-Ndour, Cécile</author><author>Chaigneau, Thomas</author><author>Calle, Vanessa</author><author>Cagnard, Nicolas</author><author>Holzenberger, Martin</author><author>Piaggio, Eliane</author><author>Aucouturier, Pierre</author><author>Dorothée, Guillaume</author></authors></contributors><titles><title>Regulatory T cells delay disease progression in Alzheimer-like pathology</title><secondary-title>Brain</secondary-title></titles><periodical><full-title>Brain</full-title></periodical><pages>1237-1251</pages><volume>139</volume><number>4</number><dates><year>2016</year><pub-dates><date>2016/02/01</date></pub-dates></dates><publisher>Oxford University Press (OUP)</publisher><isbn>0006-8950&#xD;1460-2156</isbn><urls><related-urls><url> has been also argued that surveillance of the brain by T cells, and indeed other peripheral immune cells, can occur when cells are retained in perivascular spaces and/or trafficked from the choroid plexus. This peripheral cell presence also plays a role from the periphery by the molecular environment implemented involving cytokines, chemokines. For cytokines, it has been shown in 5XFAD/Tg197 AD/TNF transgenic mice (Alzheimer and arthritis phenotype) that peripheral TNF-α significantly decreased amyloid deposition, robust glial activation, and compromised neuronal integrity ADDIN EN.CITE <EndNote><Cite><Author>Paouri</Author><Year>2017</Year><RecNum>1185</RecNum><DisplayText><style face="superscript">199</style></DisplayText><record><rec-number>1185</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1185</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Paouri, Evi</author><author>Tzara, Ourania</author><author>Kartalou, Georgia-Ioanna</author><author>Zenelak, Sofia</author><author>Georgopoulos, Spiros</author></authors></contributors><titles><title>Peripheral Tumor Necrosis Factor-Alpha (TNF-α) Modulates Amyloid Pathology by Regulating Blood-Derived Immune Cells and Glial Response in the Brain of AD/TNF Transgenic Mice</title><secondary-title>The Journal of Neuroscience</secondary-title></titles><pages>5155-5171</pages><volume>37</volume><number>20</number><dates><year>2017</year><pub-dates><date>2017/04/25</date></pub-dates></dates><publisher>Society for Neuroscience</publisher><isbn>0270-6474&#xD;1529-2401</isbn><urls><related-urls><url>. This impact of molecular environment in AD phenotype was also observed in three recent articles: first, some factors in young blood have the potential to ameliorate disease in a model of AD ADDIN EN.CITE <EndNote><Cite><Author>Middeldorp</Author><Year>2016</Year><RecNum>1186</RecNum><DisplayText><style face="superscript">200</style></DisplayText><record><rec-number>1186</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1186</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Middeldorp, Jinte</author><author>Lehallier, Benoit</author><author>Villeda, Saul A.</author><author>Miedema, Suzanne S. M.</author><author>Evans, Emily</author><author>Czirr, Eva</author><author>Zhang, Hui</author><author>Luo, Jian</author><author>Stan, Trisha</author><author>Mosher, Kira I.</author><author>Masliah, Eliezer</author><author>Wyss-Coray, Tony</author></authors></contributors><titles><title>Preclinical Assessment of Young Blood Plasma for Alzheimer Disease</title><secondary-title>JAMA Neurology</secondary-title></titles><pages>1325</pages><volume>73</volume><number>11</number><dates><year>2016</year><pub-dates><date>2016/11/01</date></pub-dates></dates><publisher>American Medical Association (AMA)</publisher><isbn>2168-6149</isbn><urls><related-urls><url>, secondly blood-derived amyloid-β protein induces AD by using a model of parabiosis between APPswe/PS1dE9 Tg AD mice and their wild-type littermates ADDIN EN.CITE <EndNote><Cite><Author>Bu</Author><Year>2017</Year><RecNum>1187</RecNum><DisplayText><style face="superscript">201</style></DisplayText><record><rec-number>1187</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1187</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bu, X. L.</author><author>Xiang, Y.</author><author>Jin, W. S.</author><author>Wang, J.</author><author>Shen, L. L.</author><author>Huang, Z. L.</author><author>Zhang, K.</author><author>Liu, Y. H.</author><author>Zeng, F.</author><author>Liu, J. H.</author><author>Sun, H. L.</author><author>Zhuang, Z. Q.</author><author>Chen, S. H.</author><author>Yao, X. Q.</author><author>Giunta, B.</author><author>Shan, Y. C.</author><author>Tan, J.</author><author>Chen, X. W.</author><author>Dong, Z. F.</author><author>Zhou, H. D.</author><author>Zhou, X. F.</author><author>Song, W.</author><author>Wang, Y. J.</author></authors></contributors><titles><title>Blood-derived amyloid-β protein induces Alzheimer’s disease pathologies</title><secondary-title>Molecular Psychiatry</secondary-title></titles><dates><year>2017</year><pub-dates><date>2017/10/31</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>1359-4184&#xD;1476-5578</isbn><urls><related-urls><url> and thirdly in a prospective clinical study, a cohort of control subjects aged about 53 years had a blood test at inclusion to determine the white blood cell count, albumin, fibrinogen, von Willebrand and factor VIII. Then, 24 years later, they were called back to assess their episodic memory and regional brain volumes. Results showed that the number of elevated inflammatory markers measured during midlife is independently associated with lower regional brain volume and reduced episodic memory 24 years later among older adults without dementia ADDIN EN.CITE <EndNote><Cite><Author>Walker</Author><Year>2017</Year><RecNum>1188</RecNum><DisplayText><style face="superscript">202</style></DisplayText><record><rec-number>1188</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1188</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Walker, Keenan A.</author><author>Hoogeveen, Ron C.</author><author>Folsom, Aaron R.</author><author>Ballantyne, Christie M.</author><author>Knopman, David S.</author><author>Windham, B. Gwen</author><author>Jack, Clifford R.</author><author>Gottesman, Rebecca F.</author></authors></contributors><titles><title>Midlife systemic inflammatory markers are associated with late-life brain volume</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title></periodical><pages>2262-2270</pages><volume>89</volume><number>22</number><dates><year>2017</year><pub-dates><date>2017/11/01</date></pub-dates></dates><publisher>Ovid Technologies (Wolters Kluwer Health)</publisher><isbn>0028-3878&#xD;1526-632X</isbn><urls><related-urls><url> conclusion concerning the impact of the periphery on the Alzheimer's phenotype, we should remember that peripheral blood mononuclear cells (PBMCs) and/or blood factors are able to modulate the Alzheimer's phenotype. It would be crucial to conduct longitudinal studies to better characterize cell subpopulations and factors involved following the stage of the disease. A therapeutic strategy aimed at reprogramming the peripheral blood environment could then be an innovative field of research to limit the progression of this disease. The dosage of this program must be finely regulated to prevent any uncontrolled inflammatory response.Chemokines as critical targets for diagnosis or therapeutic strategiesAmong the peripheral molecular actors, we can target chemokines. Indeed, many articles have shown the involvement of chemokines in the pathophysiology of AD ADDIN EN.CITE <EndNote><Cite><Author>Bagyinszky</Author><Year>2017</Year><RecNum>1189</RecNum><DisplayText><style face="superscript">203</style></DisplayText><record><rec-number>1189</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1189</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bagyinszky, Eva</author><author>Giau, Vo Van</author><author>Shim, Kyuhwan</author><author>Suk, Kyoungho</author><author>An, Seong Soo A.</author><author>Kim, SangYun</author></authors></contributors><titles><title>Role of inflammatory molecules in the Alzheimer&apos;s disease progression and diagnosis</title><secondary-title>Journal of the Neurological Sciences</secondary-title></titles><pages>242-254</pages><volume>376</volume><dates><year>2017</year><pub-dates><date>2017/05</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>0022-510X</isbn><urls><related-urls><url>. Of those that are deleterious, the pro-inflammatory chemokines CXCL10/CXCR3, CCL3, CCL4, CXCL8/CXCR8 and CX3CL1/CX3CR1 increase in AD, lead to inhibition of Aβ clearance, increased adhesion of PBMCs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYXVyZW50PC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjExODA8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4xOTQsMjA0LTIwODwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEx

ODA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1

MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTkxOCI+MTE4

MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3

PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TGF1cmVudCwgQ3lyaWw8

L2F1dGhvcj48YXV0aG9yPkRvcm90aMOpZSwgR3VpbGxhdW1lPC9hdXRob3I+PGF1dGhvcj5IdW5v

dCwgU3TDqXBoYW5lPC9hdXRob3I+PGF1dGhvcj5NYXJ0aW4sIEVsb2RpZTwvYXV0aG9yPjxhdXRo

b3I+TW9ubmV0LCBZYW5uPC9hdXRob3I+PGF1dGhvcj5EdWNoYW1wLCBNYXJpZTwvYXV0aG9yPjxh

dXRob3I+RG9uZywgWXVhbjwvYXV0aG9yPjxhdXRob3I+TMOpZ2Vyb24sIEZyYW7Dp29pcy1QaWVy

cmU8L2F1dGhvcj48YXV0aG9yPkxlYm91Y2hlciwgQW50b2luZTwvYXV0aG9yPjxhdXRob3I+QnVy

bm91ZiwgU3lsdmllPC9hdXRob3I+PGF1dGhvcj5GYWl2cmUsIEVtaWxpZTwvYXV0aG9yPjxhdXRo

b3I+Q2FydmFsaG8sIEvDqXZpbjwvYXV0aG9yPjxhdXRob3I+Q2FpbGxpZXJleiwgUmFwaGHDq2xs

ZTwvYXV0aG9yPjxhdXRob3I+Wm9tbWVyLCBOYWTDqGdlPC9hdXRob3I+PGF1dGhvcj5EZW1leWVy

LCBEb21pbmlxdWU8L2F1dGhvcj48YXV0aG9yPkpvdXksIE5hdGhhbGllPC9hdXRob3I+PGF1dGhv

cj5TYXpkb3ZpdGNoLCBWZXJvbmlxdWU8L2F1dGhvcj48YXV0aG9yPlNjaHJhZW4tTWFzY2hrZSwg

U3VzYW5uYTwvYXV0aG9yPjxhdXRob3I+RGVsYXJhc3NlLCBDw6ljaWxlPC9hdXRob3I+PGF1dGhv

cj5CdcOpZSwgTHVjPC9hdXRob3I+PGF1dGhvcj5CbHVtLCBEYXZpZDwvYXV0aG9yPjwvYXV0aG9y

cz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5IaXBwb2NhbXBhbCBUIGNlbGwgaW5maWx0

cmF0aW9uIHByb21vdGVzIG5ldXJvaW5mbGFtbWF0aW9uIGFuZCBjb2duaXRpdmUgZGVjbGluZSBp

biBhIG1vdXNlIG1vZGVsIG9mIHRhdW9wYXRoeTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5CcmFp

bjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkJyYWlu

PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTg0LTIwMDwvcGFnZXM+PHZvbHVtZT4x

NDA8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHVi

LWRhdGVzPjxkYXRlPjIwMTYvMTEvMDU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlz

aGVyPk94Zm9yZCBVbml2ZXJzaXR5IFByZXNzIChPVVApPC9wdWJsaXNoZXI+PGlzYm4+MDAwNi04

OTUwJiN4RDsxNDYwLTIxNTY8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9k

eC5kb2kub3JnLzEwLjEwOTMvYnJhaW4vYXd3MjcwPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxz

PjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDkzL2JyYWluL2F3dzI3MDwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+S3JhdXRoYXVzZW48

L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNOdW0+MTE5MDwvUmVjTnVtPjxyZWNvcmQ+PHJl

Yy1udW1iZXI+MTE5MDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGIt

aWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMy

ODY1OTE4Ij4xMTkwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwg

QXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LcmF1

dGhhdXNlbiwgTWFyaXVzPC9hdXRob3I+PGF1dGhvcj5LdW1tZXIsIE1hcmt1cyBQLjwvYXV0aG9y

PjxhdXRob3I+WmltbWVybWFubiwgSnVsaWFuPC9hdXRob3I+PGF1dGhvcj5SZXllcy1JcmlzYXJy

aSwgRWxpc2FiZXQ8L2F1dGhvcj48YXV0aG9yPlRlcndlbCwgRGljazwvYXV0aG9yPjxhdXRob3I+

QnVsaWMsIEJydW5vPC9hdXRob3I+PGF1dGhvcj5IZW5la2EsIE1pY2hhZWwgVC48L2F1dGhvcj48

YXV0aG9yPk3DvGxsZXIsIE1hcmN1czwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48

dGl0bGVzPjx0aXRsZT5DWENSMyBwcm9tb3RlcyBwbGFxdWUgZm9ybWF0aW9uIGFuZCBiZWhhdmlv

cmFsIGRlZmljaXRzIGluIGFuIEFsemhlaW1lcuKAmXMgZGlzZWFzZSBtb2RlbDwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5Kb3VybmFsIG9mIENsaW5pY2FsIEludmVzdGlnYXRpb248L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGFnZXM+MzY1LTM3ODwvcGFnZXM+PHZvbHVtZT4xMjU8L3ZvbHVt

ZT48bnVtYmVyPjE8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48cHViLWRhdGVzPjxk

YXRlPjIwMTQvMTIvMTU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkFtZXJp

Y2FuIFNvY2lldHkgZm9yIENsaW5pY2FsIEludmVzdGlnYXRpb248L3B1Ymxpc2hlcj48aXNibj4w

MDIxLTk3Mzg8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3Jn

LzEwLjExNzIvamNpNjY3NzE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjEwLjExNzIvamNpNjY3NzE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwv

cmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlRvcnJlczwvQXV0aG9yPjxZZWFyPjIwMTI8L1ll

YXI+PFJlY051bT4xMTkxPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4xMTkxPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU5MTgiPjExOTE8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlRvcnJlcywgS2FyZW4gQy4gTC48L2F1dGhv

cj48YXV0aG9yPlNhbnRvcywgUm9kcmlnbyBSLjwvYXV0aG9yPjxhdXRob3I+ZGUgTGltYSwgR2lz

ZWxsZSBTLiBGLjwvYXV0aG9yPjxhdXRob3I+RmVycmVpcmEsIFJhcGhhZWwgTy4gUy48L2F1dGhv

cj48YXV0aG9yPk1hcGEsIEZpbGlwZSBDLjwvYXV0aG9yPjxhdXRob3I+UGVyZWlyYSwgUGF0csOt

Y2lhIEEuPC9hdXRob3I+PGF1dGhvcj5SZXplbmRlLCBWaXRvciBCLjwvYXV0aG9yPjxhdXRob3I+

TWFydGlucywgTHVpemEgQy4gQS48L2F1dGhvcj48YXV0aG9yPkJpY2FsaG8sIE1hcmlhIEEuIEMu

PC9hdXRob3I+PGF1dGhvcj5Nb3JhZXMsIEVkZ2FyIE4uPC9hdXRob3I+PGF1dGhvcj5SZWlzLCBI

ZWx0b24gSi48L2F1dGhvcj48YXV0aG9yPlRlaXhlaXJhLCBBbnRvbmlvIEwuPC9hdXRob3I+PGF1

dGhvcj5Sb21hbm8tU2lsdmEsIE1hcmNvIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjx0aXRsZXM+PHRpdGxlPkRlY3JlYXNlZCBFeHByZXNzaW9uIG9mIENDTDMgaW4gTW9ub2N5

dGVzIGFuZCBDQ1I1IGluIEx5bXBob2N5dGVzIEZyb20gRnJvbnRvdGVtcG9yYWwgRGVtZW50aWEg

YXMgQ29tcGFyZWQgV2l0aCBBbHpoZWltZXLigJlzIERpc2Vhc2UgUGF0aWVudHM8L3RpdGxlPjxz

ZWNvbmRhcnktdGl0bGU+VGhlIEpvdXJuYWwgb2YgTmV1cm9wc3ljaGlhdHJ5IGFuZCBDbGluaWNh

bCBOZXVyb3NjaWVuY2VzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPkUxMS1FMTI8

L3BhZ2VzPjx2b2x1bWU+MjQ8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48ZGF0ZXM+PHllYXI+

MjAxMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTIvMDE8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48cHVibGlzaGVyPkFtZXJpY2FuIFBzeWNoaWF0cmljIFB1Ymxpc2hpbmc8L3B1Ymxpc2hl

cj48aXNibj4wODk1LTAxNzImI3hEOzE1NDUtNzIyMjwvaXNibj48dXJscz48cmVsYXRlZC11cmxz

Pjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTE3Ni9hcHBpLm5ldXJvcHN5Y2guMTEwNjAxNDM8

L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEx

NzYvYXBwaS5uZXVyb3BzeWNoLjExMDYwMTQzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3Jl

Y29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5aaHU8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS

ZWNOdW0+MTE5MjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTE5MjwvcmVjLW51bWJlcj48

Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4

OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyODY1OTE4Ij4xMTkyPC9rZXk+PC9mb3JlaWdu

LWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250

cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5aaHUsIE1pbjwvYXV0aG9yPjxhdXRob3I+QWxsYXJk

LCBKb2FubmUgUy48L2F1dGhvcj48YXV0aG9yPlpoYW5nLCBZb25ncWluZzwvYXV0aG9yPjxhdXRo

b3I+UGVyZXosIEV2ZWx5bjwvYXV0aG9yPjxhdXRob3I+U3BhbmdsZXIsIEVkd2FyZCBMLjwvYXV0

aG9yPjxhdXRob3I+QmVja2VyLCBLZXZpbiBHLjwvYXV0aG9yPjxhdXRob3I+UmFwcCwgUGV0ZXIg

Ui48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QWdlLVJl

bGF0ZWQgQnJhaW4gRXhwcmVzc2lvbiBhbmQgUmVndWxhdGlvbiBvZiB0aGUgQ2hlbW9raW5lIEND

TDQvTUlQLTHOsiBpbiBBUFAvUFMxIERvdWJsZS1UcmFuc2dlbmljIE1pY2U8L3RpdGxlPjxzZWNv

bmRhcnktdGl0bGU+Sm91cm5hbCBvZiBOZXVyb3BhdGhvbG9neSAmYW1wOyBFeHBlcmltZW50YWwg

TmV1cm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjM2Mi0zNzQ8L3BhZ2Vz

Pjx2b2x1bWU+NzM8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNDwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTQvMDQ8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

cHVibGlzaGVyPk94Zm9yZCBVbml2ZXJzaXR5IFByZXNzIChPVVApPC9wdWJsaXNoZXI+PGlzYm4+

MDAyMi0zMDY5PC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9y

Zy8xMC4xMDk3L25lbi4wMDAwMDAwMDAwMDAwMDYwPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxz

PjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDk3L25lbi4wMDAwMDAwMDAwMDAwMDYwPC9l

bGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5GcmFu

Y2lvc2k8L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxSZWNOdW0+MTE5MzwvUmVjTnVtPjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTE5MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1w

PSIxNTMyODY1OTE4Ij4xMTkzPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5GcmFuY2lvc2ksIFNvbmlhPC9hdXRob3I+PGF1dGhvcj5DaG9pLCBIeXVuIEIuPC9hdXRob3I+

PGF1dGhvcj5LaW0sIFNldW5nIFUuPC9hdXRob3I+PGF1dGhvcj5NY0xhcm5vbiwgSmFtZXMgRy48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+SUwtOCBlbmhh

bmNlbWVudCBvZiBhbXlsb2lkLWJldGEgKEHOsjEtNDIpLWluZHVjZWQgZXhwcmVzc2lvbiBhbmQg

cHJvZHVjdGlvbiBvZiBwcm8taW5mbGFtbWF0b3J5IGN5dG9raW5lcyBhbmQgQ09YLTIgaW4gY3Vs

dHVyZWQgaHVtYW4gbWljcm9nbGlhPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkpvdXJuYWwgb2Yg

TmV1cm9pbW11bm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjY2LTc0PC9w

YWdlcz48dm9sdW1lPjE1OTwvdm9sdW1lPjxudW1iZXI+MS0yPC9udW1iZXI+PGRhdGVzPjx5ZWFy

PjIwMDU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDA1LzAyPC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PHB1Ymxpc2hlcj5FbHNldmllciBCVjwvcHVibGlzaGVyPjxpc2JuPjAxNjUtNTcyODwv

aXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAxNi9q

LmpuZXVyb2ltLjIwMDQuMTAuMDA2PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJv

bmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ouam5ldXJvaW0uMjAwNC4xMC4wMDY8L2VsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkZ1aHJtYW5uPC9B

dXRob3I+PFllYXI+MjAxMDwvWWVhcj48UmVjTnVtPjExOTQ8L1JlY051bT48cmVjb3JkPjxyZWMt

bnVtYmVyPjExOTQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk

PSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2

NTkxOCI+MTE5NDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFy

dGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RnVocm1h

bm4sIE1hcnRpbjwvYXV0aG9yPjxhdXRob3I+Qml0dG5lciwgVG9iaWFzPC9hdXRob3I+PGF1dGhv

cj5KdW5nLCBDaHJpc3RpYW4gSy4gRS48L2F1dGhvcj48YXV0aG9yPkJ1cmdvbGQsIFN0ZWZmZW48

L2F1dGhvcj48YXV0aG9yPlBhZ2UsIFJpY2hhcmQgTS48L2F1dGhvcj48YXV0aG9yPk1pdHRlcmVn

Z2VyLCBHZXJkYTwvYXV0aG9yPjxhdXRob3I+SGFhc3MsIENocmlzdGlhbjwvYXV0aG9yPjxhdXRo

b3I+TGFGZXJsYSwgRnJhbmsgTS48L2F1dGhvcj48YXV0aG9yPktyZXR6c2NobWFyLCBIYW5zPC9h

dXRob3I+PGF1dGhvcj5IZXJtcywgSm9jaGVuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjx0aXRsZXM+PHRpdGxlPk1pY3JvZ2xpYWwgQ3gzY3IxIGtub2Nrb3V0IHByZXZlbnRzIG5l

dXJvbiBsb3NzIGluIGEgbW91c2UgbW9kZWwgb2YgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5hdHVyZSBOZXVyb3NjaWVuY2U8L3NlY29uZGFyeS10aXRs

ZT48L3RpdGxlcz48cGFnZXM+NDExLTQxMzwvcGFnZXM+PHZvbHVtZT4xMzwvdm9sdW1lPjxudW1i

ZXI+NDwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAx

MC8wMy8yMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxwdWJsaXNoZXI+U3ByaW5nZXIgTmF0

dXJlPC9wdWJsaXNoZXI+PGlzYm4+MTA5Ny02MjU2JiN4RDsxNTQ2LTE3MjY8L2lzYm4+PHVybHM+

PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjEwMzgvbm4uMjUxMTwvdXJs

PjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9u

bi4yNTExPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3Rl

PgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYXVyZW50PC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjExODA8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4xOTQsMjA0LTIwODwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEx

ODA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1

MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTkxOCI+MTE4

MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3

PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TGF1cmVudCwgQ3lyaWw8

L2F1dGhvcj48YXV0aG9yPkRvcm90aMOpZSwgR3VpbGxhdW1lPC9hdXRob3I+PGF1dGhvcj5IdW5v

dCwgU3TDqXBoYW5lPC9hdXRob3I+PGF1dGhvcj5NYXJ0aW4sIEVsb2RpZTwvYXV0aG9yPjxhdXRo

b3I+TW9ubmV0LCBZYW5uPC9hdXRob3I+PGF1dGhvcj5EdWNoYW1wLCBNYXJpZTwvYXV0aG9yPjxh

dXRob3I+RG9uZywgWXVhbjwvYXV0aG9yPjxhdXRob3I+TMOpZ2Vyb24sIEZyYW7Dp29pcy1QaWVy

cmU8L2F1dGhvcj48YXV0aG9yPkxlYm91Y2hlciwgQW50b2luZTwvYXV0aG9yPjxhdXRob3I+QnVy

bm91ZiwgU3lsdmllPC9hdXRob3I+PGF1dGhvcj5GYWl2cmUsIEVtaWxpZTwvYXV0aG9yPjxhdXRo

b3I+Q2FydmFsaG8sIEvDqXZpbjwvYXV0aG9yPjxhdXRob3I+Q2FpbGxpZXJleiwgUmFwaGHDq2xs

ZTwvYXV0aG9yPjxhdXRob3I+Wm9tbWVyLCBOYWTDqGdlPC9hdXRob3I+PGF1dGhvcj5EZW1leWVy

LCBEb21pbmlxdWU8L2F1dGhvcj48YXV0aG9yPkpvdXksIE5hdGhhbGllPC9hdXRob3I+PGF1dGhv

cj5TYXpkb3ZpdGNoLCBWZXJvbmlxdWU8L2F1dGhvcj48YXV0aG9yPlNjaHJhZW4tTWFzY2hrZSwg

U3VzYW5uYTwvYXV0aG9yPjxhdXRob3I+RGVsYXJhc3NlLCBDw6ljaWxlPC9hdXRob3I+PGF1dGhv

cj5CdcOpZSwgTHVjPC9hdXRob3I+PGF1dGhvcj5CbHVtLCBEYXZpZDwvYXV0aG9yPjwvYXV0aG9y

cz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5IaXBwb2NhbXBhbCBUIGNlbGwgaW5maWx0

cmF0aW9uIHByb21vdGVzIG5ldXJvaW5mbGFtbWF0aW9uIGFuZCBjb2duaXRpdmUgZGVjbGluZSBp

biBhIG1vdXNlIG1vZGVsIG9mIHRhdW9wYXRoeTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5CcmFp

bjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkJyYWlu

PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTg0LTIwMDwvcGFnZXM+PHZvbHVtZT4x

NDA8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHVi

LWRhdGVzPjxkYXRlPjIwMTYvMTEvMDU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlz

aGVyPk94Zm9yZCBVbml2ZXJzaXR5IFByZXNzIChPVVApPC9wdWJsaXNoZXI+PGlzYm4+MDAwNi04

OTUwJiN4RDsxNDYwLTIxNTY8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9k

eC5kb2kub3JnLzEwLjEwOTMvYnJhaW4vYXd3MjcwPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxz

PjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDkzL2JyYWluL2F3dzI3MDwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+S3JhdXRoYXVzZW48

L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNOdW0+MTE5MDwvUmVjTnVtPjxyZWNvcmQ+PHJl

Yy1udW1iZXI+MTE5MDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGIt

aWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMy

ODY1OTE4Ij4xMTkwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwg

QXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LcmF1

dGhhdXNlbiwgTWFyaXVzPC9hdXRob3I+PGF1dGhvcj5LdW1tZXIsIE1hcmt1cyBQLjwvYXV0aG9y

PjxhdXRob3I+WmltbWVybWFubiwgSnVsaWFuPC9hdXRob3I+PGF1dGhvcj5SZXllcy1JcmlzYXJy

aSwgRWxpc2FiZXQ8L2F1dGhvcj48YXV0aG9yPlRlcndlbCwgRGljazwvYXV0aG9yPjxhdXRob3I+

QnVsaWMsIEJydW5vPC9hdXRob3I+PGF1dGhvcj5IZW5la2EsIE1pY2hhZWwgVC48L2F1dGhvcj48

YXV0aG9yPk3DvGxsZXIsIE1hcmN1czwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48

dGl0bGVzPjx0aXRsZT5DWENSMyBwcm9tb3RlcyBwbGFxdWUgZm9ybWF0aW9uIGFuZCBiZWhhdmlv

cmFsIGRlZmljaXRzIGluIGFuIEFsemhlaW1lcuKAmXMgZGlzZWFzZSBtb2RlbDwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5Kb3VybmFsIG9mIENsaW5pY2FsIEludmVzdGlnYXRpb248L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGFnZXM+MzY1LTM3ODwvcGFnZXM+PHZvbHVtZT4xMjU8L3ZvbHVt

ZT48bnVtYmVyPjE8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48cHViLWRhdGVzPjxk

YXRlPjIwMTQvMTIvMTU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkFtZXJp

Y2FuIFNvY2lldHkgZm9yIENsaW5pY2FsIEludmVzdGlnYXRpb248L3B1Ymxpc2hlcj48aXNibj4w

MDIxLTk3Mzg8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3Jn

LzEwLjExNzIvamNpNjY3NzE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjEwLjExNzIvamNpNjY3NzE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwv

cmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlRvcnJlczwvQXV0aG9yPjxZZWFyPjIwMTI8L1ll

YXI+PFJlY051bT4xMTkxPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4xMTkxPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU5MTgiPjExOTE8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlRvcnJlcywgS2FyZW4gQy4gTC48L2F1dGhv

cj48YXV0aG9yPlNhbnRvcywgUm9kcmlnbyBSLjwvYXV0aG9yPjxhdXRob3I+ZGUgTGltYSwgR2lz

ZWxsZSBTLiBGLjwvYXV0aG9yPjxhdXRob3I+RmVycmVpcmEsIFJhcGhhZWwgTy4gUy48L2F1dGhv

cj48YXV0aG9yPk1hcGEsIEZpbGlwZSBDLjwvYXV0aG9yPjxhdXRob3I+UGVyZWlyYSwgUGF0csOt

Y2lhIEEuPC9hdXRob3I+PGF1dGhvcj5SZXplbmRlLCBWaXRvciBCLjwvYXV0aG9yPjxhdXRob3I+

TWFydGlucywgTHVpemEgQy4gQS48L2F1dGhvcj48YXV0aG9yPkJpY2FsaG8sIE1hcmlhIEEuIEMu

PC9hdXRob3I+PGF1dGhvcj5Nb3JhZXMsIEVkZ2FyIE4uPC9hdXRob3I+PGF1dGhvcj5SZWlzLCBI

ZWx0b24gSi48L2F1dGhvcj48YXV0aG9yPlRlaXhlaXJhLCBBbnRvbmlvIEwuPC9hdXRob3I+PGF1

dGhvcj5Sb21hbm8tU2lsdmEsIE1hcmNvIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjx0aXRsZXM+PHRpdGxlPkRlY3JlYXNlZCBFeHByZXNzaW9uIG9mIENDTDMgaW4gTW9ub2N5

dGVzIGFuZCBDQ1I1IGluIEx5bXBob2N5dGVzIEZyb20gRnJvbnRvdGVtcG9yYWwgRGVtZW50aWEg

YXMgQ29tcGFyZWQgV2l0aCBBbHpoZWltZXLigJlzIERpc2Vhc2UgUGF0aWVudHM8L3RpdGxlPjxz

ZWNvbmRhcnktdGl0bGU+VGhlIEpvdXJuYWwgb2YgTmV1cm9wc3ljaGlhdHJ5IGFuZCBDbGluaWNh

bCBOZXVyb3NjaWVuY2VzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPkUxMS1FMTI8

L3BhZ2VzPjx2b2x1bWU+MjQ8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48ZGF0ZXM+PHllYXI+

MjAxMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTIvMDE8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48cHVibGlzaGVyPkFtZXJpY2FuIFBzeWNoaWF0cmljIFB1Ymxpc2hpbmc8L3B1Ymxpc2hl

cj48aXNibj4wODk1LTAxNzImI3hEOzE1NDUtNzIyMjwvaXNibj48dXJscz48cmVsYXRlZC11cmxz

Pjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTE3Ni9hcHBpLm5ldXJvcHN5Y2guMTEwNjAxNDM8

L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEx

NzYvYXBwaS5uZXVyb3BzeWNoLjExMDYwMTQzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3Jl

Y29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5aaHU8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS

ZWNOdW0+MTE5MjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTE5MjwvcmVjLW51bWJlcj48

Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4

OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyODY1OTE4Ij4xMTkyPC9rZXk+PC9mb3JlaWdu

LWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250

cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5aaHUsIE1pbjwvYXV0aG9yPjxhdXRob3I+QWxsYXJk

LCBKb2FubmUgUy48L2F1dGhvcj48YXV0aG9yPlpoYW5nLCBZb25ncWluZzwvYXV0aG9yPjxhdXRo

b3I+UGVyZXosIEV2ZWx5bjwvYXV0aG9yPjxhdXRob3I+U3BhbmdsZXIsIEVkd2FyZCBMLjwvYXV0

aG9yPjxhdXRob3I+QmVja2VyLCBLZXZpbiBHLjwvYXV0aG9yPjxhdXRob3I+UmFwcCwgUGV0ZXIg

Ui48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QWdlLVJl

bGF0ZWQgQnJhaW4gRXhwcmVzc2lvbiBhbmQgUmVndWxhdGlvbiBvZiB0aGUgQ2hlbW9raW5lIEND

TDQvTUlQLTHOsiBpbiBBUFAvUFMxIERvdWJsZS1UcmFuc2dlbmljIE1pY2U8L3RpdGxlPjxzZWNv

bmRhcnktdGl0bGU+Sm91cm5hbCBvZiBOZXVyb3BhdGhvbG9neSAmYW1wOyBFeHBlcmltZW50YWwg

TmV1cm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjM2Mi0zNzQ8L3BhZ2Vz

Pjx2b2x1bWU+NzM8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNDwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTQvMDQ8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

cHVibGlzaGVyPk94Zm9yZCBVbml2ZXJzaXR5IFByZXNzIChPVVApPC9wdWJsaXNoZXI+PGlzYm4+

MDAyMi0zMDY5PC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9y

Zy8xMC4xMDk3L25lbi4wMDAwMDAwMDAwMDAwMDYwPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxz

PjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDk3L25lbi4wMDAwMDAwMDAwMDAwMDYwPC9l

bGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5GcmFu

Y2lvc2k8L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxSZWNOdW0+MTE5MzwvUmVjTnVtPjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTE5MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1w

PSIxNTMyODY1OTE4Ij4xMTkzPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5GcmFuY2lvc2ksIFNvbmlhPC9hdXRob3I+PGF1dGhvcj5DaG9pLCBIeXVuIEIuPC9hdXRob3I+

PGF1dGhvcj5LaW0sIFNldW5nIFUuPC9hdXRob3I+PGF1dGhvcj5NY0xhcm5vbiwgSmFtZXMgRy48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+SUwtOCBlbmhh

bmNlbWVudCBvZiBhbXlsb2lkLWJldGEgKEHOsjEtNDIpLWluZHVjZWQgZXhwcmVzc2lvbiBhbmQg

cHJvZHVjdGlvbiBvZiBwcm8taW5mbGFtbWF0b3J5IGN5dG9raW5lcyBhbmQgQ09YLTIgaW4gY3Vs

dHVyZWQgaHVtYW4gbWljcm9nbGlhPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkpvdXJuYWwgb2Yg

TmV1cm9pbW11bm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjY2LTc0PC9w

YWdlcz48dm9sdW1lPjE1OTwvdm9sdW1lPjxudW1iZXI+MS0yPC9udW1iZXI+PGRhdGVzPjx5ZWFy

PjIwMDU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDA1LzAyPC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PHB1Ymxpc2hlcj5FbHNldmllciBCVjwvcHVibGlzaGVyPjxpc2JuPjAxNjUtNTcyODwv

aXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAxNi9q

LmpuZXVyb2ltLjIwMDQuMTAuMDA2PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJv

bmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ouam5ldXJvaW0uMjAwNC4xMC4wMDY8L2VsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkZ1aHJtYW5uPC9B

dXRob3I+PFllYXI+MjAxMDwvWWVhcj48UmVjTnVtPjExOTQ8L1JlY051bT48cmVjb3JkPjxyZWMt

bnVtYmVyPjExOTQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk

PSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2

NTkxOCI+MTE5NDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFy

dGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RnVocm1h

bm4sIE1hcnRpbjwvYXV0aG9yPjxhdXRob3I+Qml0dG5lciwgVG9iaWFzPC9hdXRob3I+PGF1dGhv

cj5KdW5nLCBDaHJpc3RpYW4gSy4gRS48L2F1dGhvcj48YXV0aG9yPkJ1cmdvbGQsIFN0ZWZmZW48

L2F1dGhvcj48YXV0aG9yPlBhZ2UsIFJpY2hhcmQgTS48L2F1dGhvcj48YXV0aG9yPk1pdHRlcmVn

Z2VyLCBHZXJkYTwvYXV0aG9yPjxhdXRob3I+SGFhc3MsIENocmlzdGlhbjwvYXV0aG9yPjxhdXRo

b3I+TGFGZXJsYSwgRnJhbmsgTS48L2F1dGhvcj48YXV0aG9yPktyZXR6c2NobWFyLCBIYW5zPC9h

dXRob3I+PGF1dGhvcj5IZXJtcywgSm9jaGVuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjx0aXRsZXM+PHRpdGxlPk1pY3JvZ2xpYWwgQ3gzY3IxIGtub2Nrb3V0IHByZXZlbnRzIG5l

dXJvbiBsb3NzIGluIGEgbW91c2UgbW9kZWwgb2YgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5hdHVyZSBOZXVyb3NjaWVuY2U8L3NlY29uZGFyeS10aXRs

ZT48L3RpdGxlcz48cGFnZXM+NDExLTQxMzwvcGFnZXM+PHZvbHVtZT4xMzwvdm9sdW1lPjxudW1i

ZXI+NDwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAx

MC8wMy8yMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxwdWJsaXNoZXI+U3ByaW5nZXIgTmF0

dXJlPC9wdWJsaXNoZXI+PGlzYm4+MTA5Ny02MjU2JiN4RDsxNTQ2LTE3MjY8L2lzYm4+PHVybHM+

PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjEwMzgvbm4uMjUxMTwvdXJs

PjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9u

bi4yNTExPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3Rl

PgB=

ADDIN EN.CITE.DATA 194,204-208. On the contrary, CCL5 is known as neuroprotective PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UcmlwYXRoeTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+

PFJlY051bT4xMTk1PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjA5LDIxMDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjExOTU8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTkxOCI+MTE5NTwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+VHJpcGF0aHksIERlYmphbmk8

L2F1dGhvcj48YXV0aG9yPlRoaXJ1bWFuZ2FsYWt1ZGksIExha3NobWk8L2F1dGhvcj48YXV0aG9y

PkdyYW1tYXMsIFBhdWxhPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+

PHRpdGxlPlJBTlRFUyB1cHJlZ3VsYXRpb24gaW4gdGhlIEFsemhlaW1lciZhcG9zO3MgZGlzZWFz

ZSBicmFpbjogQSBwb3NzaWJsZSBuZXVyb3Byb3RlY3RpdmUgcm9sZTwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5OZXVyb2Jpb2xvZ3kgb2YgQWdpbmc8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48

cGFnZXM+OC0xNjwvcGFnZXM+PHZvbHVtZT4zMTwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxk

YXRlcz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxMC8wMTwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxwdWJsaXNoZXI+RWxzZXZpZXIgQlY8L3B1Ymxpc2hlcj48aXNibj4w

MTk3LTQ1ODA8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3Jn

LzEwLjEwMTYvai5uZXVyb2Jpb2xhZ2luZy4yMDA4LjAzLjAwOTwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLm5ldXJvYmlvbGFnaW5n

LjIwMDguMDMuMDA5PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENp

dGU+PEF1dGhvcj5MZWU8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxSZWNOdW0+MTE5NjwvUmVj

TnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTE5NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxr

ZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIg

dGltZXN0YW1wPSIxNTMyODY1OTE4Ij4xMTk2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5MZWUsIEpvbmcgS2lsPC9hdXRob3I+PGF1dGhvcj5TY2h1Y2htYW4sIEVkd2Fy

ZCBILjwvYXV0aG9yPjxhdXRob3I+SmluLCBIZWUgS3l1bmc8L2F1dGhvcj48YXV0aG9yPkJhZSwg

SmFlLVN1bmc8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+

U29sdWJsZSBDQ0w1IERlcml2ZWQgZnJvbSBCb25lIE1hcnJvdy1EZXJpdmVkIE1lc2VuY2h5bWFs

IFN0ZW0gQ2VsbHMgYW5kIEFjdGl2YXRlZCBieSBBbXlsb2lkIM6yIEFtZWxpb3JhdGVzIEFsemhl

aW1lciZhcG9zO3MgRGlzZWFzZSBpbiBNaWNlIGJ5IFJlY3J1aXRpbmcgQm9uZSBNYXJyb3ctSW5k

dWNlZCBNaWNyb2dsaWEgSW1tdW5lIFJlc3BvbnNlczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5T

VEVNIENFTExTPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjE1NDQtMTU1NTwvcGFn

ZXM+PHZvbHVtZT4zMDwvdm9sdW1lPjxudW1iZXI+NzwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDEy

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxMi8wNi8xODwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxwdWJsaXNoZXI+V2lsZXk8L3B1Ymxpc2hlcj48aXNibj4xMDY2LTUwOTk8L2lzYm4+PHVy

bHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjEwMDIvc3RlbS4xMTI1

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4x

MDAyL3N0ZW0uMTEyNTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwv

RW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UcmlwYXRoeTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+

PFJlY051bT4xMTk1PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjA5LDIxMDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjExOTU8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTkxOCI+MTE5NTwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+VHJpcGF0aHksIERlYmphbmk8

L2F1dGhvcj48YXV0aG9yPlRoaXJ1bWFuZ2FsYWt1ZGksIExha3NobWk8L2F1dGhvcj48YXV0aG9y

PkdyYW1tYXMsIFBhdWxhPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+

PHRpdGxlPlJBTlRFUyB1cHJlZ3VsYXRpb24gaW4gdGhlIEFsemhlaW1lciZhcG9zO3MgZGlzZWFz

ZSBicmFpbjogQSBwb3NzaWJsZSBuZXVyb3Byb3RlY3RpdmUgcm9sZTwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5OZXVyb2Jpb2xvZ3kgb2YgQWdpbmc8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48

cGFnZXM+OC0xNjwvcGFnZXM+PHZvbHVtZT4zMTwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxk

YXRlcz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxMC8wMTwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxwdWJsaXNoZXI+RWxzZXZpZXIgQlY8L3B1Ymxpc2hlcj48aXNibj4w

MTk3LTQ1ODA8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3Jn

LzEwLjEwMTYvai5uZXVyb2Jpb2xhZ2luZy4yMDA4LjAzLjAwOTwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLm5ldXJvYmlvbGFnaW5n

LjIwMDguMDMuMDA5PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENp

dGU+PEF1dGhvcj5MZWU8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxSZWNOdW0+MTE5NjwvUmVj

TnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTE5NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxr

ZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIg

dGltZXN0YW1wPSIxNTMyODY1OTE4Ij4xMTk2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5MZWUsIEpvbmcgS2lsPC9hdXRob3I+PGF1dGhvcj5TY2h1Y2htYW4sIEVkd2Fy

ZCBILjwvYXV0aG9yPjxhdXRob3I+SmluLCBIZWUgS3l1bmc8L2F1dGhvcj48YXV0aG9yPkJhZSwg

SmFlLVN1bmc8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+

U29sdWJsZSBDQ0w1IERlcml2ZWQgZnJvbSBCb25lIE1hcnJvdy1EZXJpdmVkIE1lc2VuY2h5bWFs

IFN0ZW0gQ2VsbHMgYW5kIEFjdGl2YXRlZCBieSBBbXlsb2lkIM6yIEFtZWxpb3JhdGVzIEFsemhl

aW1lciZhcG9zO3MgRGlzZWFzZSBpbiBNaWNlIGJ5IFJlY3J1aXRpbmcgQm9uZSBNYXJyb3ctSW5k

dWNlZCBNaWNyb2dsaWEgSW1tdW5lIFJlc3BvbnNlczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5T

VEVNIENFTExTPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjE1NDQtMTU1NTwvcGFn

ZXM+PHZvbHVtZT4zMDwvdm9sdW1lPjxudW1iZXI+NzwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDEy

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxMi8wNi8xODwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxwdWJsaXNoZXI+V2lsZXk8L3B1Ymxpc2hlcj48aXNibj4xMDY2LTUwOTk8L2lzYm4+PHVy

bHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjEwMDIvc3RlbS4xMTI1

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4x

MDAyL3N0ZW0uMTEyNTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwv

RW5kTm90ZT5=

ADDIN EN.CITE.DATA 209,210. Beside the too high or too low levels of somes chemokines including CCL2 are unfavorable in AD because the physiological activation of the CCL2/CCR2 signaling pathway is crucial to limit the progression of the disease in AD experimental models PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYWVydDwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl

Y051bT4xMTk3PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MjExLTIxMzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjExOTc8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTkxOCI+MTE5Nzwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TmFlcnQsIEcuPC9hdXRob3I+PGF1

dGhvcj5SaXZlc3QsIFMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+

PHRpdGxlPkNDIENoZW1va2luZSBSZWNlcHRvciAyIERlZmljaWVuY3kgQWdncmF2YXRlcyBDb2du

aXRpdmUgSW1wYWlybWVudHMgYW5kIEFteWxvaWQgUGF0aG9sb2d5IGluIGEgVHJhbnNnZW5pYyBN

b3VzZSBNb2RlbCBvZiBBbHpoZWltZXImYXBvcztzIERpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+Sm91cm5hbCBvZiBOZXVyb3NjaWVuY2U8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48

cGFnZXM+NjIwOC02MjIwPC9wYWdlcz48dm9sdW1lPjMxPC92b2x1bWU+PG51bWJlcj4xNjwvbnVt

YmVyPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxMS8wNC8yMDwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxwdWJsaXNoZXI+U29jaWV0eSBmb3IgTmV1cm9zY2ll

bmNlPC9wdWJsaXNoZXI+PGlzYm4+MDI3MC02NDc0JiN4RDsxNTI5LTI0MDE8L2lzYm4+PHVybHM+

PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjE1MjMvam5ldXJvc2NpLjAy

OTktMTEuMjAxMTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJj

ZS1udW0+MTAuMTUyMy9qbmV1cm9zY2kuMDI5OS0xMS4yMDExPC9lbGVjdHJvbmljLXJlc291cmNl

LW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5LaXlvdGE8L0F1dGhvcj48WWVhcj4y

MDA5PC9ZZWFyPjxSZWNOdW0+MTE5ODwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTE5ODwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyODY1OTE4Ij4xMTk4PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LaXlvdGEsIFRvbW9taTwvYXV0

aG9yPjxhdXRob3I+WWFtYW1vdG8sIE1hc2FydTwvYXV0aG9yPjxhdXRob3I+WGlvbmcsIEh1YW5n

dWk8L2F1dGhvcj48YXV0aG9yPkxhbWJlcnQsIE1hcnkgUC48L2F1dGhvcj48YXV0aG9yPktsZWlu

LCBXaWxsaWFtIEwuPC9hdXRob3I+PGF1dGhvcj5HZW5kZWxtYW4sIEhvd2FyZCBFLjwvYXV0aG9y

PjxhdXRob3I+UmFuc29ob2ZmLCBSaWNoYXJkIE0uPC9hdXRob3I+PGF1dGhvcj5Ja2V6dSwgVHN1

bmV5YTwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5DQ0wy

IEFjY2VsZXJhdGVzIE1pY3JvZ2xpYS1NZWRpYXRlZCBBzrIgT2xpZ29tZXIgRm9ybWF0aW9uIGFu

ZCBQcm9ncmVzc2lvbiBvZiBOZXVyb2NvZ25pdGl2ZSBEeXNmdW5jdGlvbjwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5QTG9TIE9ORTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPlBMb1MgT25lPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+ZTYx

OTc8L3BhZ2VzPjx2b2x1bWU+NDwvdm9sdW1lPjxudW1iZXI+NzwvbnVtYmVyPjxkYXRlcz48eWVh

cj4yMDA5PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAwOS8wNy8xMDwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxwdWJsaXNoZXI+UHVibGljIExpYnJhcnkgb2YgU2NpZW5jZSAoUExvUyk8L3B1

Ymxpc2hlcj48aXNibj4xOTMyLTYyMDM8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0

dHA6Ly9keC5kb2kub3JnLzEwLjEzNzEvam91cm5hbC5wb25lLjAwMDYxOTc8L3VybD48L3JlbGF0

ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEzNzEvam91cm5hbC5w

b25lLjAwMDYxOTc8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0

ZT48QXV0aG9yPllhbWFtb3RvPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48UmVjTnVtPjExOTk8

L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjExOTk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5

cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1

YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTkxOCI+MTE5OTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYt

dHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxh

dXRob3JzPjxhdXRob3I+WWFtYW1vdG8sIE1hc2FydTwvYXV0aG9yPjxhdXRob3I+SG9yaWJhLCBN

YXNhaGlkZTwvYXV0aG9yPjxhdXRob3I+QnVlc2NoZXIsIEphbWVzIEwuPC9hdXRob3I+PGF1dGhv

cj5IdWFuZywgRGVSZW5nPC9hdXRob3I+PGF1dGhvcj5HZW5kZWxtYW4sIEhvd2FyZCBFLjwvYXV0

aG9yPjxhdXRob3I+UmFuc29ob2ZmLCBSaWNoYXJkIE0uPC9hdXRob3I+PGF1dGhvcj5Ja2V6dSwg

VHN1bmV5YTwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5P

dmVyZXhwcmVzc2lvbiBvZiBNb25vY3l0ZSBDaGVtb3RhY3RpYyBQcm90ZWluLTEvQ0NMMiBpbiDO

si1BbXlsb2lkIFByZWN1cnNvciBQcm90ZWluIFRyYW5zZ2VuaWMgTWljZSBTaG93IEFjY2VsZXJh

dGVkIERpZmZ1c2UgzrItQW15bG9pZCBEZXBvc2l0aW9uPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PlRoZSBBbWVyaWNhbiBKb3VybmFsIG9mIFBhdGhvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0

bGVzPjxwYWdlcz4xNDc1LTE0ODU8L3BhZ2VzPjx2b2x1bWU+MTY2PC92b2x1bWU+PG51bWJlcj41

PC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMDU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDA1LzA1

PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5FbHNldmllciBCVjwvcHVibGlz

aGVyPjxpc2JuPjAwMDItOTQ0MDwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDov

L2R4LmRvaS5vcmcvMTAuMTAxNi9zMDAwMi05NDQwKDEwKTYyMzY0LTQ8L3VybD48L3JlbGF0ZWQt

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvczAwMDItOTQ0MCgx

MCk2MjM2NC00PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmRO

b3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYWVydDwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl

Y051bT4xMTk3PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MjExLTIxMzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjExOTc8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTkxOCI+MTE5Nzwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TmFlcnQsIEcuPC9hdXRob3I+PGF1

dGhvcj5SaXZlc3QsIFMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+

PHRpdGxlPkNDIENoZW1va2luZSBSZWNlcHRvciAyIERlZmljaWVuY3kgQWdncmF2YXRlcyBDb2du

aXRpdmUgSW1wYWlybWVudHMgYW5kIEFteWxvaWQgUGF0aG9sb2d5IGluIGEgVHJhbnNnZW5pYyBN

b3VzZSBNb2RlbCBvZiBBbHpoZWltZXImYXBvcztzIERpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+Sm91cm5hbCBvZiBOZXVyb3NjaWVuY2U8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48

cGFnZXM+NjIwOC02MjIwPC9wYWdlcz48dm9sdW1lPjMxPC92b2x1bWU+PG51bWJlcj4xNjwvbnVt

YmVyPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxMS8wNC8yMDwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxwdWJsaXNoZXI+U29jaWV0eSBmb3IgTmV1cm9zY2ll

bmNlPC9wdWJsaXNoZXI+PGlzYm4+MDI3MC02NDc0JiN4RDsxNTI5LTI0MDE8L2lzYm4+PHVybHM+

PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjE1MjMvam5ldXJvc2NpLjAy

OTktMTEuMjAxMTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJj

ZS1udW0+MTAuMTUyMy9qbmV1cm9zY2kuMDI5OS0xMS4yMDExPC9lbGVjdHJvbmljLXJlc291cmNl

LW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5LaXlvdGE8L0F1dGhvcj48WWVhcj4y

MDA5PC9ZZWFyPjxSZWNOdW0+MTE5ODwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTE5ODwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyODY1OTE4Ij4xMTk4PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LaXlvdGEsIFRvbW9taTwvYXV0

aG9yPjxhdXRob3I+WWFtYW1vdG8sIE1hc2FydTwvYXV0aG9yPjxhdXRob3I+WGlvbmcsIEh1YW5n

dWk8L2F1dGhvcj48YXV0aG9yPkxhbWJlcnQsIE1hcnkgUC48L2F1dGhvcj48YXV0aG9yPktsZWlu

LCBXaWxsaWFtIEwuPC9hdXRob3I+PGF1dGhvcj5HZW5kZWxtYW4sIEhvd2FyZCBFLjwvYXV0aG9y

PjxhdXRob3I+UmFuc29ob2ZmLCBSaWNoYXJkIE0uPC9hdXRob3I+PGF1dGhvcj5Ja2V6dSwgVHN1

bmV5YTwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5DQ0wy

IEFjY2VsZXJhdGVzIE1pY3JvZ2xpYS1NZWRpYXRlZCBBzrIgT2xpZ29tZXIgRm9ybWF0aW9uIGFu

ZCBQcm9ncmVzc2lvbiBvZiBOZXVyb2NvZ25pdGl2ZSBEeXNmdW5jdGlvbjwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5QTG9TIE9ORTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPlBMb1MgT25lPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+ZTYx

OTc8L3BhZ2VzPjx2b2x1bWU+NDwvdm9sdW1lPjxudW1iZXI+NzwvbnVtYmVyPjxkYXRlcz48eWVh

cj4yMDA5PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAwOS8wNy8xMDwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxwdWJsaXNoZXI+UHVibGljIExpYnJhcnkgb2YgU2NpZW5jZSAoUExvUyk8L3B1

Ymxpc2hlcj48aXNibj4xOTMyLTYyMDM8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0

dHA6Ly9keC5kb2kub3JnLzEwLjEzNzEvam91cm5hbC5wb25lLjAwMDYxOTc8L3VybD48L3JlbGF0

ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEzNzEvam91cm5hbC5w

b25lLjAwMDYxOTc8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0

ZT48QXV0aG9yPllhbWFtb3RvPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48UmVjTnVtPjExOTk8

L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjExOTk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5

cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1

YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTkxOCI+MTE5OTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYt

dHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxh

dXRob3JzPjxhdXRob3I+WWFtYW1vdG8sIE1hc2FydTwvYXV0aG9yPjxhdXRob3I+SG9yaWJhLCBN

YXNhaGlkZTwvYXV0aG9yPjxhdXRob3I+QnVlc2NoZXIsIEphbWVzIEwuPC9hdXRob3I+PGF1dGhv

cj5IdWFuZywgRGVSZW5nPC9hdXRob3I+PGF1dGhvcj5HZW5kZWxtYW4sIEhvd2FyZCBFLjwvYXV0

aG9yPjxhdXRob3I+UmFuc29ob2ZmLCBSaWNoYXJkIE0uPC9hdXRob3I+PGF1dGhvcj5Ja2V6dSwg

VHN1bmV5YTwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5P

dmVyZXhwcmVzc2lvbiBvZiBNb25vY3l0ZSBDaGVtb3RhY3RpYyBQcm90ZWluLTEvQ0NMMiBpbiDO

si1BbXlsb2lkIFByZWN1cnNvciBQcm90ZWluIFRyYW5zZ2VuaWMgTWljZSBTaG93IEFjY2VsZXJh

dGVkIERpZmZ1c2UgzrItQW15bG9pZCBEZXBvc2l0aW9uPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PlRoZSBBbWVyaWNhbiBKb3VybmFsIG9mIFBhdGhvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0

bGVzPjxwYWdlcz4xNDc1LTE0ODU8L3BhZ2VzPjx2b2x1bWU+MTY2PC92b2x1bWU+PG51bWJlcj41

PC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMDU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDA1LzA1

PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5FbHNldmllciBCVjwvcHVibGlz

aGVyPjxpc2JuPjAwMDItOTQ0MDwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDov

L2R4LmRvaS5vcmcvMTAuMTAxNi9zMDAwMi05NDQwKDEwKTYyMzY0LTQ8L3VybD48L3JlbGF0ZWQt

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvczAwMDItOTQ0MCgx

MCk2MjM2NC00PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmRO

b3RlPn==

ADDIN EN.CITE.DATA 211-213.In the light of these elements of the literature, we studied the impact of PBMCs issued from AD patients on the chemokines' signature at the level of a healthy BBB, given that the current data on chemokine levels are derived from isolated biological samples (Plasma, serum, brain, cell culture ...) while BBB displays a great cellular and molecular complexity, finely orchestrated to preserve the brain.In a human BBB model comprising two cell lines, an endothelial cell line (hCMEC/D3) and U87 cell line (human glioblastoma), PBMCs from patients (control, mild and moderate AD patients) were added in the luminal medium. It should be noted that all analyses were also performed on isolated cultures of each cell type and on a BBB model without PBMCs. A previous work on a group of patients with AD at a moderate stage has already been published and we also verified in this study with the 3 groups of patients the interest to go to an integrated model to take into account the cellular and molecular interactions in the neurovascular unit ADDIN EN.CITE <EndNote><Cite><Author>Verite</Author><Year>2017</Year><RecNum>1200</RecNum><DisplayText><style face="superscript">214</style></DisplayText><record><rec-number>1200</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865918">1200</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Verite, Julie</author><author>Janet, Thierry</author><author>Julian, Adrien</author><author>Chassaing, Damien</author><author>Page, Guylene</author><author>Paccalin, Marc</author></authors></contributors><titles><title>Peripheral Blood Mononuclear Cells of Alzheimer&apos;s Disease Patients Control CCL4 and CXCL10 Levels in a Human Blood Brain Barrier Model</title><secondary-title>Current Alzheimer Research</secondary-title></titles><volume>14</volume><number>11</number><dates><year>2017</year><pub-dates><date>2017/10/06</date></pub-dates></dates><publisher>Bentham Science Publishers Ltd.</publisher><isbn>1567-2050</isbn><urls><related-urls><url>. Results showed that PBMCs from moderate AD patients decreased CCL2 and CCL5 levels in luminal and abluminal compartments (2-3 fold) and CXCL10 only in the abluminal compartment (3-4 fold) compared to PBMCs from mild AD patients. Levels of CCL2 and CCL5 also significantly decreased on PBMCs of moderate AD patients compared to PBMCs from mild AD patients. The CX3CL1 expression increased in luminal and abluminal compartments with PBMCs from mild AD patients compared to controls ADDIN EN.CITE <EndNote><Cite><Author>Verite</Author><Year>2018</Year><RecNum>4326</RecNum><DisplayText><style face="superscript">215</style></DisplayText><record><rec-number>4326</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1540940484">4326</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Verite, J.</author><author>Janet, T.</author><author>Chassaing, D.</author><author>Fauconneau, B.</author><author>Rabeony, H.</author><author>Page, G.</author></authors></contributors><auth-address>EA3808, molecular Targets and Therapeutics of Alzheimer&apos;s disease, University of Poitiers, 86073, Poitiers, France.&#xD;SATT Grand Centre- Societe d&apos;Acceleration du Transfert de Technologie, 8, rue Pablo Picasso, 63000, Clermont-Ferrand, France.&#xD;EA3808, molecular Targets and Therapeutics of Alzheimer&apos;s disease, University of Poitiers, 86073, Poitiers, France. guylene.page@univ-poitiers.fr.</auth-address><titles><title>Longitudinal chemokine profile expression in a blood-brain barrier model from Alzheimer transgenic versus wild-type mice</title><secondary-title>J Neuroinflammation</secondary-title></titles><periodical><full-title>J Neuroinflammation</full-title></periodical><pages>182</pages><volume>15</volume><number>1</number><keywords><keyword>Alzheimer</keyword><keyword>Blood-brain barrier</keyword><keyword>Chemokines</keyword><keyword>Longitudinal study</keyword><keyword>Mouse</keyword><keyword>Peripheral blood mononuclear cells</keyword><keyword>Primary cell culture</keyword></keywords><dates><year>2018</year><pub-dates><date>Jun 13</date></pub-dates></dates><isbn>1742-2094 (Electronic)&#xD;1742-2094 (Linking)</isbn><accession-num>29898739</accession-num><urls><related-urls><url> a murine BBB model (French patent in August 2017 and PCT extension in August 2018), the impact of mouse PBMCs from transgenic mice (APPswePS1dE9) or their control littermates in the signature of chemokines in BBB prepared from mouse brains was studied at 3, 6 and 12 months. In this model, a healthy abluminal compartment is used, and PBMCs and luminal compartments came from AD or wild-type mice. Compared to results obtained in human BBB model, we also showed a decrease in CCL2 expression (about 6-fold) was shown in the abluminal medium by PBMCs issued from AD mice at 12 months compared to WT mice. Furthermore, results showed an increase in CX3CL1 in the abluminal compartment (2.3-fold) and a decrease (4-5 fold) in cells used in luminal compartment in 12-month-old mice compared to 3-month-old mice ADDIN EN.CITE <EndNote><Cite><Author>Verite</Author><Year>2018</Year><RecNum>4326</RecNum><DisplayText><style face="superscript">215</style></DisplayText><record><rec-number>4326</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1540940484">4326</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Verite, J.</author><author>Janet, T.</author><author>Chassaing, D.</author><author>Fauconneau, B.</author><author>Rabeony, H.</author><author>Page, G.</author></authors></contributors><auth-address>EA3808, molecular Targets and Therapeutics of Alzheimer&apos;s disease, University of Poitiers, 86073, Poitiers, France.&#xD;SATT Grand Centre- Societe d&apos;Acceleration du Transfert de Technologie, 8, rue Pablo Picasso, 63000, Clermont-Ferrand, France.&#xD;EA3808, molecular Targets and Therapeutics of Alzheimer&apos;s disease, University of Poitiers, 86073, Poitiers, France. guylene.page@univ-poitiers.fr.</auth-address><titles><title>Longitudinal chemokine profile expression in a blood-brain barrier model from Alzheimer transgenic versus wild-type mice</title><secondary-title>J Neuroinflammation</secondary-title></titles><periodical><full-title>J Neuroinflammation</full-title></periodical><pages>182</pages><volume>15</volume><number>1</number><keywords><keyword>Alzheimer</keyword><keyword>Blood-brain barrier</keyword><keyword>Chemokines</keyword><keyword>Longitudinal study</keyword><keyword>Mouse</keyword><keyword>Peripheral blood mononuclear cells</keyword><keyword>Primary cell culture</keyword></keywords><dates><year>2018</year><pub-dates><date>Jun 13</date></pub-dates></dates><isbn>1742-2094 (Electronic)&#xD;1742-2094 (Linking)</isbn><accession-num>29898739</accession-num><urls><related-urls><url> both BBB models, the PBMCs come from patients or mice with advanced disease (moderate and 12 months) and the abluminal compartment is healthy. Even if the luminal compartment is AD in the mouse model, we observed: - a significant decrease in CCL2 in abluminal compartment with AD PBMCS (moderate stage or 12 months)- an early increase in CX3CL1 (mild versus controls) in luminal and abluminal media and also an increase in abluminal compartment with mouse AD PBMCs (12 months versus 3 months).It is known that the variations of these two chemokines are deleterious in AD, and it has been demonstrated that they are induced by PBMCs from AD patients or mice with advanced AD. Thus, the results join other publications highlighting an origin of peripheral blood in AD. The modulation of the blood-brain interface by targeting CCL2 and CX3CL1 could be a new therapeutic pathway.Neurovascular junction damage and therapeutic targets: Insights from preclinical research on vascular dementia and microbleedsBackground and rationaleVascular dementia and its most prominent subtype, subcortical atherosclerotic encephalopathy (M. Binswanger), represent the second most frequent and important form of dementia in the elderly after Alzheimer’s disease. It represents about 15% of all dementia cases, while another 15% of cases are mixed forms occurring together with Alzheimer’s disease. Vascular dementia has therefore rapidly gained attention as a growing medical and socioeconomic burden. Vascular dementia and in particular M. Binswanger are characterized by progressive white matter lesions that are strongly related to cognitive decline and believed to be an important pathophysiological hallmark of almost half of all dementias in the elderly (and even beyond “pure” forms of vascular dementia; ADDIN EN.CITE <EndNote><Cite><Author>Gorelick</Author><Year>2011</Year><RecNum>1022</RecNum><DisplayText><style face="superscript">216</style></DisplayText><record><rec-number>1022</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865663">1022</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gorelick, P. B.</author><author>Scuteri, A.</author><author>Black, S. E.</author><author>DeCarli, C.</author><author>Greenberg, S. M.</author><author>Iadecola, C.</author><author>Launer, L. J.</author><author>Laurent, S.</author><author>Lopez, O. L.</author><author>Nyenhuis, D.</author><author>Petersen, R. C.</author><author>Schneider, J. A.</author><author>Tzourio, C.</author><author>Arnett, D. K.</author><author>Bennett, D. A.</author><author>Chui, H. C.</author><author>Higashida, R. T.</author><author>Lindquist, R.</author><author>Nilsson, P. M.</author><author>Roman, G. C.</author><author>Sellke, F. W.</author><author>Seshadri, S.</author></authors></contributors><titles><title>Vascular Contributions to Cognitive Impairment and Dementia: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>2672-2713</pages><volume>42</volume><number>9</number><dates><year>2011</year><pub-dates><date>2011/07/21</date></pub-dates></dates><publisher>Ovid Technologies (Wolters Kluwer Health)</publisher><isbn>0039-2499&#xD;1524-4628</isbn><urls><related-urls><url>. Symptoms of vascular dementia are also observed in cases of disseminated cerebral microbleeds.Despite its significant impact, relatively little is known about central pathomechanisms, and no casual treatments are available so far. It is known, however, that hypertension plays an important role in vascular dementia and rigorously controlling blood pressure may slow down its progress. In turn, increased systolic BP progressively disrupts white matter integrity already in young adults and increases the risk for late-life dementia ADDIN EN.CITE <EndNote><Cite><Author>Maillard</Author><Year>2012</Year><RecNum>1033</RecNum><DisplayText><style face="superscript">217</style></DisplayText><record><rec-number>1033</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865663">1033</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Maillard, Pauline</author><author>Seshadri, Sudha</author><author>Beiser, Alexa</author><author>Himali, Jayandra J.</author><author>Au, Rhoda</author><author>Fletcher, Evan</author><author>Carmichael, Owen</author><author>Wolf, Philip A.</author><author>DeCarli, Charles</author></authors></contributors><titles><title>Effects of systolic blood pressure on white-matter integrity in young adults in the Framingham Heart Study: a cross-sectional study</title><secondary-title>The Lancet Neurology</secondary-title></titles><pages>1039-1047</pages><volume>11</volume><number>12</number><dates><year>2012</year><pub-dates><date>2012/12</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>1474-4422</isbn><urls><related-urls><url>(12)70241-7</url></related-urls></urls><electronic-resource-num>10.1016/s1474-4422(12)70241-7</electronic-resource-num></record></Cite></EndNote>217.In human vascular dementia patients, microbleeds and lacunar infarcts typically occur in the basal ganglia while white matter hyperintensities preferentially develop in the centrum semiovale. Anatomical factors might explain these differing predilection sites: arterioles entering the deep white matter from the superficial cortex are coated by a single leptomeningeal layer rendering them more susceptible to hypertension-related vascular damage PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjMyODY8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4yMTgsMjE5PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzI4Njwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1NjQxNzk4Ij4zMjg2PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XYXJkbGF3LCBKLiBNLjwvYXV0

aG9yPjxhdXRob3I+U21pdGgsIEMuPC9hdXRob3I+PGF1dGhvcj5EaWNoZ2FucywgTS48L2F1dGhv

cj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5OZXVyb2ltYWdpbmcgU2Np

ZW5jZXMsIFVuaXZlcnNpdHkgb2YgRWRpbmJ1cmdoLCBXZXN0ZXJuIEdlbmVyYWwgSG9zcGl0YWws

IEVkaW5idXJnaCBFSDQgMlhVLCBVSy4gam9hbm5hLndhcmRsYXdAZWQuYWMudWs8L2F1dGgtYWRk

cmVzcz48dGl0bGVzPjx0aXRsZT5NZWNoYW5pc21zIG9mIHNwb3JhZGljIGNlcmVicmFsIHNtYWxs

IHZlc3NlbCBkaXNlYXNlOiBpbnNpZ2h0cyBmcm9tIG5ldXJvaW1hZ2luZzwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5MYW5jZXQgTmV1cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2Vz

PjQ4My05NzwvcGFnZXM+PHZvbHVtZT4xMjwvdm9sdW1lPjxudW1iZXI+NTwvbnVtYmVyPjxrZXl3

b3Jkcz48a2V5d29yZD5CcmFpbi8qYmxvb2Qgc3VwcGx5L3BhdGhvbG9neTwva2V5d29yZD48a2V5

d29yZD5DZXJlYnJhbCBTbWFsbCBWZXNzZWwgRGlzZWFzZXMvKnBhdGhvbG9neTwva2V5d29yZD48

a2V5d29yZD5EZW1lbnRpYSwgVmFzY3VsYXIvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5I

dW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9pbWFnaW5nPC9rZXl3b3JkPjwva2V5d29yZHM+

PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXk8L2RhdGU+PC9wdWIt

ZGF0ZXM+PC9kYXRlcz48aXNibj4xNDc0LTQ0NjUgKEVsZWN0cm9uaWMpJiN4RDsxNDc0LTQ0MjIg

KExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIzNjAyMTYyPC9hY2Nlc3Npb24tbnVtPjx1

cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVk

LzIzNjAyMTYyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzM4MzYyNDc8

L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvUzE0NzQtNDQyMigxMyk3

MDA2MC03PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1

dGhvcj5Zb3NoaW5vPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVjTnVtPjMyODU8L1JlY051

bT48cmVjb3JkPjxyZWMtbnVtYmVyPjMyODU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5

IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRp

bWVzdGFtcD0iMTUzNTY0MTc3MSI+MzI4NTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBu

YW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3Jz

PjxhdXRob3I+WW9zaGlubywgSC48L2F1dGhvcj48YXV0aG9yPlNha3VyYWksIFQuPC9hdXRob3I+

PGF1dGhvcj5PaXp1bWksIFguIFMuPC9hdXRob3I+PGF1dGhvcj5Ba2lzYWtpLCBULjwvYXV0aG9y

PjxhdXRob3I+V2FuZywgWC48L2F1dGhvcj48YXV0aG9yPllva29ubywgSy48L2F1dGhvcj48YXV0

aG9yPktvbmRvaCwgVC48L2F1dGhvcj48YXV0aG9yPktvaG11cmEsIEUuPC9hdXRob3I+PGF1dGhv

cj5VbWVudGFuaSwgSy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk

cmVzcz5EZXBhcnRtZW50IG9mIEludGVybmFsIGFuZCBHZXJpYXRyaWMgTWVkaWNpbmUsIEtvYmUg

VW5pdmVyc2l0eSBHcmFkdWF0ZSBTY2hvb2wgb2YgTWVkaWNpbmUsIDctNS0xIEt1c3Vub2tpLWNo

bywgQ2h1by1rdSwgS29iZSA2NTAtMDAxNywgSmFwYW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48

dGl0bGU+RGlsYXRpb24gb2YgcGVyZm9yYXRpbmcgYXJ0ZXJpZXMgaW4gcmF0IGJyYWluIGluIHJl

c3BvbnNlIHRvIHN5c3RlbWljIGh5cG90ZW5zaW9uIGlzIG1vcmUgc2Vuc2l0aXZlIGFuZCBwcm9u

b3VuY2VkIHRoYW4gdGhhdCBvZiBwaWFsIGFydGVyaW9sZXM6IHNpbXVsdGFuZW91cyB2aXN1YWxp

emF0aW9uIG9mIHBlcmZvcmF0aW5nIGFuZCBjb3J0aWNhbCB2ZXNzZWxzIGJ5IGluLXZpdm8gbWlj

cm9hbmdpb2dyYXBoeTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5NaWNyb3Zhc2MgUmVzPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjIzMC0zPC9wYWdlcz48dm9sdW1lPjc3PC92b2x1

bWU+PG51bWJlcj4yPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+

PGtleXdvcmQ+QXJ0ZXJpb2xlcy9kaWFnbm9zdGljIGltYWdpbmcvcGh5c2lvcGF0aG9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPkJsb29kIFByZXNzdXJlPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFs

IEFuZ2lvZ3JhcGh5LyptZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFydGVyaWVz

LypkaWFnbm9zdGljIGltYWdpbmcvKnBoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5D

ZXJlYnJhbCBDb3J0ZXgvYmxvb2Qgc3VwcGx5L2RpYWdub3N0aWMgaW1hZ2luZzwva2V5d29yZD48

a2V5d29yZD5DZXJlYnJvdmFzY3VsYXIgQ2lyY3VsYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+SG9t

ZW9zdGFzaXM8L2tleXdvcmQ+PGtleXdvcmQ+SHlwb3RlbnNpb24vKmRpYWdub3N0aWMgaW1hZ2lu

Zy8qcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdv

cmQ+UGlhIE1hdGVyL2Jsb29kIHN1cHBseS9kaWFnbm9zdGljIGltYWdpbmc8L2tleXdvcmQ+PGtl

eXdvcmQ+UmF0czwva2V5d29yZD48a2V5d29yZD5SYXRzLCBXaXN0YXI8L2tleXdvcmQ+PGtleXdv

cmQ+VmFzb2RpbGF0aW9uPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDk8L3ll

YXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

MDk1LTkzMTkgKEVsZWN0cm9uaWMpJiN4RDswMDI2LTI4NjIgKExpbmtpbmcpPC9pc2JuPjxhY2Nl

c3Npb24tbnVtPjE4OTkyMjYyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy

bD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE4OTkyMjYyPC91cmw+PC9yZWxh

dGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2oubXZyLjIw

MDguMDkuMDExPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmRO

b3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjMyODY8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4yMTgsMjE5PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzI4Njwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1NjQxNzk4Ij4zMjg2PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XYXJkbGF3LCBKLiBNLjwvYXV0

aG9yPjxhdXRob3I+U21pdGgsIEMuPC9hdXRob3I+PGF1dGhvcj5EaWNoZ2FucywgTS48L2F1dGhv

cj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5OZXVyb2ltYWdpbmcgU2Np

ZW5jZXMsIFVuaXZlcnNpdHkgb2YgRWRpbmJ1cmdoLCBXZXN0ZXJuIEdlbmVyYWwgSG9zcGl0YWws

IEVkaW5idXJnaCBFSDQgMlhVLCBVSy4gam9hbm5hLndhcmRsYXdAZWQuYWMudWs8L2F1dGgtYWRk

cmVzcz48dGl0bGVzPjx0aXRsZT5NZWNoYW5pc21zIG9mIHNwb3JhZGljIGNlcmVicmFsIHNtYWxs

IHZlc3NlbCBkaXNlYXNlOiBpbnNpZ2h0cyBmcm9tIG5ldXJvaW1hZ2luZzwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5MYW5jZXQgTmV1cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2Vz

PjQ4My05NzwvcGFnZXM+PHZvbHVtZT4xMjwvdm9sdW1lPjxudW1iZXI+NTwvbnVtYmVyPjxrZXl3

b3Jkcz48a2V5d29yZD5CcmFpbi8qYmxvb2Qgc3VwcGx5L3BhdGhvbG9neTwva2V5d29yZD48a2V5

d29yZD5DZXJlYnJhbCBTbWFsbCBWZXNzZWwgRGlzZWFzZXMvKnBhdGhvbG9neTwva2V5d29yZD48

a2V5d29yZD5EZW1lbnRpYSwgVmFzY3VsYXIvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5I

dW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9pbWFnaW5nPC9rZXl3b3JkPjwva2V5d29yZHM+

PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXk8L2RhdGU+PC9wdWIt

ZGF0ZXM+PC9kYXRlcz48aXNibj4xNDc0LTQ0NjUgKEVsZWN0cm9uaWMpJiN4RDsxNDc0LTQ0MjIg

KExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIzNjAyMTYyPC9hY2Nlc3Npb24tbnVtPjx1

cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVk

LzIzNjAyMTYyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzM4MzYyNDc8

L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvUzE0NzQtNDQyMigxMyk3

MDA2MC03PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1

dGhvcj5Zb3NoaW5vPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVjTnVtPjMyODU8L1JlY051

bT48cmVjb3JkPjxyZWMtbnVtYmVyPjMyODU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5

IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRp

bWVzdGFtcD0iMTUzNTY0MTc3MSI+MzI4NTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBu

YW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3Jz

PjxhdXRob3I+WW9zaGlubywgSC48L2F1dGhvcj48YXV0aG9yPlNha3VyYWksIFQuPC9hdXRob3I+

PGF1dGhvcj5PaXp1bWksIFguIFMuPC9hdXRob3I+PGF1dGhvcj5Ba2lzYWtpLCBULjwvYXV0aG9y

PjxhdXRob3I+V2FuZywgWC48L2F1dGhvcj48YXV0aG9yPllva29ubywgSy48L2F1dGhvcj48YXV0

aG9yPktvbmRvaCwgVC48L2F1dGhvcj48YXV0aG9yPktvaG11cmEsIEUuPC9hdXRob3I+PGF1dGhv

cj5VbWVudGFuaSwgSy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk

cmVzcz5EZXBhcnRtZW50IG9mIEludGVybmFsIGFuZCBHZXJpYXRyaWMgTWVkaWNpbmUsIEtvYmUg

VW5pdmVyc2l0eSBHcmFkdWF0ZSBTY2hvb2wgb2YgTWVkaWNpbmUsIDctNS0xIEt1c3Vub2tpLWNo

bywgQ2h1by1rdSwgS29iZSA2NTAtMDAxNywgSmFwYW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48

dGl0bGU+RGlsYXRpb24gb2YgcGVyZm9yYXRpbmcgYXJ0ZXJpZXMgaW4gcmF0IGJyYWluIGluIHJl

c3BvbnNlIHRvIHN5c3RlbWljIGh5cG90ZW5zaW9uIGlzIG1vcmUgc2Vuc2l0aXZlIGFuZCBwcm9u

b3VuY2VkIHRoYW4gdGhhdCBvZiBwaWFsIGFydGVyaW9sZXM6IHNpbXVsdGFuZW91cyB2aXN1YWxp

emF0aW9uIG9mIHBlcmZvcmF0aW5nIGFuZCBjb3J0aWNhbCB2ZXNzZWxzIGJ5IGluLXZpdm8gbWlj

cm9hbmdpb2dyYXBoeTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5NaWNyb3Zhc2MgUmVzPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjIzMC0zPC9wYWdlcz48dm9sdW1lPjc3PC92b2x1

bWU+PG51bWJlcj4yPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+

PGtleXdvcmQ+QXJ0ZXJpb2xlcy9kaWFnbm9zdGljIGltYWdpbmcvcGh5c2lvcGF0aG9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPkJsb29kIFByZXNzdXJlPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFs

IEFuZ2lvZ3JhcGh5LyptZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFydGVyaWVz

LypkaWFnbm9zdGljIGltYWdpbmcvKnBoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5D

ZXJlYnJhbCBDb3J0ZXgvYmxvb2Qgc3VwcGx5L2RpYWdub3N0aWMgaW1hZ2luZzwva2V5d29yZD48

a2V5d29yZD5DZXJlYnJvdmFzY3VsYXIgQ2lyY3VsYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+SG9t

ZW9zdGFzaXM8L2tleXdvcmQ+PGtleXdvcmQ+SHlwb3RlbnNpb24vKmRpYWdub3N0aWMgaW1hZ2lu

Zy8qcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdv

cmQ+UGlhIE1hdGVyL2Jsb29kIHN1cHBseS9kaWFnbm9zdGljIGltYWdpbmc8L2tleXdvcmQ+PGtl

eXdvcmQ+UmF0czwva2V5d29yZD48a2V5d29yZD5SYXRzLCBXaXN0YXI8L2tleXdvcmQ+PGtleXdv

cmQ+VmFzb2RpbGF0aW9uPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDk8L3ll

YXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

MDk1LTkzMTkgKEVsZWN0cm9uaWMpJiN4RDswMDI2LTI4NjIgKExpbmtpbmcpPC9pc2JuPjxhY2Nl

c3Npb24tbnVtPjE4OTkyMjYyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy

bD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE4OTkyMjYyPC91cmw+PC9yZWxh

dGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2oubXZyLjIw

MDguMDkuMDExPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmRO

b3RlPgB=

ADDIN EN.CITE.DATA 218,219. Microbleeds preferably appear in the basal ganglia.Central hypothesis: Vascular dementia pathophysiology can involve both ischemic and hemorrhagic mechanisms, often occurring simultaneously and contributing to disease progress, neuronal loss, and increasing cognitive decline. Since both occur in areas of blood-brain barrier (BBB) breakdown, processes taking place at the neurovascular junction may be interesting targets to counter vascular dementia. Moreover, inflammation is believed to be a linking element and a major contributor to decline. Another hypothesis is that spontaneously hypertensive rats (SHR) may be a suitable preclinical model system to study vascular dementia and novel therapeutics.In this section, current findings will be outlined from preclinical research that may indicate such novel therapeutic targets for vascular dementia, which, at least in part, may also be relevant for Alzheimer’s disease. Potential therapeutic approaches will also briefly be presented.Preclinical research in vascular dementia: state of the artPreclinical research in vascular dementia relies on a number of animal models, most of which separately mimic a selected aspect of human disease, predominantly lacunar infarcts, white matter damage, and vessel dysfunction. An important animal model are stroke-prone spontaneously hypertensive rats (SHR-SP). They feature most of the cardinal histopathological signs of cerebral small vessel disease (cSVD) ADDIN EN.CITE <EndNote><Cite><Author>Hainsworth</Author><Year>2008</Year><RecNum>1023</RecNum><DisplayText><style face="superscript">220</style></DisplayText><record><rec-number>1023</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865663">1023</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hainsworth, Atticus H.</author><author>Markus, Hugh S.</author></authors></contributors><titles><title>Do in vivo Experimental Models Reflect Human Cerebral Small Vessel Disease? a Systematic Review</title><secondary-title>Journal of Cerebral Blood Flow &amp; Metabolism</secondary-title></titles><pages>1877-1891</pages><volume>28</volume><number>12</number><dates><year>2008</year><pub-dates><date>2008/08/13</date></pub-dates></dates><publisher>SAGE Publications</publisher><isbn>0271-678X&#xD;1559-7016</isbn><urls><related-urls><url> likely as a consequence of chronically increased arterial blood pressure that causes vascular dysfunction ADDIN EN.CITE <EndNote><Cite><Author>Schreiber</Author><Year>2011</Year><RecNum>4278</RecNum><DisplayText><style face="superscript">221</style></DisplayText><record><rec-number>4278</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1540887829">4278</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schreiber, S.</author><author>Bueche, C. Z.</author><author>Garz, C.</author><author>Kropf, S.</author><author>Kuester, D.</author><author>Amann, K.</author><author>Heinze, H. J.</author><author>Goertler, M.</author><author>Reymann, K. G.</author><author>Braun, H.</author></authors></contributors><auth-address>Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany. stefanie.schreiber@med.ovgu.de</auth-address><titles><title>Kidney pathology precedes and predicts the pathological cascade of cerebrovascular lesions in stroke prone rats</title><secondary-title>PLoS One</secondary-title></titles><periodical><full-title>PLoS One</full-title></periodical><pages>e26287</pages><volume>6</volume><number>10</number><edition>2011/10/28</edition><keywords><keyword>Animals</keyword><keyword>Brain/pathology</keyword><keyword>Cerebral Small Vessel Diseases/etiology/metabolism/pathology</keyword><keyword>Cerebrovascular Disorders/*etiology/metabolism/*pathology</keyword><keyword>Kidney/pathology</keyword><keyword>Kidney Diseases/*complications/metabolism/*physiopathology</keyword><keyword>Rats</keyword><keyword>Rats, Inbred SHR</keyword></keywords><dates><year>2011</year></dates><isbn>1932-6203 (Electronic)&#xD;1932-6203 (Linking)</isbn><accession-num>22031827</accession-num><urls><related-urls><url>. However, the SHR-SP model is biased towards the bleeding facet of cSVD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2hyZWliZXI8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFy

PjxSZWNOdW0+NDI3NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjIyMjwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQyNzc8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0MDg4NzgwMCI+NDI3Nzwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U2NocmVpYmVyLCBTLjwvYXV0aG9y

PjxhdXRob3I+QnVlY2hlLCBDLiBaLjwvYXV0aG9yPjxhdXRob3I+R2FyeiwgQy48L2F1dGhvcj48

YXV0aG9yPktyb3BmLCBTLjwvYXV0aG9yPjxhdXRob3I+QW5nZW5zdGVpbiwgRi48L2F1dGhvcj48

YXV0aG9yPkdvbGRzY2htaWR0LCBKLjwvYXV0aG9yPjxhdXRob3I+TmV1bWFubiwgSi48L2F1dGhv

cj48YXV0aG9yPkhlaW56ZSwgSC4gSi48L2F1dGhvcj48YXV0aG9yPkdvZXJ0bGVyLCBNLjwvYXV0

aG9yPjxhdXRob3I+UmV5bWFubiwgSy4gRy48L2F1dGhvcj48YXV0aG9yPkJyYXVuLCBILjwvYXV0

aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPktsaW5payBmdXIgTmV1

cm9sb2dpZSwgT3R0by12b24tR3Vlcmlja2UgVW5pdmVyc2l0YXQsIE1hZ2RlYnVyZywgR2VybWFu

eS4gc3RlZmFuaWUuc2NocmVpYmVyQG1lZC5vdmd1LmRlPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48

dGl0bGU+VGhlIHBhdGhvbG9naWMgY2FzY2FkZSBvZiBjZXJlYnJvdmFzY3VsYXIgbGVzaW9ucyBp

biBTSFJTUDogaXMgZXJ5dGhyb2N5dGUgYWNjdW11bGF0aW9uIGFuIGVhcmx5IHBoYXNlPzwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5KIENlcmViIEJsb29kIEZsb3cgTWV0YWI8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIENlcmViIEJsb29kIEZsb3cg

TWV0YWI8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yNzgtOTA8L3BhZ2VzPjx2b2x1

bWU+MzI8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48ZWRpdGlvbj4yMDExLzA5LzAxPC9lZGl0

aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJsb29kLUJy

YWluIEJhcnJpZXIvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluLypibG9vZCBzdXBw

bHkvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBTbWFsbCBWZXNzZWwgRGlz

ZWFzZXMvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5Fcnl0aHJvY3l0ZXMvKnBhdGhvbG9n

eTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFnbmV0aWMgUmVz

b25hbmNlIEltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5N

aWNyb3Zlc3NlbHMvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5SYXRzPC9rZXl3b3JkPjxr

ZXl3b3JkPlJhdHMsIEluYnJlZCBTSFI8L2tleXdvcmQ+PGtleXdvcmQ+UmF0cywgV2lzdGFyPC9r

ZXl3b3JkPjxrZXl3b3JkPlRvbW9ncmFwaHksIEVtaXNzaW9uLUNvbXB1dGVkLCBTaW5nbGUtUGhv

dG9uPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTI8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT5GZWI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTU5LTcwMTYgKEVs

ZWN0cm9uaWMpJiN4RDswMjcxLTY3OFggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIx

ODc4OTQ1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3

dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMTg3ODk0NTwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48Y3VzdG9tMj5QTUMzMjcyNTk1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4xMDM4L2pjYmZtLjIwMTEuMTIyPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29y

ZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2hyZWliZXI8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFy

PjxSZWNOdW0+NDI3NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjIyMjwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQyNzc8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0MDg4NzgwMCI+NDI3Nzwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U2NocmVpYmVyLCBTLjwvYXV0aG9y

PjxhdXRob3I+QnVlY2hlLCBDLiBaLjwvYXV0aG9yPjxhdXRob3I+R2FyeiwgQy48L2F1dGhvcj48

YXV0aG9yPktyb3BmLCBTLjwvYXV0aG9yPjxhdXRob3I+QW5nZW5zdGVpbiwgRi48L2F1dGhvcj48

YXV0aG9yPkdvbGRzY2htaWR0LCBKLjwvYXV0aG9yPjxhdXRob3I+TmV1bWFubiwgSi48L2F1dGhv

cj48YXV0aG9yPkhlaW56ZSwgSC4gSi48L2F1dGhvcj48YXV0aG9yPkdvZXJ0bGVyLCBNLjwvYXV0

aG9yPjxhdXRob3I+UmV5bWFubiwgSy4gRy48L2F1dGhvcj48YXV0aG9yPkJyYXVuLCBILjwvYXV0

aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPktsaW5payBmdXIgTmV1

cm9sb2dpZSwgT3R0by12b24tR3Vlcmlja2UgVW5pdmVyc2l0YXQsIE1hZ2RlYnVyZywgR2VybWFu

eS4gc3RlZmFuaWUuc2NocmVpYmVyQG1lZC5vdmd1LmRlPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48

dGl0bGU+VGhlIHBhdGhvbG9naWMgY2FzY2FkZSBvZiBjZXJlYnJvdmFzY3VsYXIgbGVzaW9ucyBp

biBTSFJTUDogaXMgZXJ5dGhyb2N5dGUgYWNjdW11bGF0aW9uIGFuIGVhcmx5IHBoYXNlPzwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5KIENlcmViIEJsb29kIEZsb3cgTWV0YWI8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIENlcmViIEJsb29kIEZsb3cg

TWV0YWI8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yNzgtOTA8L3BhZ2VzPjx2b2x1

bWU+MzI8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48ZWRpdGlvbj4yMDExLzA5LzAxPC9lZGl0

aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJsb29kLUJy

YWluIEJhcnJpZXIvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluLypibG9vZCBzdXBw

bHkvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBTbWFsbCBWZXNzZWwgRGlz

ZWFzZXMvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5Fcnl0aHJvY3l0ZXMvKnBhdGhvbG9n

eTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFnbmV0aWMgUmVz

b25hbmNlIEltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5N

aWNyb3Zlc3NlbHMvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5SYXRzPC9rZXl3b3JkPjxr

ZXl3b3JkPlJhdHMsIEluYnJlZCBTSFI8L2tleXdvcmQ+PGtleXdvcmQ+UmF0cywgV2lzdGFyPC9r

ZXl3b3JkPjxrZXl3b3JkPlRvbW9ncmFwaHksIEVtaXNzaW9uLUNvbXB1dGVkLCBTaW5nbGUtUGhv

dG9uPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTI8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT5GZWI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTU5LTcwMTYgKEVs

ZWN0cm9uaWMpJiN4RDswMjcxLTY3OFggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIx

ODc4OTQ1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3

dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMTg3ODk0NTwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48Y3VzdG9tMj5QTUMzMjcyNTk1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4xMDM4L2pjYmZtLjIwMTEuMTIyPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29y

ZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 222 which might be due to genetically fixed alterations of the endothelial tight junctions ADDIN EN.CITE <EndNote><Cite><Author>Bailey</Author><Year>2011</Year><RecNum>1015</RecNum><DisplayText><style face="superscript">223</style></DisplayText><record><rec-number>1015</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865663">1015</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bailey, E. L.</author><author>Wardlaw, J. M.</author><author>Graham, D.</author><author>Dominiczak, A. F.</author><author>Sudlow, C. L. M.</author><author>Smith, C.</author></authors></contributors><titles><title>Cerebral small vessel endothelial structural changes predate hypertension in stroke-prone spontaneously hypertensive rats: a blinded, controlled immunohistochemical study of 5- to 21-week-old rats</title><secondary-title>Neuropathology and Applied Neurobiology</secondary-title></titles><pages>711-726</pages><volume>37</volume><number>7</number><dates><year>2011</year><pub-dates><date>2011/10/27</date></pub-dates></dates><publisher>Wiley</publisher><isbn>0305-1846</isbn><urls><related-urls><url> and a massively increased blood pressure by far exceeding that observed in human patients. Recent research on (SHR), which present high, but not extremely increased systolic blood pressure, revealed very similar behavioral and histological findings as seen in human vascular dementia patients ADDIN EN.CITE <EndNote><Cite><Author>Kaiser</Author><Year>2014</Year><RecNum>1028</RecNum><DisplayText><style face="superscript">224</style></DisplayText><record><rec-number>1028</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865663">1028</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kaiser, Daniel</author><author>Weise, Gesa</author><author>M?ller, Karoline</author><author>Scheibe, Johanna</author><author>P?sel, Claudia</author><author>Baasch, Sebastian</author><author>Gawlitza, Matthias</author><author>Lobsien, Donald</author><author>Diederich, Kai</author><author>Minnerup, Jens</author><author>Kranz, Alexander</author><author>Boltze, Johannes</author><author>Wagner, Daniel-Christoph</author></authors></contributors><titles><title>Spontaneous white matter damage, cognitive decline and neuroinflammation in middle-aged hypertensive rats: an animal model of early-stage cerebral small vessel disease</title><secondary-title>Acta Neuropathologica Communications</secondary-title></titles><volume>2</volume><number>1</number><dates><year>2014</year><pub-dates><date>2014/12</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>2051-5960</isbn><urls><related-urls><url> (Fig. 3). Moreover, a number of disease-driving alterations such as focal BBB breakdown, macro- and microglial activation, and immune alterations may also provide promising targets for early-stage AD (Fig. 3). Figure 3. Spontaneously hypertensive rats as a model of vascular dementia. Spontaneously hypertensive rats develop cognitive deficits in their middle age that continue to aggravate with age. The animals also show an increasing loss of brain tissue with age, particular in in deep cortical regions, subcortical areas, and the corpus callosum. The primary cause of this cognitive decline could be chronic hypertension and the animals exhibit a number of pathophysiological hallmarks of vascular dementia such as blood-brain-barrier damage, impaired microcirculation, glial response and chronic inflammation. Scheme drawing based on study of Kaiser et al., 2014 ADDIN EN.CITE <EndNote><Cite><Author>Kaiser</Author><Year>2014</Year><RecNum>1028</RecNum><DisplayText><style face="superscript">224</style></DisplayText><record><rec-number>1028</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865663">1028</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kaiser, Daniel</author><author>Weise, Gesa</author><author>M?ller, Karoline</author><author>Scheibe, Johanna</author><author>P?sel, Claudia</author><author>Baasch, Sebastian</author><author>Gawlitza, Matthias</author><author>Lobsien, Donald</author><author>Diederich, Kai</author><author>Minnerup, Jens</author><author>Kranz, Alexander</author><author>Boltze, Johannes</author><author>Wagner, Daniel-Christoph</author></authors></contributors><titles><title>Spontaneous white matter damage, cognitive decline and neuroinflammation in middle-aged hypertensive rats: an animal model of early-stage cerebral small vessel disease</title><secondary-title>Acta Neuropathologica Communications</secondary-title></titles><volume>2</volume><number>1</number><dates><year>2014</year><pub-dates><date>2014/12</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>2051-5960</isbn><urls><related-urls><url> changes in SHR, white matter and BBB breakdownMiddle-aged SHR showed a reduced discrimination capability between known and unknown objects, indicating a decline of the non-spatial working memory, primarily related to frontal-subcortical circuits ADDIN EN.CITE <EndNote><Cite><Author>Ennaceur</Author><Year>1988</Year><RecNum>1021</RecNum><DisplayText><style face="superscript">225</style></DisplayText><record><rec-number>1021</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865663">1021</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ennaceur, A.</author><author>Delacour, J.</author></authors></contributors><titles><title>A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data</title><secondary-title>Behavioural Brain Research</secondary-title></titles><pages>47-59</pages><volume>31</volume><number>1</number><dates><year>1988</year><pub-dates><date>1988/11</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>0166-4328</isbn><urls><related-urls><url>(88)90157-x</url></related-urls></urls><electronic-resource-num>10.1016/0166-4328(88)90157-x</electronic-resource-num></record></Cite></EndNote>225. Spatial memory is initially not affected. However, spatial memory deficits being typical in human vascular dementia patients ADDIN EN.CITE <EndNote><Cite><Author>den Heijer</Author><Year>2005</Year><RecNum>1018</RecNum><DisplayText><style face="superscript">226</style></DisplayText><record><rec-number>1018</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865663">1018</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>den Heijer, T.</author><author>Launer, L. J.</author><author>Prins, N. D.</author><author>van Dijk, E. J.</author><author>Vermeer, S. E.</author><author>Hofman, A.</author><author>Koudstaal, P. J.</author><author>Breteler, M. M. B.</author></authors></contributors><titles><title>Association between blood pressure, white matter lesions, and atrophy of the medial temporal lobe</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title></periodical><pages>263-267</pages><volume>64</volume><number>2</number><dates><year>2005</year><pub-dates><date>2005/01/24</date></pub-dates></dates><publisher>Ovid Technologies (Wolters Kluwer Health)</publisher><isbn>0028-3878&#xD;1526-632X</isbn><urls><related-urls><url> may develop over time since time-dependent loss of cornu ammonis 1 pyramidal neurons occurs in SHR PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWJiYXRpbmk8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFy

PjxSZWNOdW0+NDI5MzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjIyNzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQyOTM8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0MDg4ODAxOCI+NDI5Mzwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U2FiYmF0aW5pLCBNLjwvYXV0aG9y

PjxhdXRob3I+Q2F0YWxhbmksIEEuPC9hdXRob3I+PGF1dGhvcj5Db25zb2xpLCBDLjwvYXV0aG9y

PjxhdXRob3I+TWFybGV0dGEsIE4uPC9hdXRob3I+PGF1dGhvcj5Ub21hc3NvbmksIEQuPC9hdXRo

b3I+PGF1dGhvcj5Bdm9sYSwgUi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1

dGgtYWRkcmVzcz5TZXppb25lIGRpIEFuYXRvbWlhIFVtYW5hLCBEaXBhcnRpbWVudG8gZGkgU2Np

ZW56ZSBGYXJtYWNvbG9naWNoZSBlIE1lZGljaW5hIFNwZXJpbWVudGFsZSwgVW5pdmVyc2l0YSBk

aSBDYW1lcmlubywgVmlhIE0uIFNjYWx6aW5vIDUsIDYyMDMyLCBDYW1lcmlubywgSXRhbHkuIG1h

dXJpemlvQGNhbWJpby51bmljYW0uaXQ8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5UaGUg

aGlwcG9jYW1wdXMgaW4gc3BvbnRhbmVvdXNseSBoeXBlcnRlbnNpdmUgcmF0czogYW4gYW5pbWFs

IG1vZGVsIG9mIHZhc2N1bGFyIGRlbWVudGlhPzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5NZWNo

IEFnZWluZyBEZXY8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10

aXRsZT5NZWNoIEFnZWluZyBEZXY8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz41NDct

NTk8L3BhZ2VzPjx2b2x1bWU+MTIzPC92b2x1bWU+PG51bWJlcj41PC9udW1iZXI+PGVkaXRpb24+

MjAwMi8wMi8xNDwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWdpbmcvKm1ldGFib2xpc20v

cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+Qmlv

bWFya2Vyczwva2V5d29yZD48a2V5d29yZD5CbG9vZCBQcmVzc3VyZTwva2V5d29yZD48a2V5d29y

ZD5CbG90dGluZywgV2VzdGVybi9tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluPC9rZXl3

b3JkPjxrZXl3b3JkPkRlbWVudGlhLCBWYXNjdWxhci8qbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFuaW1hbDwva2V5d29yZD48a2V5d29yZD5H

bGlhbCBGaWJyaWxsYXJ5IEFjaWRpYyBQcm90ZWluL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+SGlwcG9jYW1wdXMvKm1ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh5

cGVydGVuc2lvbi8qbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5v

ZW56eW1lIFRlY2huaXF1ZXM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29y

ZD5NaWNyb3R1YnVsZS1Bc3NvY2lhdGVkIFByb3RlaW5zL21ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+TmV1cm9maWxhbWVudCBQcm90ZWlucy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

Pk9yZ2FuIFNpemU8L2tleXdvcmQ+PGtleXdvcmQ+UmF0czwva2V5d29yZD48a2V5d29yZD5SYXRz

LCBJbmJyZWQgU0hSPC9rZXl3b3JkPjxrZXl3b3JkPlJhdHMsIEluYnJlZCBXS1k8L2tleXdvcmQ+

PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1hciAx

NTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwNDctNjM3NCAoUHJpbnQpJiN4RDsw

MDQ3LTYzNzQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjExNzk2MTQwPC9hY2Nlc3Np

b24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWgu

Z292L3B1Ym1lZC8xMTc5NjE0MDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48

L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWJiYXRpbmk8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFy

PjxSZWNOdW0+NDI5MzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjIyNzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQyOTM8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0MDg4ODAxOCI+NDI5Mzwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U2FiYmF0aW5pLCBNLjwvYXV0aG9y

PjxhdXRob3I+Q2F0YWxhbmksIEEuPC9hdXRob3I+PGF1dGhvcj5Db25zb2xpLCBDLjwvYXV0aG9y

PjxhdXRob3I+TWFybGV0dGEsIE4uPC9hdXRob3I+PGF1dGhvcj5Ub21hc3NvbmksIEQuPC9hdXRo

b3I+PGF1dGhvcj5Bdm9sYSwgUi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1

dGgtYWRkcmVzcz5TZXppb25lIGRpIEFuYXRvbWlhIFVtYW5hLCBEaXBhcnRpbWVudG8gZGkgU2Np

ZW56ZSBGYXJtYWNvbG9naWNoZSBlIE1lZGljaW5hIFNwZXJpbWVudGFsZSwgVW5pdmVyc2l0YSBk

aSBDYW1lcmlubywgVmlhIE0uIFNjYWx6aW5vIDUsIDYyMDMyLCBDYW1lcmlubywgSXRhbHkuIG1h

dXJpemlvQGNhbWJpby51bmljYW0uaXQ8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5UaGUg

aGlwcG9jYW1wdXMgaW4gc3BvbnRhbmVvdXNseSBoeXBlcnRlbnNpdmUgcmF0czogYW4gYW5pbWFs

IG1vZGVsIG9mIHZhc2N1bGFyIGRlbWVudGlhPzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5NZWNo

IEFnZWluZyBEZXY8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10

aXRsZT5NZWNoIEFnZWluZyBEZXY8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz41NDct

NTk8L3BhZ2VzPjx2b2x1bWU+MTIzPC92b2x1bWU+PG51bWJlcj41PC9udW1iZXI+PGVkaXRpb24+

MjAwMi8wMi8xNDwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWdpbmcvKm1ldGFib2xpc20v

cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+Qmlv

bWFya2Vyczwva2V5d29yZD48a2V5d29yZD5CbG9vZCBQcmVzc3VyZTwva2V5d29yZD48a2V5d29y

ZD5CbG90dGluZywgV2VzdGVybi9tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluPC9rZXl3

b3JkPjxrZXl3b3JkPkRlbWVudGlhLCBWYXNjdWxhci8qbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFuaW1hbDwva2V5d29yZD48a2V5d29yZD5H

bGlhbCBGaWJyaWxsYXJ5IEFjaWRpYyBQcm90ZWluL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+SGlwcG9jYW1wdXMvKm1ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh5

cGVydGVuc2lvbi8qbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5v

ZW56eW1lIFRlY2huaXF1ZXM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29y

ZD5NaWNyb3R1YnVsZS1Bc3NvY2lhdGVkIFByb3RlaW5zL21ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+TmV1cm9maWxhbWVudCBQcm90ZWlucy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

Pk9yZ2FuIFNpemU8L2tleXdvcmQ+PGtleXdvcmQ+UmF0czwva2V5d29yZD48a2V5d29yZD5SYXRz

LCBJbmJyZWQgU0hSPC9rZXl3b3JkPjxrZXl3b3JkPlJhdHMsIEluYnJlZCBXS1k8L2tleXdvcmQ+

PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1hciAx

NTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwNDctNjM3NCAoUHJpbnQpJiN4RDsw

MDQ3LTYzNzQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjExNzk2MTQwPC9hY2Nlc3Np

b24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWgu

Z292L3B1Ym1lZC8xMTc5NjE0MDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48

L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 227. SHR also exhibit reduced white matter content and brain atrophy, along with BBB breakdown predominantly in white matter areas and deep cortical regions. Macro- and microglial activationA sustained macro- and microglial activation in deep cortical regions can be observed in SHR. Although the number of Iba1-positive microglia in DCR is comparable results between SHR and normotensive Wistar Kyoto rats (WKY), single cell morphological analysis increased cellular volumes being indicative of microglial hypertrophy. Microglial activation is further indicated by increased CD11b expression ADDIN EN.CITE <EndNote><Cite><Author>Kaiser</Author><Year>2014</Year><RecNum>1028</RecNum><DisplayText><style face="superscript">224</style></DisplayText><record><rec-number>1028</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865663">1028</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kaiser, Daniel</author><author>Weise, Gesa</author><author>M?ller, Karoline</author><author>Scheibe, Johanna</author><author>P?sel, Claudia</author><author>Baasch, Sebastian</author><author>Gawlitza, Matthias</author><author>Lobsien, Donald</author><author>Diederich, Kai</author><author>Minnerup, Jens</author><author>Kranz, Alexander</author><author>Boltze, Johannes</author><author>Wagner, Daniel-Christoph</author></authors></contributors><titles><title>Spontaneous white matter damage, cognitive decline and neuroinflammation in middle-aged hypertensive rats: an animal model of early-stage cerebral small vessel disease</title><secondary-title>Acta Neuropathologica Communications</secondary-title></titles><volume>2</volume><number>1</number><dates><year>2014</year><pub-dates><date>2014/12</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>2051-5960</isbn><urls><related-urls><url> mechanisms potentially contributing to vascular dementiaThere is increasing evidence that the immune system significantly contributes to the development and progression of vascular dementia. For instance, serum levels of soluble adhesion molecules were increased in patients with white matter lesions ADDIN EN.CITE <EndNote><Cite><Author>Leeuw</Author><Year>2002</Year><RecNum>1017</RecNum><DisplayText><style face="superscript">228</style></DisplayText><record><rec-number>1017</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865663">1017</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Leeuw, F. E.</author><author>Kleine, M.</author><author>Frijns, C. J. M.</author><author>Fijnheer, R.</author><author>Gijn, J.</author><author>Kappelle, L. J.</author></authors></contributors><titles><title>Endothelial Cell Activation Is Associated with Cerebral White Matter Lesions in Patients with Cerebrovascular Disease</title><secondary-title>Annals of the New York Academy of Sciences</secondary-title></titles><pages>306-314</pages><volume>977</volume><number>1</number><dates><year>2002</year><pub-dates><date>2002/11</date></pub-dates></dates><publisher>Wiley</publisher><isbn>0077-8923&#xD;1749-6632</isbn><urls><related-urls><url> and c-reactive protein (CRP) levels correlate with the existence and progression of white matter damage ADDIN EN.CITE <EndNote><Cite><Author>den Heijer</Author><Year>2005</Year><RecNum>1018</RecNum><DisplayText><style face="superscript">226</style></DisplayText><record><rec-number>1018</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865663">1018</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>den Heijer, T.</author><author>Launer, L. J.</author><author>Prins, N. D.</author><author>van Dijk, E. J.</author><author>Vermeer, S. E.</author><author>Hofman, A.</author><author>Koudstaal, P. J.</author><author>Breteler, M. M. B.</author></authors></contributors><titles><title>Association between blood pressure, white matter lesions, and atrophy of the medial temporal lobe</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title></periodical><pages>263-267</pages><volume>64</volume><number>2</number><dates><year>2005</year><pub-dates><date>2005/01/24</date></pub-dates></dates><publisher>Ovid Technologies (Wolters Kluwer Health)</publisher><isbn>0028-3878&#xD;1526-632X</isbn><urls><related-urls><url>. The association of inflammation and vascular dementia is not surprising since chronic inflammation also plays an important role in the pathophysiology of its primary risk factor hypertension PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2hpZmZyaW48L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy

PjxSZWNOdW0+NDMwNzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjIyOSwyMzA8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40MzA3

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDA5MDQ1NzMiPjQzMDc8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNjaGlmZnJpbiwgRS4gTC48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz4qTGFkeSBEYXZp

cyBJbnN0aXR1dGUgZm9yIE1lZGljYWwgUmVzZWFyY2ggYW5kIERlcGFydG1lbnQgb2YgTWVkaWNp

bmUsIFNpciBNb3J0aW1lciBCLiBEYXZpcy1KZXdpc2ggR2VuZXJhbCBIb3NwaXRhbCwgTWNHaWxs

IFVuaXZlcnNpdHksIE1vbnRyZWFsLCBQUSwgQ2FuYWRhLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+

PHRpdGxlPkltbXVuZSBtZWNoYW5pc21zIGluIGh5cGVydGVuc2lvbiBhbmQgdmFzY3VsYXIgaW5q

dXJ5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNsaW4gU2NpIChMb25kKTwvc2Vjb25kYXJ5LXRp

dGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkNsaW4gU2NpIChMb25kKTwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjI2Ny03NDwvcGFnZXM+PHZvbHVtZT4xMjY8L3Zv

bHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZWRpdGlvbj4yMDEzLzEwLzIzPC9lZGl0aW9uPjxrZXl3

b3Jkcz48a2V5d29yZD5BZGFwdGl2ZSBJbW11bml0eS9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2FyZGlvdmFzY3VsYXIgRGlzZWFzZXMvKmlt

bXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q3l0b2tpbmVzL2ltbXVub2xvZ3kvbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlwZXJ0ZW5zaW9u

LyppbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1hdGlvbi9pbW11bm9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPlQtTHltcGhvY3l0ZSBTdWJzZXRzL2N5dG9sb2d5L2ltbXVub2xvZ3k8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48cHViLWRhdGVzPjxk

YXRlPkZlYjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0NzAtODczNiAoRWxlY3Ry

b25pYykmI3hEOzAxNDMtNTIyMSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjQxNDQz

NTU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5j

YmkubmxtLm5paC5nb3YvcHVibWVkLzI0MTQ0MzU1PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxz

PjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDQyL0NTMjAxMzA0MDc8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk1vbGxlcjwvQXV0aG9y

PjxZZWFyPjIwMTU8L1llYXI+PFJlY051bT40MzA2PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJl

cj40MzA2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndh

MHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDA5MDQ1NDIi

PjQzMDY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xl

Ij4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1vbGxlciwgSy48

L2F1dGhvcj48YXV0aG9yPlBvc2VsLCBDLjwvYXV0aG9yPjxhdXRob3I+S3JhbnosIEEuPC9hdXRo

b3I+PGF1dGhvcj5TY2h1bHosIEkuPC9hdXRob3I+PGF1dGhvcj5TY2hlaWJlLCBKLjwvYXV0aG9y

PjxhdXRob3I+RGlkd2lzY2h1cywgTi48L2F1dGhvcj48YXV0aG9yPkJvbHR6ZSwgSi48L2F1dGhv

cj48YXV0aG9yPldlaXNlLCBHLjwvYXV0aG9yPjxhdXRob3I+V2FnbmVyLCBELiBDLjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkZyYXVuaG9mZXIgSW5zdGl0

dXRlIGZvciBDZWxsIFRoZXJhcHkgYW5kIEltbXVub2xvZ3kgTGVpcHppZywgR2VybWFueSA7IElu

c3RpdHV0ZSBvZiBBbmF0b215LCBIaXN0b2xvZ3kgYW5kIEVtYnJ5b2xvZ3ksIFVuaXZlcnNpdHkg

b2YgTGVpcHppZyBMZWlwemlnLCBHZXJtYW55LiYjeEQ7RnJhdW5ob2ZlciBJbnN0aXR1dGUgZm9y

IENlbGwgVGhlcmFweSBhbmQgSW1tdW5vbG9neSBMZWlwemlnLCBHZXJtYW55LiYjeEQ7RnJhdW5o

b2ZlciBJbnN0aXR1dGUgZm9yIENlbGwgVGhlcmFweSBhbmQgSW1tdW5vbG9neSBMZWlwemlnLCBH

ZXJtYW55IDsgUmVzZWFyY2ggR3JvdXAgSHVtYW4gQmlvbG9neSwgSW5zdGl0dXRlIG9mIEJpb2xv

Z3ksIFVuaXZlcnNpdHkgb2YgTGVpcHppZyBMZWlwemlnLCBHZXJtYW55LiYjeEQ7RnJhdW5ob2Zl

ciBJbnN0aXR1dGUgZm9yIENlbGwgVGhlcmFweSBhbmQgSW1tdW5vbG9neSBMZWlwemlnLCBHZXJt

YW55IDsgRnJhdW5ob2ZlciBSZXNlYXJjaCBJbnN0aXR1dGlvbiBmb3IgTWFyaW5lIEJpb3RlY2hu

b2xvZ3kgYW5kIEluc3RpdHV0ZSBmb3IgTWVkaWNhbCBhbmQgTWFyaW5lIEJpb3RlY2hub2xvZ3ks

IFVuaXZlcnNpdHkgb2YgTHViZWNrIEx1YmVjaywgR2VybWFueS4mI3hEO0ZyYXVuaG9mZXIgSW5z

dGl0dXRlIGZvciBDZWxsIFRoZXJhcHkgYW5kIEltbXVub2xvZ3kgTGVpcHppZywgR2VybWFueSA7

IERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IG9mIExlaXB6aWcgTGVpcHppZywg

R2VybWFueS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BcnRlcmlhbCBIeXBlcnRlbnNp

b24gQWdncmF2YXRlcyBJbm5hdGUgSW1tdW5lIFJlc3BvbnNlcyBhZnRlciBFeHBlcmltZW50YWwg

U3Ryb2tlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkZyb250IENlbGwgTmV1cm9zY2k8L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Gcm9udCBDZWxsIE5l

dXJvc2NpPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NDYxPC9wYWdlcz48dm9sdW1l

Pjk8L3ZvbHVtZT48ZWRpdGlvbj4yMDE1LzEyLzA4PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29y

ZD5hZGhlc2lvbiBtb2xlY3VsZXM8L2tleXdvcmQ+PGtleXdvcmQ+YW5pbWFsIG1vZGVsPC9rZXl3

b3JkPjxrZXl3b3JkPmNoZW1va2luZXM8L2tleXdvcmQ+PGtleXdvcmQ+aHlwZXJ0ZW5zaW9uPC9r

ZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5tYWNyb3BoYWdl

czwva2V5d29yZD48a2V5d29yZD5uZXV0cm9waGlsczwva2V5d29yZD48a2V5d29yZD5zdHJva2U8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNTwveWVhcj48L2RhdGVzPjxpc2Ju

PjE2NjItNTEwMiAoUHJpbnQpJiN4RDsxNjYyLTUxMDIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI2NjQwNDI4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjY0MDQyODwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NjYxMjgwPC9jdXN0b20yPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4zMzg5L2ZuY2VsLjIwMTUuMDA0NjE8L2VsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2hpZmZyaW48L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy

PjxSZWNOdW0+NDMwNzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjIyOSwyMzA8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40MzA3

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDA5MDQ1NzMiPjQzMDc8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNjaGlmZnJpbiwgRS4gTC48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz4qTGFkeSBEYXZp

cyBJbnN0aXR1dGUgZm9yIE1lZGljYWwgUmVzZWFyY2ggYW5kIERlcGFydG1lbnQgb2YgTWVkaWNp

bmUsIFNpciBNb3J0aW1lciBCLiBEYXZpcy1KZXdpc2ggR2VuZXJhbCBIb3NwaXRhbCwgTWNHaWxs

IFVuaXZlcnNpdHksIE1vbnRyZWFsLCBQUSwgQ2FuYWRhLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+

PHRpdGxlPkltbXVuZSBtZWNoYW5pc21zIGluIGh5cGVydGVuc2lvbiBhbmQgdmFzY3VsYXIgaW5q

dXJ5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNsaW4gU2NpIChMb25kKTwvc2Vjb25kYXJ5LXRp

dGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkNsaW4gU2NpIChMb25kKTwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjI2Ny03NDwvcGFnZXM+PHZvbHVtZT4xMjY8L3Zv

bHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZWRpdGlvbj4yMDEzLzEwLzIzPC9lZGl0aW9uPjxrZXl3

b3Jkcz48a2V5d29yZD5BZGFwdGl2ZSBJbW11bml0eS9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2FyZGlvdmFzY3VsYXIgRGlzZWFzZXMvKmlt

bXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q3l0b2tpbmVzL2ltbXVub2xvZ3kvbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlwZXJ0ZW5zaW9u

LyppbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1hdGlvbi9pbW11bm9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPlQtTHltcGhvY3l0ZSBTdWJzZXRzL2N5dG9sb2d5L2ltbXVub2xvZ3k8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48cHViLWRhdGVzPjxk

YXRlPkZlYjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0NzAtODczNiAoRWxlY3Ry

b25pYykmI3hEOzAxNDMtNTIyMSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjQxNDQz

NTU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5j

YmkubmxtLm5paC5nb3YvcHVibWVkLzI0MTQ0MzU1PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxz

PjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDQyL0NTMjAxMzA0MDc8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk1vbGxlcjwvQXV0aG9y

PjxZZWFyPjIwMTU8L1llYXI+PFJlY051bT40MzA2PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJl

cj40MzA2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndh

MHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDA5MDQ1NDIi

PjQzMDY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xl

Ij4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1vbGxlciwgSy48

L2F1dGhvcj48YXV0aG9yPlBvc2VsLCBDLjwvYXV0aG9yPjxhdXRob3I+S3JhbnosIEEuPC9hdXRo

b3I+PGF1dGhvcj5TY2h1bHosIEkuPC9hdXRob3I+PGF1dGhvcj5TY2hlaWJlLCBKLjwvYXV0aG9y

PjxhdXRob3I+RGlkd2lzY2h1cywgTi48L2F1dGhvcj48YXV0aG9yPkJvbHR6ZSwgSi48L2F1dGhv

cj48YXV0aG9yPldlaXNlLCBHLjwvYXV0aG9yPjxhdXRob3I+V2FnbmVyLCBELiBDLjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkZyYXVuaG9mZXIgSW5zdGl0

dXRlIGZvciBDZWxsIFRoZXJhcHkgYW5kIEltbXVub2xvZ3kgTGVpcHppZywgR2VybWFueSA7IElu

c3RpdHV0ZSBvZiBBbmF0b215LCBIaXN0b2xvZ3kgYW5kIEVtYnJ5b2xvZ3ksIFVuaXZlcnNpdHkg

b2YgTGVpcHppZyBMZWlwemlnLCBHZXJtYW55LiYjeEQ7RnJhdW5ob2ZlciBJbnN0aXR1dGUgZm9y

IENlbGwgVGhlcmFweSBhbmQgSW1tdW5vbG9neSBMZWlwemlnLCBHZXJtYW55LiYjeEQ7RnJhdW5o

b2ZlciBJbnN0aXR1dGUgZm9yIENlbGwgVGhlcmFweSBhbmQgSW1tdW5vbG9neSBMZWlwemlnLCBH

ZXJtYW55IDsgUmVzZWFyY2ggR3JvdXAgSHVtYW4gQmlvbG9neSwgSW5zdGl0dXRlIG9mIEJpb2xv

Z3ksIFVuaXZlcnNpdHkgb2YgTGVpcHppZyBMZWlwemlnLCBHZXJtYW55LiYjeEQ7RnJhdW5ob2Zl

ciBJbnN0aXR1dGUgZm9yIENlbGwgVGhlcmFweSBhbmQgSW1tdW5vbG9neSBMZWlwemlnLCBHZXJt

YW55IDsgRnJhdW5ob2ZlciBSZXNlYXJjaCBJbnN0aXR1dGlvbiBmb3IgTWFyaW5lIEJpb3RlY2hu

b2xvZ3kgYW5kIEluc3RpdHV0ZSBmb3IgTWVkaWNhbCBhbmQgTWFyaW5lIEJpb3RlY2hub2xvZ3ks

IFVuaXZlcnNpdHkgb2YgTHViZWNrIEx1YmVjaywgR2VybWFueS4mI3hEO0ZyYXVuaG9mZXIgSW5z

dGl0dXRlIGZvciBDZWxsIFRoZXJhcHkgYW5kIEltbXVub2xvZ3kgTGVpcHppZywgR2VybWFueSA7

IERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IG9mIExlaXB6aWcgTGVpcHppZywg

R2VybWFueS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BcnRlcmlhbCBIeXBlcnRlbnNp

b24gQWdncmF2YXRlcyBJbm5hdGUgSW1tdW5lIFJlc3BvbnNlcyBhZnRlciBFeHBlcmltZW50YWwg

U3Ryb2tlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkZyb250IENlbGwgTmV1cm9zY2k8L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Gcm9udCBDZWxsIE5l

dXJvc2NpPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NDYxPC9wYWdlcz48dm9sdW1l

Pjk8L3ZvbHVtZT48ZWRpdGlvbj4yMDE1LzEyLzA4PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29y

ZD5hZGhlc2lvbiBtb2xlY3VsZXM8L2tleXdvcmQ+PGtleXdvcmQ+YW5pbWFsIG1vZGVsPC9rZXl3

b3JkPjxrZXl3b3JkPmNoZW1va2luZXM8L2tleXdvcmQ+PGtleXdvcmQ+aHlwZXJ0ZW5zaW9uPC9r

ZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5tYWNyb3BoYWdl

czwva2V5d29yZD48a2V5d29yZD5uZXV0cm9waGlsczwva2V5d29yZD48a2V5d29yZD5zdHJva2U8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNTwveWVhcj48L2RhdGVzPjxpc2Ju

PjE2NjItNTEwMiAoUHJpbnQpJiN4RDsxNjYyLTUxMDIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI2NjQwNDI4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjY0MDQyODwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NjYxMjgwPC9jdXN0b20yPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4zMzg5L2ZuY2VsLjIwMTUuMDA0NjE8L2VsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 229,230. However, whether such inflammatory processes initiate vascular and tissue damage, promote its propagation, or simply constitute a response to ongoing reorganization remains unclear. Similar relationships have been described for Alzheimer’s disease.Distribution of blood-borne leukocytes differs between SHR and WKY strains. In WKY, T cells were mostly localized within the meninges and the choroid plexus (CP), while the majority of T cells populated microvessels within the SHR brain parenchyma. The different T cell distribution patterns may be explained, for instance, by an upregulation of VCAM-1 in brain endothelial cells, which occurs as a consequence of an activated renin-angiotensin system during arterial hypertension in hypertensive rats PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UdW1tYWxhPC9BdXRob3I+PFllYXI+MTk5OTwvWWVhcj48

UmVjTnVtPjQzMDg8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4yMzE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40MzA4PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDA5MDUzNjkiPjQzMDg8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlR1bW1hbGEsIFAuIEUuPC9hdXRob3I+

PGF1dGhvcj5DaGVuLCBYLiBMLjwvYXV0aG9yPjxhdXRob3I+U3VuZGVsbCwgQy4gTC48L2F1dGhv

cj48YXV0aG9yPkxhdXJzZW4sIEouIEIuPC9hdXRob3I+PGF1dGhvcj5IYW1tZXMsIEMuIFAuPC9h

dXRob3I+PGF1dGhvcj5BbGV4YW5kZXIsIFIuIFcuPC9hdXRob3I+PGF1dGhvcj5IYXJyaXNvbiwg

RC4gRy48L2F1dGhvcj48YXV0aG9yPk1lZGZvcmQsIFIuIE0uPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGl2aXNpb24gb2YgQ2FyZGlvbG9neSwgRGVwYXJ0

bWVudCBvZiBNZWRpY2luZSwgRW1vcnkgVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUsIEF0

bGFudGEsIEdBLCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QW5naW90ZW5zaW4g

SUkgaW5kdWNlcyB2YXNjdWxhciBjZWxsIGFkaGVzaW9uIG1vbGVjdWxlLTEgZXhwcmVzc2lvbiBp

biByYXQgdmFzY3VsYXR1cmU6IEEgcG90ZW50aWFsIGxpbmsgYmV0d2VlbiB0aGUgcmVuaW4tYW5n

aW90ZW5zaW4gc3lzdGVtIGFuZCBhdGhlcm9zY2xlcm9zaXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0

bGU+Q2lyY3VsYXRpb248L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVs

bC10aXRsZT5DaXJjdWxhdGlvbjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjEyMjMt

OTwvcGFnZXM+PHZvbHVtZT4xMDA8L3ZvbHVtZT48bnVtYmVyPjExPC9udW1iZXI+PGVkaXRpb24+

MTk5OS8wOS8xNDwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QW5naW90ZW5zaW4gSUkvKnBo

YXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkFy

dGVyaW9zY2xlcm9zaXMvKnBoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5CbG9vZCBQ

cmVzc3VyZS9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVkPC9r

ZXl3b3JkPjxrZXl3b3JkPkdlbmUgRXhwcmVzc2lvbi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtl

eXdvcmQ+SHlwZXJ0ZW5zaW9uL3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5JbW11

bm9oaXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3Jk

Pk5vcmVwaW5lcGhyaW5lL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5SYXRzPC9rZXl3

b3JkPjxrZXl3b3JkPlJhdHMsIFNwcmFndWUtRGF3bGV5PC9rZXl3b3JkPjxrZXl3b3JkPlJlY2Vw

dG9ycywgQW5naW90ZW5zaW4vcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5SZW5pbi1Bbmdp

b3RlbnNpbiBTeXN0ZW0vKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+VmFzY3VsYXIgQ2Vs

bCBBZGhlc2lvbiBNb2xlY3VsZS0xLypiaW9zeW50aGVzaXMvZ2VuZXRpY3M8L2tleXdvcmQ+PC9r

ZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MTk5OTwveWVhcj48cHViLWRhdGVzPjxkYXRlPlNlcCAxNDwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1MjQtNDUzOSAoRWxlY3Ryb25pYykmI3hE

OzAwMDktNzMyMiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTA0ODQ1NDQ8L2FjY2Vz

c2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5p

aC5nb3YvcHVibWVkLzEwNDg0NTQ0PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3Jk

PjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UdW1tYWxhPC9BdXRob3I+PFllYXI+MTk5OTwvWWVhcj48

UmVjTnVtPjQzMDg8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4yMzE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40MzA4PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDA5MDUzNjkiPjQzMDg8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlR1bW1hbGEsIFAuIEUuPC9hdXRob3I+

PGF1dGhvcj5DaGVuLCBYLiBMLjwvYXV0aG9yPjxhdXRob3I+U3VuZGVsbCwgQy4gTC48L2F1dGhv

cj48YXV0aG9yPkxhdXJzZW4sIEouIEIuPC9hdXRob3I+PGF1dGhvcj5IYW1tZXMsIEMuIFAuPC9h

dXRob3I+PGF1dGhvcj5BbGV4YW5kZXIsIFIuIFcuPC9hdXRob3I+PGF1dGhvcj5IYXJyaXNvbiwg

RC4gRy48L2F1dGhvcj48YXV0aG9yPk1lZGZvcmQsIFIuIE0uPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGl2aXNpb24gb2YgQ2FyZGlvbG9neSwgRGVwYXJ0

bWVudCBvZiBNZWRpY2luZSwgRW1vcnkgVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUsIEF0

bGFudGEsIEdBLCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QW5naW90ZW5zaW4g

SUkgaW5kdWNlcyB2YXNjdWxhciBjZWxsIGFkaGVzaW9uIG1vbGVjdWxlLTEgZXhwcmVzc2lvbiBp

biByYXQgdmFzY3VsYXR1cmU6IEEgcG90ZW50aWFsIGxpbmsgYmV0d2VlbiB0aGUgcmVuaW4tYW5n

aW90ZW5zaW4gc3lzdGVtIGFuZCBhdGhlcm9zY2xlcm9zaXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0

bGU+Q2lyY3VsYXRpb248L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVs

bC10aXRsZT5DaXJjdWxhdGlvbjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjEyMjMt

OTwvcGFnZXM+PHZvbHVtZT4xMDA8L3ZvbHVtZT48bnVtYmVyPjExPC9udW1iZXI+PGVkaXRpb24+

MTk5OS8wOS8xNDwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QW5naW90ZW5zaW4gSUkvKnBo

YXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkFy

dGVyaW9zY2xlcm9zaXMvKnBoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5CbG9vZCBQ

cmVzc3VyZS9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVkPC9r

ZXl3b3JkPjxrZXl3b3JkPkdlbmUgRXhwcmVzc2lvbi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtl

eXdvcmQ+SHlwZXJ0ZW5zaW9uL3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5JbW11

bm9oaXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3Jk

Pk5vcmVwaW5lcGhyaW5lL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5SYXRzPC9rZXl3

b3JkPjxrZXl3b3JkPlJhdHMsIFNwcmFndWUtRGF3bGV5PC9rZXl3b3JkPjxrZXl3b3JkPlJlY2Vw

dG9ycywgQW5naW90ZW5zaW4vcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5SZW5pbi1Bbmdp

b3RlbnNpbiBTeXN0ZW0vKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+VmFzY3VsYXIgQ2Vs

bCBBZGhlc2lvbiBNb2xlY3VsZS0xLypiaW9zeW50aGVzaXMvZ2VuZXRpY3M8L2tleXdvcmQ+PC9r

ZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MTk5OTwveWVhcj48cHViLWRhdGVzPjxkYXRlPlNlcCAxNDwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1MjQtNDUzOSAoRWxlY3Ryb25pYykmI3hE

OzAwMDktNzMyMiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTA0ODQ1NDQ8L2FjY2Vz

c2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5p

aC5nb3YvcHVibWVkLzEwNDg0NTQ0PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3Jk

PjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 231 and vascular dementia patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3VobDwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl

Y051bT40MzA5PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MjMyPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDMwOTwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTQwOTA1NDI5Ij40MzA5PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Sb3VobCwgUi4gUC48L2F1dGhvcj48YXV0

aG9yPkRhbW9pc2VhdXgsIEouIEcuPC9hdXRob3I+PGF1dGhvcj5Mb2RkZXIsIEouPC9hdXRob3I+

PGF1dGhvcj5UaGV1bmlzc2VuLCBSLiBPLjwvYXV0aG9yPjxhdXRob3I+S25vdHRuZXJ1cywgSS4g

TC48L2F1dGhvcj48YXV0aG9yPlN0YWFscywgSi48L2F1dGhvcj48YXV0aG9yPkhlbnNrZW5zLCBM

LiBILjwvYXV0aG9yPjxhdXRob3I+S3Jvb24sIEEuIEEuPC9hdXRob3I+PGF1dGhvcj5kZSBMZWV1

dywgUC4gVy48L2F1dGhvcj48YXV0aG9yPlRlcnZhZXJ0LCBKLiBXLjwvYXV0aG9yPjxhdXRob3I+

dmFuIE9vc3RlbmJydWdnZSwgUi4gSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+

PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgTWFhc3RyaWNodCBVbml2ZXJz

aXR5IE1lZGljYWwgQ2VudHJlLCBNYWFzdHJpY2h0LCB0aGUgTmV0aGVybGFuZHMuIFIuUm91aGxA

bXVtYy5ubDwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlZhc2N1bGFyIGluZmxhbW1hdGlv

biBpbiBjZXJlYnJhbCBzbWFsbCB2ZXNzZWwgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5OZXVyb2Jpb2wgQWdpbmc8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5OZXVyb2Jpb2wgQWdpbmc8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdl

cz4xODAwLTY8L3BhZ2VzPjx2b2x1bWU+MzM8L3ZvbHVtZT48bnVtYmVyPjg8L251bWJlcj48ZWRp

dGlvbj4yMDExLzA1LzI0PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZG9sZXNjZW50PC9r

ZXl3b3JkPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBBZGhlc2lvbiBN

b2xlY3VsZXMvKmJsb29kPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIFNtYWxsIFZlc3NlbCBE

aXNlYXNlcy9jb21wbGljYXRpb25zLyptZXRhYm9saXNtLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD4q

TWFjcm9waGFnZSBBY3RpdmF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtl

eXdvcmQ+TWljcm92ZXNzZWxzL21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

Pk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPk5lb3B0ZXJpbi8qYmxvb2Q8L2tleXdvcmQ+

PGtleXdvcmQ+VmFzY3VsaXRpcy9jb21wbGljYXRpb25zLyptZXRhYm9saXNtLypwYXRob2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+WW91bmcgQWR1bHQ8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkF1ZzwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjE1NTgtMTQ5NyAoRWxlY3Ryb25pYykmI3hEOzAxOTctNDU4MCAoTGlua2lu

Zyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjE2MDEzMTQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJl

bGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIxNjAx

MzE0PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4x

MC4xMDE2L2oubmV1cm9iaW9sYWdpbmcuMjAxMS4wNC4wMDg8L2VsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3VobDwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl

Y051bT40MzA5PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MjMyPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDMwOTwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTQwOTA1NDI5Ij40MzA5PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Sb3VobCwgUi4gUC48L2F1dGhvcj48YXV0

aG9yPkRhbW9pc2VhdXgsIEouIEcuPC9hdXRob3I+PGF1dGhvcj5Mb2RkZXIsIEouPC9hdXRob3I+

PGF1dGhvcj5UaGV1bmlzc2VuLCBSLiBPLjwvYXV0aG9yPjxhdXRob3I+S25vdHRuZXJ1cywgSS4g

TC48L2F1dGhvcj48YXV0aG9yPlN0YWFscywgSi48L2F1dGhvcj48YXV0aG9yPkhlbnNrZW5zLCBM

LiBILjwvYXV0aG9yPjxhdXRob3I+S3Jvb24sIEEuIEEuPC9hdXRob3I+PGF1dGhvcj5kZSBMZWV1

dywgUC4gVy48L2F1dGhvcj48YXV0aG9yPlRlcnZhZXJ0LCBKLiBXLjwvYXV0aG9yPjxhdXRob3I+

dmFuIE9vc3RlbmJydWdnZSwgUi4gSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+

PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgTWFhc3RyaWNodCBVbml2ZXJz

aXR5IE1lZGljYWwgQ2VudHJlLCBNYWFzdHJpY2h0LCB0aGUgTmV0aGVybGFuZHMuIFIuUm91aGxA

bXVtYy5ubDwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlZhc2N1bGFyIGluZmxhbW1hdGlv

biBpbiBjZXJlYnJhbCBzbWFsbCB2ZXNzZWwgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5OZXVyb2Jpb2wgQWdpbmc8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5OZXVyb2Jpb2wgQWdpbmc8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdl

cz4xODAwLTY8L3BhZ2VzPjx2b2x1bWU+MzM8L3ZvbHVtZT48bnVtYmVyPjg8L251bWJlcj48ZWRp

dGlvbj4yMDExLzA1LzI0PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZG9sZXNjZW50PC9r

ZXl3b3JkPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBBZGhlc2lvbiBN

b2xlY3VsZXMvKmJsb29kPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIFNtYWxsIFZlc3NlbCBE

aXNlYXNlcy9jb21wbGljYXRpb25zLyptZXRhYm9saXNtLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD4q

TWFjcm9waGFnZSBBY3RpdmF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtl

eXdvcmQ+TWljcm92ZXNzZWxzL21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

Pk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPk5lb3B0ZXJpbi8qYmxvb2Q8L2tleXdvcmQ+

PGtleXdvcmQ+VmFzY3VsaXRpcy9jb21wbGljYXRpb25zLyptZXRhYm9saXNtLypwYXRob2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+WW91bmcgQWR1bHQ8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkF1ZzwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjE1NTgtMTQ5NyAoRWxlY3Ryb25pYykmI3hEOzAxOTctNDU4MCAoTGlua2lu

Zyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjE2MDEzMTQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJl

bGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIxNjAx

MzE0PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4x

MC4xMDE2L2oubmV1cm9iaW9sYWdpbmcuMjAxMS4wNC4wMDg8L2VsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 232. The increased presence of T cells adhering to the luminal side of cerebral microvessels might indicate slowed vascular transit time of leukocytes due to pseudopod formation ADDIN EN.CITE <EndNote><Cite><Author>Harrison</Author><Year>2012</Year><RecNum>1024</RecNum><DisplayText><style face="superscript">233</style></DisplayText><record><rec-number>1024</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865663">1024</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Harrison, David G.</author><author>Marvar, Paul J.</author><author>Titze, Jens M.</author></authors></contributors><titles><title>Vascular Inflammatory Cells in Hypertension</title><secondary-title>Frontiers in Physiology</secondary-title></titles><volume>3</volume><dates><year>2012</year></dates><publisher>Frontiers Media SA</publisher><isbn>1664-042X</isbn><urls><related-urls><url> or may be part of a systemic adaptive immune response against vascular neoantigens. Importantly, T cells directly promote endothelial dysfunction.An interesting finding was the considerable decrease of T cells in the meningeal space and the choroid plexus of SHR. Meningeal T cells have a significant impact on learning behavior, memory function, and mood stabilization ADDIN EN.CITE <EndNote><Cite><Author>Derecki</Author><Year>2010</Year><RecNum>1019</RecNum><DisplayText><style face="superscript">234</style></DisplayText><record><rec-number>1019</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865663">1019</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Derecki, No?l C.</author><author>Cardani, Amber N.</author><author>Yang, Chun Hui</author><author>Quinnies, Kayla M.</author><author>Crihfield, Anastasia</author><author>Lynch, Kevin R.</author><author>Kipnis, Jonathan</author></authors></contributors><titles><title>Regulation of learning and memory by meningeal immunity: a key role for IL-4</title><secondary-title>The Journal of Experimental Medicine</secondary-title></titles><pages>1067-1080</pages><volume>207</volume><number>5</number><dates><year>2010</year><pub-dates><date>2010/05/03</date></pub-dates></dates><publisher>Rockefeller University Press</publisher><isbn>0022-1007&#xD;1540-9538</isbn><urls><related-urls><url>. Moreover, higher amounts of natural killer (NK) cells were present in the SHR brain. Besides their direct participation in endothelial dysfunction (as an indicator of BBB disintegration), T and NK cells may play an important role in cerebral arteriogenesis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gV2VlbDwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+

PFJlY051bT40MzEwPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjM1PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDMxMDwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTQwOTA1NTM2Ij40MzEwPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj52YW4gV2VlbCwgVi48L2F1dGhvcj48

YXV0aG9yPlRvZXMsIFIuIEUuPC9hdXRob3I+PGF1dGhvcj5TZWdoZXJzLCBMLjwvYXV0aG9yPjxh

dXRob3I+RGVja2VycywgTS4gTS48L2F1dGhvcj48YXV0aG9yPmRlIFZyaWVzLCBNLiBSLjwvYXV0

aG9yPjxhdXRob3I+RWlsZXJzLCBQLiBILjwvYXV0aG9yPjxhdXRob3I+U2lwa2VucywgSi48L2F1

dGhvcj48YXV0aG9yPlNjaGVwZXJzLCBBLjwvYXV0aG9yPjxhdXRob3I+RWVmdGluZywgRC48L2F1

dGhvcj48YXV0aG9yPnZhbiBIaW5zYmVyZ2gsIFYuIFcuPC9hdXRob3I+PGF1dGhvcj52YW4gQm9j

a2VsLCBKLiBILjwvYXV0aG9yPjxhdXRob3I+UXVheCwgUC4gSC48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5HYXViaXVzIExhYm9yYXRvcnksIFROTy1RT0ws

IFAuTy4gQm94IDIyMTUsIDIzMDFDRSBMZWlkZW4sIFRoZSBOZXRoZXJsYW5kcy48L2F1dGgtYWRk

cmVzcz48dGl0bGVzPjx0aXRsZT5OYXR1cmFsIGtpbGxlciBjZWxscyBhbmQgQ0Q0KyBULWNlbGxz

IG1vZHVsYXRlIGNvbGxhdGVyYWwgYXJ0ZXJ5IGRldmVsb3BtZW50PC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPkFydGVyaW9zY2xlciBUaHJvbWIgVmFzYyBCaW9sPC9zZWNvbmRhcnktdGl0bGU+PC90

aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QXJ0ZXJpb3NjbGVyIFRocm9tYiBWYXNjIEJp

b2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yMzEwLTg8L3BhZ2VzPjx2b2x1bWU+

Mjc8L3ZvbHVtZT48bnVtYmVyPjExPC9udW1iZXI+PGVkaXRpb24+MjAwNy8wOC8yNTwvZWRpdGlv

bj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BcnRlcmlhbCBP

Y2NsdXNpdmUgRGlzZWFzZXMvKmltbXVub2xvZ3kvcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPkNENC1Qb3NpdGl2ZSBULUx5bXBob2N5dGVzLyppbW11bm9sb2d5L21ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+Q29sbGF0ZXJhbCBDaXJjdWxhdGlvbi8qaW1tdW5vbG9neTwva2V5

d29yZD48a2V5d29yZD5EaXNlYXNlIE1vZGVscywgQW5pbWFsPC9rZXl3b3JkPjxrZXl3b3JkPkZl

bW9yYWwgQXJ0ZXJ5L2dyb3d0aCAmYW1wOyBkZXZlbG9wbWVudDwva2V5d29yZD48a2V5d29yZD5I

aW5kbGltYi9ibG9vZCBzdXBwbHk8L2tleXdvcmQ+PGtleXdvcmQ+SXNjaGVtaWE8L2tleXdvcmQ+

PGtleXdvcmQ+S2lsbGVyIENlbGxzLCBOYXR1cmFsLyppbW11bm9sb2d5L21ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQkFMQiBD

PC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIEtub2Nrb3V0PC9rZXl3b3JkPjxrZXl3b3JkPk5lb3Zh

c2N1bGFyaXphdGlvbiwgUGh5c2lvbG9naWMvKmltbXVub2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAwNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdjwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1MjQtNDYzNiAoRWxlY3Ryb25pYykmI3hEOzEwNzktNTY0

MiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTc3MTcyOTU8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVi

bWVkLzE3NzE3Mjk1PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC4xMTYxL0FUVkJBSEEuMTA3LjE1MTQwNzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gV2VlbDwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+

PFJlY051bT40MzEwPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjM1PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDMxMDwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTQwOTA1NTM2Ij40MzEwPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj52YW4gV2VlbCwgVi48L2F1dGhvcj48

YXV0aG9yPlRvZXMsIFIuIEUuPC9hdXRob3I+PGF1dGhvcj5TZWdoZXJzLCBMLjwvYXV0aG9yPjxh

dXRob3I+RGVja2VycywgTS4gTS48L2F1dGhvcj48YXV0aG9yPmRlIFZyaWVzLCBNLiBSLjwvYXV0

aG9yPjxhdXRob3I+RWlsZXJzLCBQLiBILjwvYXV0aG9yPjxhdXRob3I+U2lwa2VucywgSi48L2F1

dGhvcj48YXV0aG9yPlNjaGVwZXJzLCBBLjwvYXV0aG9yPjxhdXRob3I+RWVmdGluZywgRC48L2F1

dGhvcj48YXV0aG9yPnZhbiBIaW5zYmVyZ2gsIFYuIFcuPC9hdXRob3I+PGF1dGhvcj52YW4gQm9j

a2VsLCBKLiBILjwvYXV0aG9yPjxhdXRob3I+UXVheCwgUC4gSC48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5HYXViaXVzIExhYm9yYXRvcnksIFROTy1RT0ws

IFAuTy4gQm94IDIyMTUsIDIzMDFDRSBMZWlkZW4sIFRoZSBOZXRoZXJsYW5kcy48L2F1dGgtYWRk

cmVzcz48dGl0bGVzPjx0aXRsZT5OYXR1cmFsIGtpbGxlciBjZWxscyBhbmQgQ0Q0KyBULWNlbGxz

IG1vZHVsYXRlIGNvbGxhdGVyYWwgYXJ0ZXJ5IGRldmVsb3BtZW50PC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPkFydGVyaW9zY2xlciBUaHJvbWIgVmFzYyBCaW9sPC9zZWNvbmRhcnktdGl0bGU+PC90

aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QXJ0ZXJpb3NjbGVyIFRocm9tYiBWYXNjIEJp

b2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yMzEwLTg8L3BhZ2VzPjx2b2x1bWU+

Mjc8L3ZvbHVtZT48bnVtYmVyPjExPC9udW1iZXI+PGVkaXRpb24+MjAwNy8wOC8yNTwvZWRpdGlv

bj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BcnRlcmlhbCBP

Y2NsdXNpdmUgRGlzZWFzZXMvKmltbXVub2xvZ3kvcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPkNENC1Qb3NpdGl2ZSBULUx5bXBob2N5dGVzLyppbW11bm9sb2d5L21ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+Q29sbGF0ZXJhbCBDaXJjdWxhdGlvbi8qaW1tdW5vbG9neTwva2V5

d29yZD48a2V5d29yZD5EaXNlYXNlIE1vZGVscywgQW5pbWFsPC9rZXl3b3JkPjxrZXl3b3JkPkZl

bW9yYWwgQXJ0ZXJ5L2dyb3d0aCAmYW1wOyBkZXZlbG9wbWVudDwva2V5d29yZD48a2V5d29yZD5I

aW5kbGltYi9ibG9vZCBzdXBwbHk8L2tleXdvcmQ+PGtleXdvcmQ+SXNjaGVtaWE8L2tleXdvcmQ+

PGtleXdvcmQ+S2lsbGVyIENlbGxzLCBOYXR1cmFsLyppbW11bm9sb2d5L21ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQkFMQiBD

PC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIEtub2Nrb3V0PC9rZXl3b3JkPjxrZXl3b3JkPk5lb3Zh

c2N1bGFyaXphdGlvbiwgUGh5c2lvbG9naWMvKmltbXVub2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAwNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdjwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1MjQtNDYzNiAoRWxlY3Ryb25pYykmI3hEOzEwNzktNTY0

MiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTc3MTcyOTU8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVi

bWVkLzE3NzE3Mjk1PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC4xMTYxL0FUVkJBSEEuMTA3LjE1MTQwNzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 235 owing to perfusion deficits and shear stress. Increased angiogenesis helps to restore the neurovascular junction in areas where blood vessels become rare due to continuous vascular damage. This may indicate repair processes, along with an increase of DCX-positive neural progenitors in the SHR subventricular zone. Neurogenesis might indeed be initiated by white matter injury in vascular dementia PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3NlbmJlcmc8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFy

PjxSZWNOdW0+MzYwPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjM2PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzYwPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI1NDg2MzQiPjM2MDwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Um9zZW5iZXJnLCBBLjwvYXV0aG9yPjxh

dXRob3I+TmdhbmR1LCBULjwvYXV0aG9yPjxhdXRob3I+UnVzYW5lbiwgTS48L2F1dGhvcj48YXV0

aG9yPkFudGlrYWluZW4sIFIuPC9hdXRob3I+PGF1dGhvcj5CYWNrbWFuLCBMLjwvYXV0aG9yPjxh

dXRob3I+SGF2dWxpbm5hLCBTLjwvYXV0aG9yPjxhdXRob3I+SGFubmluZW4sIFQuPC9hdXRob3I+

PGF1dGhvcj5MYWF0aWthaW5lbiwgVC48L2F1dGhvcj48YXV0aG9yPkxlaHRpc2FsbywgSi48L2F1

dGhvcj48YXV0aG9yPkxldmFsYWh0aSwgRS48L2F1dGhvcj48YXV0aG9yPkxpbmRzdHJvbSwgSi48

L2F1dGhvcj48YXV0aG9yPlBhYWphbmVuLCBULjwvYXV0aG9yPjxhdXRob3I+UGVsdG9uZW4sIE0u

PC9hdXRob3I+PGF1dGhvcj5Tb2luaW5lbiwgSC48L2F1dGhvcj48YXV0aG9yPlN0aWdzZG90dGVy

LU5lZWx5LCBBLjwvYXV0aG9yPjxhdXRob3I+U3RyYW5kYmVyZywgVC48L2F1dGhvcj48YXV0aG9y

PlR1b21pbGVodG8sIEouPC9hdXRob3I+PGF1dGhvcj5Tb2xvbW9uLCBBLjwvYXV0aG9yPjxhdXRo

b3I+S2l2aXBlbHRvLCBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1h

ZGRyZXNzPkluc3RpdHV0ZSBvZiBDbGluaWNhbCBNZWRpY2luZSwgRGVwYXJ0bWVudCBvZiBOZXVy

b2xvZ3ksIFVuaXZlcnNpdHkgb2YgRWFzdGVybiBGaW5sYW5kLCBLdW9waW8sIEZpbmxhbmQuIEVs

ZWN0cm9uaWMgYWRkcmVzczogYW5uYS5yb3NlbmJlcmdAdWVmLmZpLiYjeEQ7RGVwYXJ0bWVudCBv

ZiBQdWJsaWMgSGVhbHRoIFNvbHV0aW9ucywgQ2hyb25pYyBEaXNlYXNlIFByZXZlbnRpb24gVW5p

dCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5kIFdlbGZhcmUsIEhlbHNpbmtpLCBG

aW5sYW5kOyBEaXZpc2lvbiBvZiBDbGluaWNhbCBHZXJpYXRyaWNzLCBDZW50ZXIgZm9yIEFsemhl

aW1lciBSZXNlYXJjaCwgTlZTLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dl

ZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoIFNvbHV0aW9ucywgQ2hyb25pYyBE

aXNlYXNlIFByZXZlbnRpb24gVW5pdCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5k

IFdlbGZhcmUsIEhlbHNpbmtpLCBGaW5sYW5kOyBEaXZpc2lvbiBvZiBDbGluaWNhbCBHZXJpYXRy

aWNzLCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgTlZTLCBLYXJvbGluc2thIEluc3Rp

dHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVuOyBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgTm9ydGgg

S2FyZWxpYSBDZW50cmFsIEhvc3BpdGFsLCBKb2Vuc3V1LCBGaW5sYW5kLiYjeEQ7Q2VudGVyIGZv

ciBMaWZlIENvdXJzZSBIZWFsdGggUmVzZWFyY2gvR2VyaWF0cmljcywgVW5pdmVyc2l0eSBvZiBP

dWx1LCBPdWx1LCBGaW5sYW5kOyBNZWRpY2FsIFJlc2VhcmNoIENlbnRlciBPdWx1LCBPdWx1IFVu

aXZlcnNpdHkgSG9zcGl0YWwsIE91bHUsIEZpbmxhbmQ7IE91bHUgQ2l0eSBIb3NwaXRhbCwgT3Vs

dSwgRmlubGFuZC4mI3hEO0FnaW5nIFJlc2VhcmNoIENlbnRlciwgS2Fyb2xpbnNrYSBJbnN0aXR1

dGV0LVN0b2NraG9sbSBVbml2ZXJzaXR5LCBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0FnaW5nLCBE

aXNhYmlsaXR5IGFuZCBGdW5jdGlvbmluZyBVbml0LCBOYXRpb25hbCBJbnN0aXR1dGUgZm9yIEhl

YWx0aCBhbmQgV2VsZmFyZSwgSGVsc2lua2ksIEZpbmxhbmQuJiN4RDtEZXBhcnRtZW50IG9mIE5l

dXJvbG9neSwgS3VvcGlvIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEt1b3BpbywgRmlubGFuZC4mI3hE

O0RlcGFydG1lbnQgb2YgUHVibGljIEhlYWx0aCBTb2x1dGlvbnMsIENocm9uaWMgRGlzZWFzZSBQ

cmV2ZW50aW9uIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJl

LCBIZWxzaW5raSwgRmlubGFuZDsgSW5zdGl0dXRlIG9mIFB1YmxpYyBIZWFsdGggYW5kIENsaW5p

Y2FsIE51dHJpdGlvbiwgVW5pdmVyc2l0eSBvZiBFYXN0ZXJuIEZpbmxhbmQsIEt1b3BpbywgRmlu

bGFuZDsgSm9pbnQgbXVuaWNpcGFsIGF1dGhvcml0eSBmb3IgTm9ydGggS2FyZWxpYSBTb2NpYWwg

YW5kIEhlYWx0aCBzZXJ2aWNlcywgSm9lbnN1dSwgRmlubGFuZC4mI3hEO0RlcGFydG1lbnQgb2Yg

UHVibGljIEhlYWx0aCBTb2x1dGlvbnMsIENocm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQs

IE5hdGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlu

bGFuZDsgRGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoLCBVbml2ZXJzaXR5IG9mIEhlbHNpbmtp

LCBIZWxzaW5raSwgRmlubGFuZC4mI3hEO0RlcGFydG1lbnQgb2YgUHVibGljIEhlYWx0aCBTb2x1

dGlvbnMsIENocm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0

ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlubGFuZC4mI3hEO0Zpbm5pc2gg

SW5zdGl0dXRlIG9mIE9jY3VwYXRpb25hbCBIZWFsdGgsIEhlbHNpbmtpLCBGaW5sYW5kLiYjeEQ7

SW5zdGl0dXRlIG9mIENsaW5pY2FsIE1lZGljaW5lLCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwg

VW5pdmVyc2l0eSBvZiBFYXN0ZXJuIEZpbmxhbmQsIEt1b3BpbywgRmlubGFuZDsgTmV1cm9jZW50

ZXIsIE5ldXJvbG9neSwgS3VvcGlvIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEt1b3BpbywgRmlubGFu

ZC4mI3hEO0RlcGFydG1lbnQgb2YgUHN5Y2hvbG9neSwgVW1lYSBVbml2ZXJzaXR5LCBVbWVhLCBT

d2VkZW47IERlcGFydG1lbnQgb2YgU29jaWFsIGFuZCBQc3ljaG9sb2dpY2FsIFNjaWVuY2VzLCBL

YXJsc3RhZCBVbml2ZXJzaXR5LCBLYXJsc3RhZCwgU3dlZGVuLiYjeEQ7Q2VudGVyIGZvciBMaWZl

IENvdXJzZSBIZWFsdGggUmVzZWFyY2gvR2VyaWF0cmljcywgVW5pdmVyc2l0eSBvZiBPdWx1LCBP

dWx1LCBGaW5sYW5kOyBNZWRpY2FsIFJlc2VhcmNoIENlbnRlciBPdWx1LCBPdWx1IFVuaXZlcnNp

dHkgSG9zcGl0YWwsIE91bHUsIEZpbmxhbmQ7IFVuaXZlcnNpdHkgb2YgSGVsc2lua2ksIEhlbHNp

bmtpIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEhlbHNpbmtpLCBGaW5sYW5kLiYjeEQ7RGVwYXJ0bWVu

dCBvZiBQdWJsaWMgSGVhbHRoIFNvbHV0aW9ucywgQ2hyb25pYyBEaXNlYXNlIFByZXZlbnRpb24g

VW5pdCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5kIFdlbGZhcmUsIEhlbHNpbmtp

LCBGaW5sYW5kOyBEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFsdGgsIFVuaXZlcnNpdHkgb2YgSGVs

c2lua2ksIEhlbHNpbmtpLCBGaW5sYW5kOyBTb3V0aCBPc3Ryb2JvdGhuaWEgQ2VudHJhbCBIb3Nw

aXRhbCwgU2VpbmFqb2tpLCBGaW5sYW5kLiYjeEQ7SW5zdGl0dXRlIG9mIENsaW5pY2FsIE1lZGlj

aW5lLCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgVW5pdmVyc2l0eSBvZiBFYXN0ZXJuIEZpbmxh

bmQsIEt1b3BpbywgRmlubGFuZDsgRGl2aXNpb24gb2YgQ2xpbmljYWwgR2VyaWF0cmljcywgQ2Vu

dGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIE5WUywgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBT

dG9ja2hvbG0sIFN3ZWRlbjsgQWdpbmcgUmVzZWFyY2ggQ2VudGVyLCBLYXJvbGluc2thIEluc3Rp

dHV0ZXQtU3RvY2tob2xtIFVuaXZlcnNpdHksIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7SW5zdGl0

dXRlIG9mIENsaW5pY2FsIE1lZGljaW5lLCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgVW5pdmVy

c2l0eSBvZiBFYXN0ZXJuIEZpbmxhbmQsIEt1b3BpbywgRmlubGFuZDsgRGVwYXJ0bWVudCBvZiBQ

dWJsaWMgSGVhbHRoIFNvbHV0aW9ucywgQ2hyb25pYyBEaXNlYXNlIFByZXZlbnRpb24gVW5pdCwg

TmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5kIFdlbGZhcmUsIEhlbHNpbmtpLCBGaW5s

YW5kOyBEaXZpc2lvbiBvZiBDbGluaWNhbCBHZXJpYXRyaWNzLCBDZW50ZXIgZm9yIEFsemhlaW1l

ciBSZXNlYXJjaCwgTlZTLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVu

OyBBZ2luZyBSZXNlYXJjaCBDZW50ZXIsIEthcm9saW5za2EgSW5zdGl0dXRldC1TdG9ja2hvbG0g

VW5pdmVyc2l0eSwgU3RvY2tob2xtLCBTd2VkZW47IFN0b2NraG9sbXMgU2p1a2hlbSwgUmVzZWFy

Y2ggJmFtcDsgRGV2ZWxvcG1lbnQgVW5pdCwgU3RvY2tob2xtLCBTd2VkZW4uPC9hdXRoLWFkZHJl

c3M+PHRpdGxlcz48dGl0bGU+TXVsdGlkb21haW4gbGlmZXN0eWxlIGludGVydmVudGlvbiBiZW5l

Zml0cyBhIGxhcmdlIGVsZGVybHkgcG9wdWxhdGlvbiBhdCByaXNrIGZvciBjb2duaXRpdmUgZGVj

bGluZSBhbmQgZGVtZW50aWEgcmVnYXJkbGVzcyBvZiBiYXNlbGluZSBjaGFyYWN0ZXJpc3RpY3M6

IFRoZSBGSU5HRVIgdHJpYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWx6aGVpbWVycyBEZW1l

bnQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MjYzLTI3MDwvcGFnZXM+PHZvbHVt

ZT4xNDwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD4qQWx6aGVp

bWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPipDb2duaXRpdmUgaW1wYWlybWVu

dDwva2V5d29yZD48a2V5d29yZD4qRGVtZW50aWE8L2tleXdvcmQ+PGtleXdvcmQ+KkludGVydmVu

dGlvbjwva2V5d29yZD48a2V5d29yZD4qTGlmZXN0eWxlPC9rZXl3b3JkPjxrZXl3b3JkPipNdWx0

aWRvbWFpbjwva2V5d29yZD48a2V5d29yZD4qUHJldmVudGlvbjwva2V5d29yZD48a2V5d29yZD4q

UmFuZG9taXplZCBjb250cm9sbGVkIHRyaWFsPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5

ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXI8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4xNTUyLTUyNzkgKEVsZWN0cm9uaWMpJiN4RDsxNTUyLTUyNjAgKExpbmtpbmcp

PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5MDU1ODE0PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh

dGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI5MDU1ODE0

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4x

MDE2L2ouamFsei4yMDE3LjA5LjAwNjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+

PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3NlbmJlcmc8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFy

PjxSZWNOdW0+MzYwPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjM2PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzYwPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI1NDg2MzQiPjM2MDwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Um9zZW5iZXJnLCBBLjwvYXV0aG9yPjxh

dXRob3I+TmdhbmR1LCBULjwvYXV0aG9yPjxhdXRob3I+UnVzYW5lbiwgTS48L2F1dGhvcj48YXV0

aG9yPkFudGlrYWluZW4sIFIuPC9hdXRob3I+PGF1dGhvcj5CYWNrbWFuLCBMLjwvYXV0aG9yPjxh

dXRob3I+SGF2dWxpbm5hLCBTLjwvYXV0aG9yPjxhdXRob3I+SGFubmluZW4sIFQuPC9hdXRob3I+

PGF1dGhvcj5MYWF0aWthaW5lbiwgVC48L2F1dGhvcj48YXV0aG9yPkxlaHRpc2FsbywgSi48L2F1

dGhvcj48YXV0aG9yPkxldmFsYWh0aSwgRS48L2F1dGhvcj48YXV0aG9yPkxpbmRzdHJvbSwgSi48

L2F1dGhvcj48YXV0aG9yPlBhYWphbmVuLCBULjwvYXV0aG9yPjxhdXRob3I+UGVsdG9uZW4sIE0u

PC9hdXRob3I+PGF1dGhvcj5Tb2luaW5lbiwgSC48L2F1dGhvcj48YXV0aG9yPlN0aWdzZG90dGVy

LU5lZWx5LCBBLjwvYXV0aG9yPjxhdXRob3I+U3RyYW5kYmVyZywgVC48L2F1dGhvcj48YXV0aG9y

PlR1b21pbGVodG8sIEouPC9hdXRob3I+PGF1dGhvcj5Tb2xvbW9uLCBBLjwvYXV0aG9yPjxhdXRo

b3I+S2l2aXBlbHRvLCBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1h

ZGRyZXNzPkluc3RpdHV0ZSBvZiBDbGluaWNhbCBNZWRpY2luZSwgRGVwYXJ0bWVudCBvZiBOZXVy

b2xvZ3ksIFVuaXZlcnNpdHkgb2YgRWFzdGVybiBGaW5sYW5kLCBLdW9waW8sIEZpbmxhbmQuIEVs

ZWN0cm9uaWMgYWRkcmVzczogYW5uYS5yb3NlbmJlcmdAdWVmLmZpLiYjeEQ7RGVwYXJ0bWVudCBv

ZiBQdWJsaWMgSGVhbHRoIFNvbHV0aW9ucywgQ2hyb25pYyBEaXNlYXNlIFByZXZlbnRpb24gVW5p

dCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5kIFdlbGZhcmUsIEhlbHNpbmtpLCBG

aW5sYW5kOyBEaXZpc2lvbiBvZiBDbGluaWNhbCBHZXJpYXRyaWNzLCBDZW50ZXIgZm9yIEFsemhl

aW1lciBSZXNlYXJjaCwgTlZTLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dl

ZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoIFNvbHV0aW9ucywgQ2hyb25pYyBE

aXNlYXNlIFByZXZlbnRpb24gVW5pdCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5k

IFdlbGZhcmUsIEhlbHNpbmtpLCBGaW5sYW5kOyBEaXZpc2lvbiBvZiBDbGluaWNhbCBHZXJpYXRy

aWNzLCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgTlZTLCBLYXJvbGluc2thIEluc3Rp

dHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVuOyBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgTm9ydGgg

S2FyZWxpYSBDZW50cmFsIEhvc3BpdGFsLCBKb2Vuc3V1LCBGaW5sYW5kLiYjeEQ7Q2VudGVyIGZv

ciBMaWZlIENvdXJzZSBIZWFsdGggUmVzZWFyY2gvR2VyaWF0cmljcywgVW5pdmVyc2l0eSBvZiBP

dWx1LCBPdWx1LCBGaW5sYW5kOyBNZWRpY2FsIFJlc2VhcmNoIENlbnRlciBPdWx1LCBPdWx1IFVu

aXZlcnNpdHkgSG9zcGl0YWwsIE91bHUsIEZpbmxhbmQ7IE91bHUgQ2l0eSBIb3NwaXRhbCwgT3Vs

dSwgRmlubGFuZC4mI3hEO0FnaW5nIFJlc2VhcmNoIENlbnRlciwgS2Fyb2xpbnNrYSBJbnN0aXR1

dGV0LVN0b2NraG9sbSBVbml2ZXJzaXR5LCBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0FnaW5nLCBE

aXNhYmlsaXR5IGFuZCBGdW5jdGlvbmluZyBVbml0LCBOYXRpb25hbCBJbnN0aXR1dGUgZm9yIEhl

YWx0aCBhbmQgV2VsZmFyZSwgSGVsc2lua2ksIEZpbmxhbmQuJiN4RDtEZXBhcnRtZW50IG9mIE5l

dXJvbG9neSwgS3VvcGlvIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEt1b3BpbywgRmlubGFuZC4mI3hE

O0RlcGFydG1lbnQgb2YgUHVibGljIEhlYWx0aCBTb2x1dGlvbnMsIENocm9uaWMgRGlzZWFzZSBQ

cmV2ZW50aW9uIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJl

LCBIZWxzaW5raSwgRmlubGFuZDsgSW5zdGl0dXRlIG9mIFB1YmxpYyBIZWFsdGggYW5kIENsaW5p

Y2FsIE51dHJpdGlvbiwgVW5pdmVyc2l0eSBvZiBFYXN0ZXJuIEZpbmxhbmQsIEt1b3BpbywgRmlu

bGFuZDsgSm9pbnQgbXVuaWNpcGFsIGF1dGhvcml0eSBmb3IgTm9ydGggS2FyZWxpYSBTb2NpYWwg

YW5kIEhlYWx0aCBzZXJ2aWNlcywgSm9lbnN1dSwgRmlubGFuZC4mI3hEO0RlcGFydG1lbnQgb2Yg

UHVibGljIEhlYWx0aCBTb2x1dGlvbnMsIENocm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQs

IE5hdGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlu

bGFuZDsgRGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoLCBVbml2ZXJzaXR5IG9mIEhlbHNpbmtp

LCBIZWxzaW5raSwgRmlubGFuZC4mI3hEO0RlcGFydG1lbnQgb2YgUHVibGljIEhlYWx0aCBTb2x1

dGlvbnMsIENocm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0

ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlubGFuZC4mI3hEO0Zpbm5pc2gg

SW5zdGl0dXRlIG9mIE9jY3VwYXRpb25hbCBIZWFsdGgsIEhlbHNpbmtpLCBGaW5sYW5kLiYjeEQ7

SW5zdGl0dXRlIG9mIENsaW5pY2FsIE1lZGljaW5lLCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwg

VW5pdmVyc2l0eSBvZiBFYXN0ZXJuIEZpbmxhbmQsIEt1b3BpbywgRmlubGFuZDsgTmV1cm9jZW50

ZXIsIE5ldXJvbG9neSwgS3VvcGlvIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEt1b3BpbywgRmlubGFu

ZC4mI3hEO0RlcGFydG1lbnQgb2YgUHN5Y2hvbG9neSwgVW1lYSBVbml2ZXJzaXR5LCBVbWVhLCBT

d2VkZW47IERlcGFydG1lbnQgb2YgU29jaWFsIGFuZCBQc3ljaG9sb2dpY2FsIFNjaWVuY2VzLCBL

YXJsc3RhZCBVbml2ZXJzaXR5LCBLYXJsc3RhZCwgU3dlZGVuLiYjeEQ7Q2VudGVyIGZvciBMaWZl

IENvdXJzZSBIZWFsdGggUmVzZWFyY2gvR2VyaWF0cmljcywgVW5pdmVyc2l0eSBvZiBPdWx1LCBP

dWx1LCBGaW5sYW5kOyBNZWRpY2FsIFJlc2VhcmNoIENlbnRlciBPdWx1LCBPdWx1IFVuaXZlcnNp

dHkgSG9zcGl0YWwsIE91bHUsIEZpbmxhbmQ7IFVuaXZlcnNpdHkgb2YgSGVsc2lua2ksIEhlbHNp

bmtpIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEhlbHNpbmtpLCBGaW5sYW5kLiYjeEQ7RGVwYXJ0bWVu

dCBvZiBQdWJsaWMgSGVhbHRoIFNvbHV0aW9ucywgQ2hyb25pYyBEaXNlYXNlIFByZXZlbnRpb24g

VW5pdCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5kIFdlbGZhcmUsIEhlbHNpbmtp

LCBGaW5sYW5kOyBEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFsdGgsIFVuaXZlcnNpdHkgb2YgSGVs

c2lua2ksIEhlbHNpbmtpLCBGaW5sYW5kOyBTb3V0aCBPc3Ryb2JvdGhuaWEgQ2VudHJhbCBIb3Nw

aXRhbCwgU2VpbmFqb2tpLCBGaW5sYW5kLiYjeEQ7SW5zdGl0dXRlIG9mIENsaW5pY2FsIE1lZGlj

aW5lLCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgVW5pdmVyc2l0eSBvZiBFYXN0ZXJuIEZpbmxh

bmQsIEt1b3BpbywgRmlubGFuZDsgRGl2aXNpb24gb2YgQ2xpbmljYWwgR2VyaWF0cmljcywgQ2Vu

dGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIE5WUywgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBT

dG9ja2hvbG0sIFN3ZWRlbjsgQWdpbmcgUmVzZWFyY2ggQ2VudGVyLCBLYXJvbGluc2thIEluc3Rp

dHV0ZXQtU3RvY2tob2xtIFVuaXZlcnNpdHksIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7SW5zdGl0

dXRlIG9mIENsaW5pY2FsIE1lZGljaW5lLCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgVW5pdmVy

c2l0eSBvZiBFYXN0ZXJuIEZpbmxhbmQsIEt1b3BpbywgRmlubGFuZDsgRGVwYXJ0bWVudCBvZiBQ

dWJsaWMgSGVhbHRoIFNvbHV0aW9ucywgQ2hyb25pYyBEaXNlYXNlIFByZXZlbnRpb24gVW5pdCwg

TmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5kIFdlbGZhcmUsIEhlbHNpbmtpLCBGaW5s

YW5kOyBEaXZpc2lvbiBvZiBDbGluaWNhbCBHZXJpYXRyaWNzLCBDZW50ZXIgZm9yIEFsemhlaW1l

ciBSZXNlYXJjaCwgTlZTLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVu

OyBBZ2luZyBSZXNlYXJjaCBDZW50ZXIsIEthcm9saW5za2EgSW5zdGl0dXRldC1TdG9ja2hvbG0g

VW5pdmVyc2l0eSwgU3RvY2tob2xtLCBTd2VkZW47IFN0b2NraG9sbXMgU2p1a2hlbSwgUmVzZWFy

Y2ggJmFtcDsgRGV2ZWxvcG1lbnQgVW5pdCwgU3RvY2tob2xtLCBTd2VkZW4uPC9hdXRoLWFkZHJl

c3M+PHRpdGxlcz48dGl0bGU+TXVsdGlkb21haW4gbGlmZXN0eWxlIGludGVydmVudGlvbiBiZW5l

Zml0cyBhIGxhcmdlIGVsZGVybHkgcG9wdWxhdGlvbiBhdCByaXNrIGZvciBjb2duaXRpdmUgZGVj

bGluZSBhbmQgZGVtZW50aWEgcmVnYXJkbGVzcyBvZiBiYXNlbGluZSBjaGFyYWN0ZXJpc3RpY3M6

IFRoZSBGSU5HRVIgdHJpYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWx6aGVpbWVycyBEZW1l

bnQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MjYzLTI3MDwvcGFnZXM+PHZvbHVt

ZT4xNDwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD4qQWx6aGVp

bWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPipDb2duaXRpdmUgaW1wYWlybWVu

dDwva2V5d29yZD48a2V5d29yZD4qRGVtZW50aWE8L2tleXdvcmQ+PGtleXdvcmQ+KkludGVydmVu

dGlvbjwva2V5d29yZD48a2V5d29yZD4qTGlmZXN0eWxlPC9rZXl3b3JkPjxrZXl3b3JkPipNdWx0

aWRvbWFpbjwva2V5d29yZD48a2V5d29yZD4qUHJldmVudGlvbjwva2V5d29yZD48a2V5d29yZD4q

UmFuZG9taXplZCBjb250cm9sbGVkIHRyaWFsPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5

ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXI8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4xNTUyLTUyNzkgKEVsZWN0cm9uaWMpJiN4RDsxNTUyLTUyNjAgKExpbmtpbmcp

PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5MDU1ODE0PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh

dGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI5MDU1ODE0

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4x

MDE2L2ouamFsei4yMDE3LjA5LjAwNjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+

PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 236. Preclinical research on post-hemorrhage neuronal damage: novel insightsRecent clinical evidence suggests that the occurrence of microbleeds leads to a greater cognitive decline in vascular dementia and AD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJ0aW5lei1SYW1pcmV6PC9BdXRob3I+PFllYXI+MjAx

NDwvWWVhcj48UmVjTnVtPjQzMTE8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1

cGVyc2NyaXB0Ij4yMzctMjM5PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1i

ZXI+NDMxMTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3

YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTQwOTA1Njc2

Ij40MzExPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs

ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5NYXJ0aW5lei1S

YW1pcmV6LCBTLjwvYXV0aG9yPjxhdXRob3I+R3JlZW5iZXJnLCBTLiBNLjwvYXV0aG9yPjxhdXRo

b3I+Vmlzd2FuYXRoYW4sIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo

LWFkZHJlc3M+UGhpbGlwIEouIEtpc3RsZXIgU3Ryb2tlIFJlc2VhcmNoIENlbnRlciwgTWFzc2Fj

aHVzZXR0cyBHZW5lcmFsIEhvc3BpdGFsLCAxNzUgQ2FtYnJpZGdlIFN0cmVldCBTdWl0ZSAzMDAs

IEJvc3RvbiwgTUEgMDIxMTQsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5DZXJl

YnJhbCBtaWNyb2JsZWVkczogb3ZlcnZpZXcgYW5kIGltcGxpY2F0aW9ucyBpbiBjb2duaXRpdmUg

aW1wYWlybWVudDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbHpoZWltZXJzIFJlcyBUaGVyPC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QWx6aGVpbWVy

cyBSZXMgVGhlcjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjMzPC9wYWdlcz48dm9s

dW1lPjY8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48ZWRpdGlvbj4yMDE0LzA3LzA2PC9lZGl0

aW9uPjxkYXRlcz48eWVhcj4yMDE0PC95ZWFyPjwvZGF0ZXM+PGlzYm4+MTc1OC05MTkzIChQcmlu

dCk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjQ5ODc0Njg8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJl

bGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI0OTg3

NDY4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQwNzUxNDk8L2N1c3Rv

bTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExODYvYWx6cnQyNjM8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkRpbmc8L0F1dGhvcj48

WWVhcj4yMDE3PC9ZZWFyPjxSZWNOdW0+MTAyMDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+

MTAyMDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTBy

eDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyODY1NjYzIj4x

MDIwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+

MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5EaW5nLCBKaWU8L2F1

dGhvcj48YXV0aG9yPlNpZ3Vyw7Bzc29uLCBTaWd1csOwdXI8L2F1dGhvcj48YXV0aG9yPkrDs25z

c29uLCBQw6FsbWkgVi48L2F1dGhvcj48YXV0aG9yPkVpcmlrc2RvdHRpciwgR3Vkbnk8L2F1dGhv

cj48YXV0aG9yPk1laXJlbGxlcywgT3NvcmlvPC9hdXRob3I+PGF1dGhvcj5LamFydGFuc3Nvbiwg

T2xhZnVyPC9hdXRob3I+PGF1dGhvcj5Mb3BleiwgT3NjYXIgTC48L2F1dGhvcj48YXV0aG9yPnZh

biBCdWNoZW0sIE1hcmsgQS48L2F1dGhvcj48YXV0aG9yPkd1ZG5hc29uLCBWaWxtdW5kdXI8L2F1

dGhvcj48YXV0aG9yPkxhdW5lciwgTGVub3JlIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp

YnV0b3JzPjx0aXRsZXM+PHRpdGxlPlNwYWNlIGFuZCBsb2NhdGlvbiBvZiBjZXJlYnJhbCBtaWNy

b2JsZWVkcywgY29nbml0aXZlIGRlY2xpbmUsIGFuZCBkZW1lbnRpYSBpbiB0aGUgY29tbXVuaXR5

PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0

bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvbG9neTwvZnVsbC10aXRsZT48L3Blcmlv

ZGljYWw+PHBhZ2VzPjIwODktMjA5NzwvcGFnZXM+PHZvbHVtZT44ODwvdm9sdW1lPjxudW1iZXI+

MjI8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTcv

MDUvMDM8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPk92aWQgVGVjaG5vbG9n

aWVzIChXb2x0ZXJzIEtsdXdlciBIZWFsdGgpPC9wdWJsaXNoZXI+PGlzYm4+MDAyOC0zODc4JiN4

RDsxNTI2LTYzMlg8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2ku

b3JnLzEwLjEyMTIvd25sLjAwMDAwMDAwMDAwMDM5ODM8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEyMTIvd25sLjAwMDAwMDAwMDAwMDM5ODM8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk1h

dHN1eWFtYTwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJlY051bT40MzEyPC9SZWNOdW0+PHJl

Y29yZD48cmVjLW51bWJlcj40MzEyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3Rh

bXA9IjE1NDA5MDU3NTkiPjQzMTI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPk1hdHN1eWFtYSwgSC48L2F1dGhvcj48YXV0aG9yPklpLCBZLjwvYXV0aG9yPjxhdXRob3I+

TWFlZGEsIE0uPC9hdXRob3I+PGF1dGhvcj5VbWlubywgTS48L2F1dGhvcj48YXV0aG9yPlVlZGEs

IFkuPC9hdXRob3I+PGF1dGhvcj5UYWJlaSwgSy4gSS48L2F1dGhvcj48YXV0aG9yPktpZGEsIEgu

PC9hdXRob3I+PGF1dGhvcj5TYXRvaCwgTS48L2F1dGhvcj48YXV0aG9yPlNoaW5kbywgQS48L2F1

dGhvcj48YXV0aG9yPlRhbmlndWNoaSwgQS48L2F1dGhvcj48YXV0aG9yPlRha2FoYXNoaSwgUi48

L2F1dGhvcj48YXV0aG9yPlRvbWltb3RvLCBILjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTmV1cm9sb2d5TWllIFVuaXZlcnNpdHkg

R3JhZHVhdGUgU2Nob29sIG9mIE1lZGljaW5lVHN1TWllSmFwYW4uJiN4RDtEZXBhcnRtZW50IG9m

IEFkdmFuY2VkIERpYWdub3N0aWMgSW1hZ2luZ01pZSBVbml2ZXJzaXR5IEdyYWR1YXRlIFNjaG9v

bCBvZiBNZWRpY2luZVRzdU1pZUphcGFuLiYjeEQ7RGVwYXJ0bWVudCBvZiBSYWRpb2xvZ3lNaWUg

VW5pdmVyc2l0eSBHcmFkdWF0ZSBTY2hvb2wgb2YgTWVkaWNpbmVUc3VNaWVKYXBhbi4mI3hEO0Rl

cGFydG1lbnQgb2YgUmVoYWJpbGl0YXRpb25NaWUgVW5pdmVyc2l0eSBIb3NwaXRhbFRzdU1pZUph

cGFuLiYjeEQ7RGVwYXJ0bWVudCBvZiBEZW1lbnRpYSBQcmV2ZW50aW9uIGFuZCBUaGVyYXBldXRp

Y3NNaWUgVW5pdmVyc2l0eSBHcmFkdWF0ZSBTY2hvb2wgb2YgTWVkaWNpbmVUc3VNaWVKYXBhbi4m

I3hEO0RlcGFydG1lbnQgb2YgTmV1cm9sb2d5S3lvdG8gVW5pdmVyc2l0eSBHcmFkdWF0ZSBTY2hv

b2wgb2YgTWVkaWNpbmVLeW90b0phcGFuLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkJh

Y2tncm91bmQgYW5kIGRpc3RyaWJ1dGlvbiBvZiBsb2JhciBtaWNyb2JsZWVkcyBpbiBjb2duaXRp

dmUgZHlzZnVuY3Rpb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QnJhaW4gQmVoYXY8L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5CcmFpbiBCZWhhdjwv

ZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPmUwMDg1NjwvcGFnZXM+PHZvbHVtZT43PC92

b2x1bWU+PG51bWJlcj4xMTwvbnVtYmVyPjxlZGl0aW9uPjIwMTcvMTIvMDU8L2VkaXRpb24+PGtl

eXdvcmRzPjxrZXl3b3JkPmNlcmVicmFsIGFteWxvaWQgYW5naW9wYXRoeTwva2V5d29yZD48a2V5

d29yZD5jZXJlYnJhbCBtaWNyb2JsZWVkczwva2V5d29yZD48a2V5d29yZD5oeXBlcnRlbnNpdmUg

dmFzY3Vsb3BhdGh5PC9rZXl3b3JkPjxrZXl3b3JkPm1hZ25ldGljIHJlc29uYW5jZSBpbWFnaW5n

PC9rZXl3b3JkPjxrZXl3b3JkPm1lbW9yeSBjbGluaWM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0

ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdjwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxpc2JuPjIxNjItMzI3OSAoRWxlY3Ryb25pYyk8L2lzYm4+PGFjY2Vzc2lvbi1u

dW0+MjkyMDE1NTU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBz

Oi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI5MjAxNTU1PC91cmw+PC9yZWxhdGVkLXVy

bHM+PC91cmxzPjxjdXN0b20yPlBNQzU2OTg4NzI8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjEwMDIvYnJiMy44NTY8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3Jk

PjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJ0aW5lei1SYW1pcmV6PC9BdXRob3I+PFllYXI+MjAx

NDwvWWVhcj48UmVjTnVtPjQzMTE8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1

cGVyc2NyaXB0Ij4yMzctMjM5PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1i

ZXI+NDMxMTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3

YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTQwOTA1Njc2

Ij40MzExPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs

ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5NYXJ0aW5lei1S

YW1pcmV6LCBTLjwvYXV0aG9yPjxhdXRob3I+R3JlZW5iZXJnLCBTLiBNLjwvYXV0aG9yPjxhdXRo

b3I+Vmlzd2FuYXRoYW4sIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo

LWFkZHJlc3M+UGhpbGlwIEouIEtpc3RsZXIgU3Ryb2tlIFJlc2VhcmNoIENlbnRlciwgTWFzc2Fj

aHVzZXR0cyBHZW5lcmFsIEhvc3BpdGFsLCAxNzUgQ2FtYnJpZGdlIFN0cmVldCBTdWl0ZSAzMDAs

IEJvc3RvbiwgTUEgMDIxMTQsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5DZXJl

YnJhbCBtaWNyb2JsZWVkczogb3ZlcnZpZXcgYW5kIGltcGxpY2F0aW9ucyBpbiBjb2duaXRpdmUg

aW1wYWlybWVudDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbHpoZWltZXJzIFJlcyBUaGVyPC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QWx6aGVpbWVy

cyBSZXMgVGhlcjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjMzPC9wYWdlcz48dm9s

dW1lPjY8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48ZWRpdGlvbj4yMDE0LzA3LzA2PC9lZGl0

aW9uPjxkYXRlcz48eWVhcj4yMDE0PC95ZWFyPjwvZGF0ZXM+PGlzYm4+MTc1OC05MTkzIChQcmlu

dCk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjQ5ODc0Njg8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJl

bGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI0OTg3

NDY4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQwNzUxNDk8L2N1c3Rv

bTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExODYvYWx6cnQyNjM8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkRpbmc8L0F1dGhvcj48

WWVhcj4yMDE3PC9ZZWFyPjxSZWNOdW0+MTAyMDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+

MTAyMDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTBy

eDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyODY1NjYzIj4x

MDIwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+

MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5EaW5nLCBKaWU8L2F1

dGhvcj48YXV0aG9yPlNpZ3Vyw7Bzc29uLCBTaWd1csOwdXI8L2F1dGhvcj48YXV0aG9yPkrDs25z

c29uLCBQw6FsbWkgVi48L2F1dGhvcj48YXV0aG9yPkVpcmlrc2RvdHRpciwgR3Vkbnk8L2F1dGhv

cj48YXV0aG9yPk1laXJlbGxlcywgT3NvcmlvPC9hdXRob3I+PGF1dGhvcj5LamFydGFuc3Nvbiwg

T2xhZnVyPC9hdXRob3I+PGF1dGhvcj5Mb3BleiwgT3NjYXIgTC48L2F1dGhvcj48YXV0aG9yPnZh

biBCdWNoZW0sIE1hcmsgQS48L2F1dGhvcj48YXV0aG9yPkd1ZG5hc29uLCBWaWxtdW5kdXI8L2F1

dGhvcj48YXV0aG9yPkxhdW5lciwgTGVub3JlIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp

YnV0b3JzPjx0aXRsZXM+PHRpdGxlPlNwYWNlIGFuZCBsb2NhdGlvbiBvZiBjZXJlYnJhbCBtaWNy

b2JsZWVkcywgY29nbml0aXZlIGRlY2xpbmUsIGFuZCBkZW1lbnRpYSBpbiB0aGUgY29tbXVuaXR5

PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0

bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvbG9neTwvZnVsbC10aXRsZT48L3Blcmlv

ZGljYWw+PHBhZ2VzPjIwODktMjA5NzwvcGFnZXM+PHZvbHVtZT44ODwvdm9sdW1lPjxudW1iZXI+

MjI8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTcv

MDUvMDM8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPk92aWQgVGVjaG5vbG9n

aWVzIChXb2x0ZXJzIEtsdXdlciBIZWFsdGgpPC9wdWJsaXNoZXI+PGlzYm4+MDAyOC0zODc4JiN4

RDsxNTI2LTYzMlg8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2ku

b3JnLzEwLjEyMTIvd25sLjAwMDAwMDAwMDAwMDM5ODM8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEyMTIvd25sLjAwMDAwMDAwMDAwMDM5ODM8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk1h

dHN1eWFtYTwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJlY051bT40MzEyPC9SZWNOdW0+PHJl

Y29yZD48cmVjLW51bWJlcj40MzEyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3Rh

bXA9IjE1NDA5MDU3NTkiPjQzMTI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPk1hdHN1eWFtYSwgSC48L2F1dGhvcj48YXV0aG9yPklpLCBZLjwvYXV0aG9yPjxhdXRob3I+

TWFlZGEsIE0uPC9hdXRob3I+PGF1dGhvcj5VbWlubywgTS48L2F1dGhvcj48YXV0aG9yPlVlZGEs

IFkuPC9hdXRob3I+PGF1dGhvcj5UYWJlaSwgSy4gSS48L2F1dGhvcj48YXV0aG9yPktpZGEsIEgu

PC9hdXRob3I+PGF1dGhvcj5TYXRvaCwgTS48L2F1dGhvcj48YXV0aG9yPlNoaW5kbywgQS48L2F1

dGhvcj48YXV0aG9yPlRhbmlndWNoaSwgQS48L2F1dGhvcj48YXV0aG9yPlRha2FoYXNoaSwgUi48

L2F1dGhvcj48YXV0aG9yPlRvbWltb3RvLCBILjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTmV1cm9sb2d5TWllIFVuaXZlcnNpdHkg

R3JhZHVhdGUgU2Nob29sIG9mIE1lZGljaW5lVHN1TWllSmFwYW4uJiN4RDtEZXBhcnRtZW50IG9m

IEFkdmFuY2VkIERpYWdub3N0aWMgSW1hZ2luZ01pZSBVbml2ZXJzaXR5IEdyYWR1YXRlIFNjaG9v

bCBvZiBNZWRpY2luZVRzdU1pZUphcGFuLiYjeEQ7RGVwYXJ0bWVudCBvZiBSYWRpb2xvZ3lNaWUg

VW5pdmVyc2l0eSBHcmFkdWF0ZSBTY2hvb2wgb2YgTWVkaWNpbmVUc3VNaWVKYXBhbi4mI3hEO0Rl

cGFydG1lbnQgb2YgUmVoYWJpbGl0YXRpb25NaWUgVW5pdmVyc2l0eSBIb3NwaXRhbFRzdU1pZUph

cGFuLiYjeEQ7RGVwYXJ0bWVudCBvZiBEZW1lbnRpYSBQcmV2ZW50aW9uIGFuZCBUaGVyYXBldXRp

Y3NNaWUgVW5pdmVyc2l0eSBHcmFkdWF0ZSBTY2hvb2wgb2YgTWVkaWNpbmVUc3VNaWVKYXBhbi4m

I3hEO0RlcGFydG1lbnQgb2YgTmV1cm9sb2d5S3lvdG8gVW5pdmVyc2l0eSBHcmFkdWF0ZSBTY2hv

b2wgb2YgTWVkaWNpbmVLeW90b0phcGFuLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkJh

Y2tncm91bmQgYW5kIGRpc3RyaWJ1dGlvbiBvZiBsb2JhciBtaWNyb2JsZWVkcyBpbiBjb2duaXRp

dmUgZHlzZnVuY3Rpb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QnJhaW4gQmVoYXY8L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5CcmFpbiBCZWhhdjwv

ZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPmUwMDg1NjwvcGFnZXM+PHZvbHVtZT43PC92

b2x1bWU+PG51bWJlcj4xMTwvbnVtYmVyPjxlZGl0aW9uPjIwMTcvMTIvMDU8L2VkaXRpb24+PGtl

eXdvcmRzPjxrZXl3b3JkPmNlcmVicmFsIGFteWxvaWQgYW5naW9wYXRoeTwva2V5d29yZD48a2V5

d29yZD5jZXJlYnJhbCBtaWNyb2JsZWVkczwva2V5d29yZD48a2V5d29yZD5oeXBlcnRlbnNpdmUg

dmFzY3Vsb3BhdGh5PC9rZXl3b3JkPjxrZXl3b3JkPm1hZ25ldGljIHJlc29uYW5jZSBpbWFnaW5n

PC9rZXl3b3JkPjxrZXl3b3JkPm1lbW9yeSBjbGluaWM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0

ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdjwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxpc2JuPjIxNjItMzI3OSAoRWxlY3Ryb25pYyk8L2lzYm4+PGFjY2Vzc2lvbi1u

dW0+MjkyMDE1NTU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBz

Oi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI5MjAxNTU1PC91cmw+PC9yZWxhdGVkLXVy

bHM+PC91cmxzPjxjdXN0b20yPlBNQzU2OTg4NzI8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjEwMDIvYnJiMy44NTY8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3Jk

PjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 237-239. In the Rotterdam Study, higher levels of plasma Aβ were associated with increasing lacunar and microbleed counts ADDIN EN.CITE <EndNote><Cite><Author>Hilal</Author><Year>2017</Year><RecNum>1025</RecNum><DisplayText><style face="superscript">240</style></DisplayText><record><rec-number>1025</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865663">1025</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hilal, Saima</author><author>Akoudad, Saloua</author><author>van Duijn, Cornelia M.</author><author>Niessen, Wiro J.</author><author>Verbeek, Marcel M.</author><author>Vanderstichele, Hugo</author><author>Stoops, Erik</author><author>Ikram, M. Arfan</author><author>Vernooij, Meike W.</author></authors></contributors><titles><title>Plasma Amyloid-β Levels, Cerebral Small Vessel Disease, and Cognition: The Rotterdam Study</title><secondary-title>Journal of Alzheimer&apos;s Disease</secondary-title></titles><pages>977-987</pages><volume>60</volume><number>3</number><dates><year>2017</year><pub-dates><date>2017/10/03</date></pub-dates></dates><publisher>IOS Press</publisher><isbn>1387-2877&#xD;1875-8908</isbn><urls><related-urls><url>. However, microbleeds are often functionally asymptomatic in patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGVobGluZzwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+

PFJlY051bT40MzEzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjQxLDI0Mjwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQzMTM8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0MDkwNjA3NCI+NDMxMzwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U3RlaGxpbmcsIEMuPC9hdXRo

b3I+PGF1dGhvcj5XZXJzY2hpbmcsIEguPC9hdXRob3I+PGF1dGhvcj5LbG9za2EsIFMuIFAuPC9h

dXRob3I+PGF1dGhvcj5LaXJjaGhvZiwgUC48L2F1dGhvcj48YXV0aG9yPlJpbmcsIEouPC9hdXRo

b3I+PGF1dGhvcj5OYXNzZW5zdGVpbiwgSS48L2F1dGhvcj48YXV0aG9yPkFsbGtlbXBlciwgVC48

L2F1dGhvcj48YXV0aG9yPktuZWNodCwgUy48L2F1dGhvcj48YXV0aG9yPkJhY2htYW5uLCBSLjwv

YXV0aG9yPjxhdXRob3I+SGVpbmRlbCwgVy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIENsaW5pY2FsIFJhZGlvbG9neSwgVW5pdmVy

c2l0eSBvZiBNdWVuc3RlciwgQWxiZXJ0LVNjaHdlaXR6ZXItU3RyLiAzMywgRCA0ODEyOSBNdW5z

dGVyLCBHZXJtYW55LiBjc3RlaGxpbmdAdW5pLW11ZW5zdGVyLmRlPC9hdXRoLWFkZHJlc3M+PHRp

dGxlcz48dGl0bGU+RGV0ZWN0aW9uIG9mIGFzeW1wdG9tYXRpYyBjZXJlYnJhbCBtaWNyb2JsZWVk

czogYSBjb21wYXJhdGl2ZSBzdHVkeSBhdCAxLjUgYW5kIDMuMCBUPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPkFjYWQgUmFkaW9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+QWNhZCBSYWRpb2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz44

OTUtOTAwPC9wYWdlcz48dm9sdW1lPjE1PC92b2x1bWU+PG51bWJlcj43PC9udW1iZXI+PGVkaXRp

b24+MjAwOC8wNi8yNDwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+

PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29y

ZD48a2V5d29yZD5DZXJlYnJhbCBIZW1vcnJoYWdlLypkaWFnbm9zaXM8L2tleXdvcmQ+PGtleXdv

cmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbWFn

ZSBJbnRlcnByZXRhdGlvbiwgQ29tcHV0ZXItQXNzaXN0ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TWFn

bmV0aWMgUmVzb25hbmNlIEltYWdpbmcvKm1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwv

a2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5Qcm9zcGVjdGl2

ZSBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPlNlbnNpdGl2aXR5IGFuZCBTcGVjaWZpY2l0eTwv

a2V5d29yZD48a2V5d29yZD5TdGF0aXN0aWNzLCBOb25wYXJhbWV0cmljPC9rZXl3b3JkPjwva2V5

d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWw8L2RhdGU+

PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMDc2LTYzMzIgKFByaW50KSYjeEQ7MTA3Ni02MzMy

IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xODU3MjEyNjwvYWNjZXNzaW9uLW51bT48

dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMTg1NzIxMjY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjEwMTYvai5hY3JhLjIwMDguMDEuMDEzPC9lbGVjdHJvbmljLXJlc291cmNlLW51

bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5WZXJub29pajwvQXV0aG9yPjxZZWFyPjIw

MDg8L1llYXI+PFJlY051bT40MzE1PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj40MzE1PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDA5MDYxNDIiPjQzMTU8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlZlcm5vb2lqLCBNLiBXLjwvYXV0

aG9yPjxhdXRob3I+dmFuIGRlciBMdWd0LCBBLjwvYXV0aG9yPjxhdXRob3I+SWtyYW0sIE0uIEEu

PC9hdXRob3I+PGF1dGhvcj5XaWVsb3BvbHNraSwgUC4gQS48L2F1dGhvcj48YXV0aG9yPk5pZXNz

ZW4sIFcuIEouPC9hdXRob3I+PGF1dGhvcj5Ib2ZtYW4sIEEuPC9hdXRob3I+PGF1dGhvcj5LcmVz

dGluLCBHLiBQLjwvYXV0aG9yPjxhdXRob3I+QnJldGVsZXIsIE0uIE0uPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBFcGlkZW1pb2xv

Z3kgYW5kIEJpb3N0YXRpc3RpY3MsIEVyYXNtdXMgTUMgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRl

ciwgRHIuIE1vbGV3YXRlcnBsZWluIDUwLCAzMDE1IEdFLCBSb3R0ZXJkYW0sIFRoZSBOZXRoZXJs

YW5kcy48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5QcmV2YWxlbmNlIGFuZCByaXNrIGZh

Y3RvcnMgb2YgY2VyZWJyYWwgbWljcm9ibGVlZHM6IHRoZSBSb3R0ZXJkYW0gU2NhbiBTdHVkeTwv

dGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb2xvZ3k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxl

cz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb2xvZ3k8L2Z1bGwtdGl0bGU+PC9wZXJpb2Rp

Y2FsPjxwYWdlcz4xMjA4LTE0PC9wYWdlcz48dm9sdW1lPjcwPC92b2x1bWU+PG51bWJlcj4xNDwv

bnVtYmVyPjxlZGl0aW9uPjIwMDgvMDQvMDI8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFn

ZSBEaXN0cmlidXRpb248L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5B

Z2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbiBFNC9nZW5l

dGljczwva2V5d29yZD48a2V5d29yZD5CcmFpbi9ibG9vZCBzdXBwbHkvcGF0aG9sb2d5L3BoeXNp

b3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBBbXlsb2lkIEFuZ2lvcGF0aHkv

ZXBpZGVtaW9sb2d5L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBBcnRlcmll

cy8qcGF0aG9sb2d5L3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBI

ZW1vcnJoYWdlLyplcGlkZW1pb2xvZ3kvKnBhdGhvbG9neS9waHlzaW9wYXRob2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+Q29ob3J0IFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+Q29tb3JiaWRpdHk8

L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmV0aWMgUHJlZGlz

cG9zaXRpb24gdG8gRGlzZWFzZS9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5HZW5vdHlwZTwv

a2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlwZXJ0ZW5zaW9uL2Vw

aWRlbWlvbG9neS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SW50cmFjcmFuaWFsIEFydGVy

aW9zY2xlcm9zaXMvZXBpZGVtaW9sb2d5L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5NYWdu

ZXRpYyBSZXNvbmFuY2UgSW1hZ2luZy8qbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9r

ZXl3b3JkPjxrZXl3b3JkPk1pY3JvY2lyY3VsYXRpb24vKnBhdGhvbG9neS9waHlzaW9wYXRob2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmV0aGVy

bGFuZHMvZXBpZGVtaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlByZWRpY3RpdmUgVmFsdWUgb2Yg

VGVzdHM8L2tleXdvcmQ+PGtleXdvcmQ+UHJldmFsZW5jZTwva2V5d29yZD48a2V5d29yZD5SaXNr

IEZhY3RvcnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwODwveWVhcj48cHVi

LWRhdGVzPjxkYXRlPkFwciAxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUyNi02

MzJYIChFbGVjdHJvbmljKSYjeEQ7MDAyOC0zODc4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4xODM3ODg4NDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTgzNzg4ODQ8L3VybD48L3JlbGF0ZWQt

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEyMTIvMDEud25sLjAwMDAz

MDc3NTAuNDE5NzAuZDk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48

L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGVobGluZzwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+

PFJlY051bT40MzEzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjQxLDI0Mjwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQzMTM8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0MDkwNjA3NCI+NDMxMzwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U3RlaGxpbmcsIEMuPC9hdXRo

b3I+PGF1dGhvcj5XZXJzY2hpbmcsIEguPC9hdXRob3I+PGF1dGhvcj5LbG9za2EsIFMuIFAuPC9h

dXRob3I+PGF1dGhvcj5LaXJjaGhvZiwgUC48L2F1dGhvcj48YXV0aG9yPlJpbmcsIEouPC9hdXRo

b3I+PGF1dGhvcj5OYXNzZW5zdGVpbiwgSS48L2F1dGhvcj48YXV0aG9yPkFsbGtlbXBlciwgVC48

L2F1dGhvcj48YXV0aG9yPktuZWNodCwgUy48L2F1dGhvcj48YXV0aG9yPkJhY2htYW5uLCBSLjwv

YXV0aG9yPjxhdXRob3I+SGVpbmRlbCwgVy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIENsaW5pY2FsIFJhZGlvbG9neSwgVW5pdmVy

c2l0eSBvZiBNdWVuc3RlciwgQWxiZXJ0LVNjaHdlaXR6ZXItU3RyLiAzMywgRCA0ODEyOSBNdW5z

dGVyLCBHZXJtYW55LiBjc3RlaGxpbmdAdW5pLW11ZW5zdGVyLmRlPC9hdXRoLWFkZHJlc3M+PHRp

dGxlcz48dGl0bGU+RGV0ZWN0aW9uIG9mIGFzeW1wdG9tYXRpYyBjZXJlYnJhbCBtaWNyb2JsZWVk

czogYSBjb21wYXJhdGl2ZSBzdHVkeSBhdCAxLjUgYW5kIDMuMCBUPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPkFjYWQgUmFkaW9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+QWNhZCBSYWRpb2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz44

OTUtOTAwPC9wYWdlcz48dm9sdW1lPjE1PC92b2x1bWU+PG51bWJlcj43PC9udW1iZXI+PGVkaXRp

b24+MjAwOC8wNi8yNDwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+

PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29y

ZD48a2V5d29yZD5DZXJlYnJhbCBIZW1vcnJoYWdlLypkaWFnbm9zaXM8L2tleXdvcmQ+PGtleXdv

cmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbWFn

ZSBJbnRlcnByZXRhdGlvbiwgQ29tcHV0ZXItQXNzaXN0ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TWFn

bmV0aWMgUmVzb25hbmNlIEltYWdpbmcvKm1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwv

a2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5Qcm9zcGVjdGl2

ZSBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPlNlbnNpdGl2aXR5IGFuZCBTcGVjaWZpY2l0eTwv

a2V5d29yZD48a2V5d29yZD5TdGF0aXN0aWNzLCBOb25wYXJhbWV0cmljPC9rZXl3b3JkPjwva2V5

d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWw8L2RhdGU+

PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMDc2LTYzMzIgKFByaW50KSYjeEQ7MTA3Ni02MzMy

IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xODU3MjEyNjwvYWNjZXNzaW9uLW51bT48

dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMTg1NzIxMjY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjEwMTYvai5hY3JhLjIwMDguMDEuMDEzPC9lbGVjdHJvbmljLXJlc291cmNlLW51

bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5WZXJub29pajwvQXV0aG9yPjxZZWFyPjIw

MDg8L1llYXI+PFJlY051bT40MzE1PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj40MzE1PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDA5MDYxNDIiPjQzMTU8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlZlcm5vb2lqLCBNLiBXLjwvYXV0

aG9yPjxhdXRob3I+dmFuIGRlciBMdWd0LCBBLjwvYXV0aG9yPjxhdXRob3I+SWtyYW0sIE0uIEEu

PC9hdXRob3I+PGF1dGhvcj5XaWVsb3BvbHNraSwgUC4gQS48L2F1dGhvcj48YXV0aG9yPk5pZXNz

ZW4sIFcuIEouPC9hdXRob3I+PGF1dGhvcj5Ib2ZtYW4sIEEuPC9hdXRob3I+PGF1dGhvcj5LcmVz

dGluLCBHLiBQLjwvYXV0aG9yPjxhdXRob3I+QnJldGVsZXIsIE0uIE0uPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBFcGlkZW1pb2xv

Z3kgYW5kIEJpb3N0YXRpc3RpY3MsIEVyYXNtdXMgTUMgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRl

ciwgRHIuIE1vbGV3YXRlcnBsZWluIDUwLCAzMDE1IEdFLCBSb3R0ZXJkYW0sIFRoZSBOZXRoZXJs

YW5kcy48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5QcmV2YWxlbmNlIGFuZCByaXNrIGZh

Y3RvcnMgb2YgY2VyZWJyYWwgbWljcm9ibGVlZHM6IHRoZSBSb3R0ZXJkYW0gU2NhbiBTdHVkeTwv

dGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb2xvZ3k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxl

cz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb2xvZ3k8L2Z1bGwtdGl0bGU+PC9wZXJpb2Rp

Y2FsPjxwYWdlcz4xMjA4LTE0PC9wYWdlcz48dm9sdW1lPjcwPC92b2x1bWU+PG51bWJlcj4xNDwv

bnVtYmVyPjxlZGl0aW9uPjIwMDgvMDQvMDI8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFn

ZSBEaXN0cmlidXRpb248L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5B

Z2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbiBFNC9nZW5l

dGljczwva2V5d29yZD48a2V5d29yZD5CcmFpbi9ibG9vZCBzdXBwbHkvcGF0aG9sb2d5L3BoeXNp

b3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBBbXlsb2lkIEFuZ2lvcGF0aHkv

ZXBpZGVtaW9sb2d5L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBBcnRlcmll

cy8qcGF0aG9sb2d5L3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBI

ZW1vcnJoYWdlLyplcGlkZW1pb2xvZ3kvKnBhdGhvbG9neS9waHlzaW9wYXRob2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+Q29ob3J0IFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+Q29tb3JiaWRpdHk8

L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmV0aWMgUHJlZGlz

cG9zaXRpb24gdG8gRGlzZWFzZS9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5HZW5vdHlwZTwv

a2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlwZXJ0ZW5zaW9uL2Vw

aWRlbWlvbG9neS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SW50cmFjcmFuaWFsIEFydGVy

aW9zY2xlcm9zaXMvZXBpZGVtaW9sb2d5L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5NYWdu

ZXRpYyBSZXNvbmFuY2UgSW1hZ2luZy8qbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9r

ZXl3b3JkPjxrZXl3b3JkPk1pY3JvY2lyY3VsYXRpb24vKnBhdGhvbG9neS9waHlzaW9wYXRob2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmV0aGVy

bGFuZHMvZXBpZGVtaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlByZWRpY3RpdmUgVmFsdWUgb2Yg

VGVzdHM8L2tleXdvcmQ+PGtleXdvcmQ+UHJldmFsZW5jZTwva2V5d29yZD48a2V5d29yZD5SaXNr

IEZhY3RvcnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwODwveWVhcj48cHVi

LWRhdGVzPjxkYXRlPkFwciAxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUyNi02

MzJYIChFbGVjdHJvbmljKSYjeEQ7MDAyOC0zODc4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4xODM3ODg4NDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTgzNzg4ODQ8L3VybD48L3JlbGF0ZWQt

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEyMTIvMDEud25sLjAwMDAz

MDc3NTAuNDE5NzAuZDk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48

L0VuZE5vdGU+

ADDIN EN.CITE.DATA 241,242 and are therefore difficult to detect clinically, except using modern imaging technology.Furthermore, cognitive decline is particularly worsened when microbleeds occur in deep brain regions or simultaneously in lobar and deep structures ADDIN EN.CITE <EndNote><Cite><Author>Ding</Author><Year>2017</Year><RecNum>1020</RecNum><DisplayText><style face="superscript">238</style></DisplayText><record><rec-number>1020</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865663">1020</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ding, Jie</author><author>Sigur?sson, Sigur?ur</author><author>Jónsson, Pálmi V.</author><author>Eiriksdottir, Gudny</author><author>Meirelles, Osorio</author><author>Kjartansson, Olafur</author><author>Lopez, Oscar L.</author><author>van Buchem, Mark A.</author><author>Gudnason, Vilmundur</author><author>Launer, Lenore J.</author></authors></contributors><titles><title>Space and location of cerebral microbleeds, cognitive decline, and dementia in the community</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title></periodical><pages>2089-2097</pages><volume>88</volume><number>22</number><dates><year>2017</year><pub-dates><date>2017/05/03</date></pub-dates></dates><publisher>Ovid Technologies (Wolters Kluwer Health)</publisher><isbn>0028-3878&#xD;1526-632X</isbn><urls><related-urls><url>. Blood breakdown products may lead to axonal and white matter injury of fibers trespassing the lesion site resulting in delayed, distal cell death. There is evidence from larger brain hemorrhages in the basal ganglia that axonal degeneration occurs in the internal capsule due to its close proximity. For example, Wallerian degeneration is common in intracerebral hemorrhage (ICH) patients and occurs particularly in the corticospinal tract in deep ICH ADDIN EN.CITE <EndNote><Cite><Author>Kumar</Author><Year>2016</Year><RecNum>1030</RecNum><DisplayText><style face="superscript">243</style></DisplayText><record><rec-number>1030</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865663">1030</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kumar, Pradeep</author><author>Yadav, Arun Kumar</author><author>Misra, Shubham</author><author>Kumar, Amit</author><author>Chakravarty, Kamalesh</author><author>Prasad, Kameshwar</author></authors></contributors><titles><title>Prediction of upper extremity motor recovery after subacute intracerebral hemorrhage through diffusion tensor imaging: a systematic review and meta-analysis</title><secondary-title>Neuroradiology</secondary-title></titles><pages>1043-1050</pages><volume>58</volume><number>10</number><dates><year>2016</year><pub-dates><date>2016/07/20</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>0028-3940&#xD;1432-1920</isbn><urls><related-urls><url> underlying molecular mechanisms of how microbleeds promote cognitive decline and axonal degeneration/white matter damage remain incompletely understood. Blood breakdown products released from the bleed can cause neuronal cell death engaging non-apoptotic forms of regulated cell death PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYXJ1cHBhZ291bmRlcjwvQXV0aG9yPjxZZWFyPjIwMTY8

L1llYXI+PFJlY051bT4xMDI5PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBl

cnNjcmlwdCI+MjQ0LDI0NTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVy

PjEwMjk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ew

cng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY2MyI+

MTAyOTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi

PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+S2FydXBwYWdvdW5k

ZXIsIFNhcmF2YW5hbiBTLjwvYXV0aG9yPjxhdXRob3I+QWxpbSwgSXNocmFxPC9hdXRob3I+PGF1

dGhvcj5LaGltLCBTb2FoIEouPC9hdXRob3I+PGF1dGhvcj5Cb3VyYXNzYSwgTWVnYW4gVy48L2F1

dGhvcj48YXV0aG9yPlNsZWltYW4sIFNhbWEgRi48L2F1dGhvcj48YXV0aG9yPkpvaG4sIFJvc2Vs

ZWVuPC9hdXRob3I+PGF1dGhvcj5UaGlubmVzLCBDeXJpbGxlIEMuPC9hdXRob3I+PGF1dGhvcj5Z

ZWgsIFR6dS1MYW48L2F1dGhvcj48YXV0aG9yPkRlbWV0cmlhZGVzLCBNYXJpbmE8L2F1dGhvcj48

YXV0aG9yPk5laXRlbWVpZXIsIFNhbmRyYTwvYXV0aG9yPjxhdXRob3I+Q3J1eiwgRGFuYTwvYXV0

aG9yPjxhdXRob3I+R2F6YXJ5YW4sIElyaW5hPC9hdXRob3I+PGF1dGhvcj5LaWxsaWxlYSwgRGF2

aWQgVy48L2F1dGhvcj48YXV0aG9yPk1vcmdlbnN0ZXJuLCBMZXdpczwvYXV0aG9yPjxhdXRob3I+

WGksIEd1b2h1YTwvYXV0aG9yPjxhdXRob3I+S2VlcCwgUmljaGFyZCBGLjwvYXV0aG9yPjxhdXRo

b3I+U2NoYWxsZXJ0LCBUaW1vdGh5PC9hdXRob3I+PGF1dGhvcj5UYXBwZXJvLCBSeWFuIFYuPC9h

dXRob3I+PGF1dGhvcj5aaG9uZywgSmlhbjwvYXV0aG9yPjxhdXRob3I+Q2hvLCBTdW5naGVlPC9h

dXRob3I+PGF1dGhvcj5NYXhmaWVsZCwgRnJlZGVyaWNrIFIuPC9hdXRob3I+PGF1dGhvcj5Ib2xt

YW4sIFRoZW9kb3JlIFIuPC9hdXRob3I+PGF1dGhvcj5DdWxtc2VlLCBDYXJzdGVuPC9hdXRob3I+

PGF1dGhvcj5Gb25nLCBHdW8tSHVhPC9hdXRob3I+PGF1dGhvcj5TdSwgWWlqaW5nPC9hdXRob3I+

PGF1dGhvcj5NaW5nLCBHdW8tbGk8L2F1dGhvcj48YXV0aG9yPlNvbmcsIEhvbmdqdW48L2F1dGhv

cj48YXV0aG9yPkNhdmUsIEpvaG4gVy48L2F1dGhvcj48YXV0aG9yPlNjaG9maWVsZCwgQ2hyaXN0

b3BoZXIgSi48L2F1dGhvcj48YXV0aG9yPkNvbGJvdXJuZSwgRnJlZGVyaWNrPC9hdXRob3I+PGF1

dGhvcj5Db3Bwb2xhLCBHaW92YW5uaTwvYXV0aG9yPjxhdXRob3I+UmF0YW4sIFJhaml2IFIuPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlRoZXJhcGV1dGlj

IHRhcmdldGluZyBvZiBveHlnZW4tc2Vuc2luZyBwcm9seWwgaHlkcm94eWxhc2VzIGFicm9nYXRl

cyBBVEY0LWRlcGVuZGVudCBuZXVyb25hbCBkZWF0aCBhbmQgaW1wcm92ZXMgb3V0Y29tZXMgYWZ0

ZXIgYnJhaW4gaGVtb3JyaGFnZSBpbiBzZXZlcmFsIHJvZGVudCBtb2RlbHM8L3RpdGxlPjxzZWNv

bmRhcnktdGl0bGU+U2NpZW5jZSBUcmFuc2xhdGlvbmFsIE1lZGljaW5lPC9zZWNvbmRhcnktdGl0

bGU+PC90aXRsZXM+PHBhZ2VzPjMyOHJhMjktMzI4cmEyOTwvcGFnZXM+PHZvbHVtZT44PC92b2x1

bWU+PG51bWJlcj4zMjg8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVz

PjxkYXRlPjIwMTYvMDMvMDI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkFt

ZXJpY2FuIEFzc29jaWF0aW9uIGZvciB0aGUgQWR2YW5jZW1lbnQgb2YgU2NpZW5jZSAoQUFBUyk8

L3B1Ymxpc2hlcj48aXNibj4xOTQ2LTYyMzQmI3hEOzE5NDYtNjI0MjwvaXNibj48dXJscz48cmVs

YXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTEyNi9zY2l0cmFuc2xtZWQuYWFj

NjAwODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

MTAuMTEyNi9zY2l0cmFuc2xtZWQuYWFjNjAwODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9y

ZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+WmlsbGU8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFy

PjxSZWNOdW0+NDMxNjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+NDMxNjwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhw

Znd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTQwOTA2MjQ5Ij40MzE2PC9rZXk+PC9mb3Jl

aWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxj

b250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5aaWxsZSwgTS48L2F1dGhvcj48YXV0aG9yPkth

cnVwcGFnb3VuZGVyLCBTLiBTLjwvYXV0aG9yPjxhdXRob3I+Q2hlbiwgWS48L2F1dGhvcj48YXV0

aG9yPkdvdWdoLCBQLiBKLjwvYXV0aG9yPjxhdXRob3I+QmVydGluLCBKLjwvYXV0aG9yPjxhdXRo

b3I+RmluZ2VyLCBKLjwvYXV0aG9yPjxhdXRob3I+TWlsbmVyLCBULiBBLjwvYXV0aG9yPjxhdXRo

b3I+Sm9uYXMsIEUuIEEuPC9hdXRob3I+PGF1dGhvcj5SYXRhbiwgUi4gUi48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Gcm9tIHRoZSBCdXJrZSBNZWRpY2Fs

IFJlc2VhcmNoIEluc3RpdHV0ZSwgV2hpdGUgUGxhaW5zLCBOZXcgWW9yayAoTS5aLiwgUy5TLksu

LCBZLkMuLCBSLlIuUi4pOyBGZWlsIEZhbWlseSBCcmFpbiBhbmQgTWluZCBSZXNlYXJjaCBJbnN0

aXR1dGUsIFdlaWxsIENvcm5lbGwgTWVkaWNpbmUsIE5ldyBZb3JrIChNLlouLCBTLlMuSy4sIFku

Qy4sIFQuQS5NLiwgUi5SLlIuKTsgSG9zdCBEZWZlbnNlIERpc2NvdmVyeSBQZXJmb3JtYW5jZSBV

bml0LCBJbmZlY3Rpb3VzIERpc2Vhc2VzIFRoZXJhcHkgQXJlYSBVbml0IChQLkouRy4pIGFuZCBQ

YXR0ZXJuIFJlY29nbml0aW9uIFJlY2VwdG9yIERpc2NvdmVyeSBQZXJmb3JtYW5jZSBVbml0LCBJ

bW11bm8tSW5mbGFtbWF0aW9uIFRoZXJhcGV1dGljIEFyZWEgKEouQi4sIEouRi4pLCBHbGF4b1Nt

aXRoS2xpbmUsIENvbGxlZ2V2aWxsZSwgUEE7IExhYm9yYXRvcnkgb2YgTmV1cm9lbmRvY3Jpbm9s

b2d5LCBUaGUgUm9ja2VmZWxsZXIgVW5pdmVyc2l0eSwgTmV3IFlvcmsgKFQuQS5NLik7IGFuZCBE

ZXBhcnRtZW50IG9mIEludGVybmFsIE1lZGljaW5lLCBTZWN0aW9uIG9mIEVuZG9jcmlub2xvZ3ks

IFlhbGUgVW5pdmVyc2l0eSwgTmV3IEhhdmVuLCBDVCAoRS5BLkouKS4mI3hEO0Zyb20gdGhlIEJ1

cmtlIE1lZGljYWwgUmVzZWFyY2ggSW5zdGl0dXRlLCBXaGl0ZSBQbGFpbnMsIE5ldyBZb3JrIChN

LlouLCBTLlMuSy4sIFkuQy4sIFIuUi5SLik7IEZlaWwgRmFtaWx5IEJyYWluIGFuZCBNaW5kIFJl

c2VhcmNoIEluc3RpdHV0ZSwgV2VpbGwgQ29ybmVsbCBNZWRpY2luZSwgTmV3IFlvcmsgKE0uWi4s

IFMuUy5LLiwgWS5DLiwgVC5BLk0uLCBSLlIuUi4pOyBIb3N0IERlZmVuc2UgRGlzY292ZXJ5IFBl

cmZvcm1hbmNlIFVuaXQsIEluZmVjdGlvdXMgRGlzZWFzZXMgVGhlcmFweSBBcmVhIFVuaXQgKFAu

Si5HLikgYW5kIFBhdHRlcm4gUmVjb2duaXRpb24gUmVjZXB0b3IgRGlzY292ZXJ5IFBlcmZvcm1h

bmNlIFVuaXQsIEltbXVuby1JbmZsYW1tYXRpb24gVGhlcmFwZXV0aWMgQXJlYSAoSi5CLiwgSi5G

LiksIEdsYXhvU21pdGhLbGluZSwgQ29sbGVnZXZpbGxlLCBQQTsgTGFib3JhdG9yeSBvZiBOZXVy

b2VuZG9jcmlub2xvZ3ksIFRoZSBSb2NrZWZlbGxlciBVbml2ZXJzaXR5LCBOZXcgWW9yayAoVC5B

Lk0uKTsgYW5kIERlcGFydG1lbnQgb2YgSW50ZXJuYWwgTWVkaWNpbmUsIFNlY3Rpb24gb2YgRW5k

b2NyaW5vbG9neSwgWWFsZSBVbml2ZXJzaXR5LCBOZXcgSGF2ZW4sIENUIChFLkEuSi4pLiBycnIy

MDAxQG1lZC5jb3JuZWxsLmVkdS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5OZXVyb25h

bCBEZWF0aCBBZnRlciBIZW1vcnJoYWdpYyBTdHJva2UgSW4gVml0cm8gYW5kIEluIFZpdm8gU2hh

cmVzIEZlYXR1cmVzIG9mIEZlcnJvcHRvc2lzIGFuZCBOZWNyb3B0b3NpczwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5TdHJva2U8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5TdHJva2U8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMDMzLTEw

NDM8L3BhZ2VzPjx2b2x1bWU+NDg8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZWRpdGlvbj4y

MDE3LzAzLzAzPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxr

ZXl3b3JkPipBcG9wdG9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVkPC9rZXl3

b3JkPjxrZXl3b3JkPkNlcmVicmFsIEhlbW9ycmhhZ2UvKm1ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFuaW1hbDwva2V5d29yZD48a2V5d29yZD5IZW1pbi8qbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5IZW1vZ2xvYmlucy8qbWV0YWJvbGlzbTwva2V5d29y

ZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+

TWljZSwgSW5icmVkIEM1N0JMPC9rZXl3b3JkPjxrZXl3b3JkPk5lY3Jvc2lzLyptZXRhYm9saXNt

PC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbnMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+

KmNlbGwgZGVhdGg8L2tleXdvcmQ+PGtleXdvcmQ+KmZlcnJvcHRvc2lzPC9rZXl3b3JkPjxrZXl3

b3JkPippbnRyYWNlcmVicmFsIGhlbW9ycmhhZ2U8L2tleXdvcmQ+PGtleXdvcmQ+Km5lY3Jvc2lz

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5BcHI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTI0LTQ2MjggKEVsZWN0

cm9uaWMpJiN4RDswMDM5LTI0OTkgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI4MjUw

MTk3PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yODI1MDE5NzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48Y3VzdG9tMj5QTUM1NjEzNzY0PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4x

MC4xMTYxL1NUUk9LRUFIQS4xMTYuMDE1NjA5PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3Jl

Y29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYXJ1cHBhZ291bmRlcjwvQXV0aG9yPjxZZWFyPjIwMTY8

L1llYXI+PFJlY051bT4xMDI5PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBl

cnNjcmlwdCI+MjQ0LDI0NTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVy

PjEwMjk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ew

cng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY2MyI+

MTAyOTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi

PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+S2FydXBwYWdvdW5k

ZXIsIFNhcmF2YW5hbiBTLjwvYXV0aG9yPjxhdXRob3I+QWxpbSwgSXNocmFxPC9hdXRob3I+PGF1

dGhvcj5LaGltLCBTb2FoIEouPC9hdXRob3I+PGF1dGhvcj5Cb3VyYXNzYSwgTWVnYW4gVy48L2F1

dGhvcj48YXV0aG9yPlNsZWltYW4sIFNhbWEgRi48L2F1dGhvcj48YXV0aG9yPkpvaG4sIFJvc2Vs

ZWVuPC9hdXRob3I+PGF1dGhvcj5UaGlubmVzLCBDeXJpbGxlIEMuPC9hdXRob3I+PGF1dGhvcj5Z

ZWgsIFR6dS1MYW48L2F1dGhvcj48YXV0aG9yPkRlbWV0cmlhZGVzLCBNYXJpbmE8L2F1dGhvcj48

YXV0aG9yPk5laXRlbWVpZXIsIFNhbmRyYTwvYXV0aG9yPjxhdXRob3I+Q3J1eiwgRGFuYTwvYXV0

aG9yPjxhdXRob3I+R2F6YXJ5YW4sIElyaW5hPC9hdXRob3I+PGF1dGhvcj5LaWxsaWxlYSwgRGF2

aWQgVy48L2F1dGhvcj48YXV0aG9yPk1vcmdlbnN0ZXJuLCBMZXdpczwvYXV0aG9yPjxhdXRob3I+

WGksIEd1b2h1YTwvYXV0aG9yPjxhdXRob3I+S2VlcCwgUmljaGFyZCBGLjwvYXV0aG9yPjxhdXRo

b3I+U2NoYWxsZXJ0LCBUaW1vdGh5PC9hdXRob3I+PGF1dGhvcj5UYXBwZXJvLCBSeWFuIFYuPC9h

dXRob3I+PGF1dGhvcj5aaG9uZywgSmlhbjwvYXV0aG9yPjxhdXRob3I+Q2hvLCBTdW5naGVlPC9h

dXRob3I+PGF1dGhvcj5NYXhmaWVsZCwgRnJlZGVyaWNrIFIuPC9hdXRob3I+PGF1dGhvcj5Ib2xt

YW4sIFRoZW9kb3JlIFIuPC9hdXRob3I+PGF1dGhvcj5DdWxtc2VlLCBDYXJzdGVuPC9hdXRob3I+

PGF1dGhvcj5Gb25nLCBHdW8tSHVhPC9hdXRob3I+PGF1dGhvcj5TdSwgWWlqaW5nPC9hdXRob3I+

PGF1dGhvcj5NaW5nLCBHdW8tbGk8L2F1dGhvcj48YXV0aG9yPlNvbmcsIEhvbmdqdW48L2F1dGhv

cj48YXV0aG9yPkNhdmUsIEpvaG4gVy48L2F1dGhvcj48YXV0aG9yPlNjaG9maWVsZCwgQ2hyaXN0

b3BoZXIgSi48L2F1dGhvcj48YXV0aG9yPkNvbGJvdXJuZSwgRnJlZGVyaWNrPC9hdXRob3I+PGF1

dGhvcj5Db3Bwb2xhLCBHaW92YW5uaTwvYXV0aG9yPjxhdXRob3I+UmF0YW4sIFJhaml2IFIuPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlRoZXJhcGV1dGlj

IHRhcmdldGluZyBvZiBveHlnZW4tc2Vuc2luZyBwcm9seWwgaHlkcm94eWxhc2VzIGFicm9nYXRl

cyBBVEY0LWRlcGVuZGVudCBuZXVyb25hbCBkZWF0aCBhbmQgaW1wcm92ZXMgb3V0Y29tZXMgYWZ0

ZXIgYnJhaW4gaGVtb3JyaGFnZSBpbiBzZXZlcmFsIHJvZGVudCBtb2RlbHM8L3RpdGxlPjxzZWNv

bmRhcnktdGl0bGU+U2NpZW5jZSBUcmFuc2xhdGlvbmFsIE1lZGljaW5lPC9zZWNvbmRhcnktdGl0

bGU+PC90aXRsZXM+PHBhZ2VzPjMyOHJhMjktMzI4cmEyOTwvcGFnZXM+PHZvbHVtZT44PC92b2x1

bWU+PG51bWJlcj4zMjg8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVz

PjxkYXRlPjIwMTYvMDMvMDI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkFt

ZXJpY2FuIEFzc29jaWF0aW9uIGZvciB0aGUgQWR2YW5jZW1lbnQgb2YgU2NpZW5jZSAoQUFBUyk8

L3B1Ymxpc2hlcj48aXNibj4xOTQ2LTYyMzQmI3hEOzE5NDYtNjI0MjwvaXNibj48dXJscz48cmVs

YXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTEyNi9zY2l0cmFuc2xtZWQuYWFj

NjAwODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

MTAuMTEyNi9zY2l0cmFuc2xtZWQuYWFjNjAwODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9y

ZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+WmlsbGU8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFy

PjxSZWNOdW0+NDMxNjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+NDMxNjwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhw

Znd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTQwOTA2MjQ5Ij40MzE2PC9rZXk+PC9mb3Jl

aWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxj

b250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5aaWxsZSwgTS48L2F1dGhvcj48YXV0aG9yPkth

cnVwcGFnb3VuZGVyLCBTLiBTLjwvYXV0aG9yPjxhdXRob3I+Q2hlbiwgWS48L2F1dGhvcj48YXV0

aG9yPkdvdWdoLCBQLiBKLjwvYXV0aG9yPjxhdXRob3I+QmVydGluLCBKLjwvYXV0aG9yPjxhdXRo

b3I+RmluZ2VyLCBKLjwvYXV0aG9yPjxhdXRob3I+TWlsbmVyLCBULiBBLjwvYXV0aG9yPjxhdXRo

b3I+Sm9uYXMsIEUuIEEuPC9hdXRob3I+PGF1dGhvcj5SYXRhbiwgUi4gUi48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Gcm9tIHRoZSBCdXJrZSBNZWRpY2Fs

IFJlc2VhcmNoIEluc3RpdHV0ZSwgV2hpdGUgUGxhaW5zLCBOZXcgWW9yayAoTS5aLiwgUy5TLksu

LCBZLkMuLCBSLlIuUi4pOyBGZWlsIEZhbWlseSBCcmFpbiBhbmQgTWluZCBSZXNlYXJjaCBJbnN0

aXR1dGUsIFdlaWxsIENvcm5lbGwgTWVkaWNpbmUsIE5ldyBZb3JrIChNLlouLCBTLlMuSy4sIFku

Qy4sIFQuQS5NLiwgUi5SLlIuKTsgSG9zdCBEZWZlbnNlIERpc2NvdmVyeSBQZXJmb3JtYW5jZSBV

bml0LCBJbmZlY3Rpb3VzIERpc2Vhc2VzIFRoZXJhcHkgQXJlYSBVbml0IChQLkouRy4pIGFuZCBQ

YXR0ZXJuIFJlY29nbml0aW9uIFJlY2VwdG9yIERpc2NvdmVyeSBQZXJmb3JtYW5jZSBVbml0LCBJ

bW11bm8tSW5mbGFtbWF0aW9uIFRoZXJhcGV1dGljIEFyZWEgKEouQi4sIEouRi4pLCBHbGF4b1Nt

aXRoS2xpbmUsIENvbGxlZ2V2aWxsZSwgUEE7IExhYm9yYXRvcnkgb2YgTmV1cm9lbmRvY3Jpbm9s

b2d5LCBUaGUgUm9ja2VmZWxsZXIgVW5pdmVyc2l0eSwgTmV3IFlvcmsgKFQuQS5NLik7IGFuZCBE

ZXBhcnRtZW50IG9mIEludGVybmFsIE1lZGljaW5lLCBTZWN0aW9uIG9mIEVuZG9jcmlub2xvZ3ks

IFlhbGUgVW5pdmVyc2l0eSwgTmV3IEhhdmVuLCBDVCAoRS5BLkouKS4mI3hEO0Zyb20gdGhlIEJ1

cmtlIE1lZGljYWwgUmVzZWFyY2ggSW5zdGl0dXRlLCBXaGl0ZSBQbGFpbnMsIE5ldyBZb3JrIChN

LlouLCBTLlMuSy4sIFkuQy4sIFIuUi5SLik7IEZlaWwgRmFtaWx5IEJyYWluIGFuZCBNaW5kIFJl

c2VhcmNoIEluc3RpdHV0ZSwgV2VpbGwgQ29ybmVsbCBNZWRpY2luZSwgTmV3IFlvcmsgKE0uWi4s

IFMuUy5LLiwgWS5DLiwgVC5BLk0uLCBSLlIuUi4pOyBIb3N0IERlZmVuc2UgRGlzY292ZXJ5IFBl

cmZvcm1hbmNlIFVuaXQsIEluZmVjdGlvdXMgRGlzZWFzZXMgVGhlcmFweSBBcmVhIFVuaXQgKFAu

Si5HLikgYW5kIFBhdHRlcm4gUmVjb2duaXRpb24gUmVjZXB0b3IgRGlzY292ZXJ5IFBlcmZvcm1h

bmNlIFVuaXQsIEltbXVuby1JbmZsYW1tYXRpb24gVGhlcmFwZXV0aWMgQXJlYSAoSi5CLiwgSi5G

LiksIEdsYXhvU21pdGhLbGluZSwgQ29sbGVnZXZpbGxlLCBQQTsgTGFib3JhdG9yeSBvZiBOZXVy

b2VuZG9jcmlub2xvZ3ksIFRoZSBSb2NrZWZlbGxlciBVbml2ZXJzaXR5LCBOZXcgWW9yayAoVC5B

Lk0uKTsgYW5kIERlcGFydG1lbnQgb2YgSW50ZXJuYWwgTWVkaWNpbmUsIFNlY3Rpb24gb2YgRW5k

b2NyaW5vbG9neSwgWWFsZSBVbml2ZXJzaXR5LCBOZXcgSGF2ZW4sIENUIChFLkEuSi4pLiBycnIy

MDAxQG1lZC5jb3JuZWxsLmVkdS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5OZXVyb25h

bCBEZWF0aCBBZnRlciBIZW1vcnJoYWdpYyBTdHJva2UgSW4gVml0cm8gYW5kIEluIFZpdm8gU2hh

cmVzIEZlYXR1cmVzIG9mIEZlcnJvcHRvc2lzIGFuZCBOZWNyb3B0b3NpczwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5TdHJva2U8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5TdHJva2U8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMDMzLTEw

NDM8L3BhZ2VzPjx2b2x1bWU+NDg8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZWRpdGlvbj4y

MDE3LzAzLzAzPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxr

ZXl3b3JkPipBcG9wdG9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVkPC9rZXl3

b3JkPjxrZXl3b3JkPkNlcmVicmFsIEhlbW9ycmhhZ2UvKm1ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFuaW1hbDwva2V5d29yZD48a2V5d29yZD5IZW1pbi8qbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5IZW1vZ2xvYmlucy8qbWV0YWJvbGlzbTwva2V5d29y

ZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+

TWljZSwgSW5icmVkIEM1N0JMPC9rZXl3b3JkPjxrZXl3b3JkPk5lY3Jvc2lzLyptZXRhYm9saXNt

PC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbnMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+

KmNlbGwgZGVhdGg8L2tleXdvcmQ+PGtleXdvcmQ+KmZlcnJvcHRvc2lzPC9rZXl3b3JkPjxrZXl3

b3JkPippbnRyYWNlcmVicmFsIGhlbW9ycmhhZ2U8L2tleXdvcmQ+PGtleXdvcmQ+Km5lY3Jvc2lz

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5BcHI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTI0LTQ2MjggKEVsZWN0

cm9uaWMpJiN4RDswMDM5LTI0OTkgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI4MjUw

MTk3PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yODI1MDE5NzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48Y3VzdG9tMj5QTUM1NjEzNzY0PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4x

MC4xMTYxL1NUUk9LRUFIQS4xMTYuMDE1NjA5PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3Jl

Y29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 244,245. In addition, it is known that degeneration of axons, in general, occurs actively, but autonomously from neuronal cell body death, and via different molecular mechanisms ADDIN EN.CITE <EndNote><Cite><Author>Raff</Author><Year>2002</Year><RecNum>4317</RecNum><DisplayText><style face="superscript">246</style></DisplayText><record><rec-number>4317</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1540906301">4317</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Raff, M. C.</author><author>Whitmore, A. V.</author><author>Finn, J. T.</author></authors></contributors><auth-address>MRC Laboratory for Molecular Cell Biology and Cell Biology Unit and the Biology Department, University College London, London WC1E 6BT, UK. m.raff@ucl.ac.uk</auth-address><titles><title>Axonal self-destruction and neurodegeneration</title><secondary-title>Science</secondary-title></titles><periodical><full-title>Science</full-title></periodical><pages>868-71</pages><volume>296</volume><number>5569</number><edition>2002/05/04</edition><keywords><keyword>Animals</keyword><keyword>Apoptosis</keyword><keyword>Axons/*physiology</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Mice, Mutant Strains</keyword><keyword>Motor Neuron Disease/pathology/physiopathology</keyword><keyword>*Nerve Degeneration</keyword><keyword>Neurodegenerative Diseases/pathology/*physiopathology</keyword><keyword>Peripheral Nervous System Diseases/pathology/physiopathology</keyword><keyword>*Wallerian Degeneration/genetics</keyword></keywords><dates><year>2002</year><pub-dates><date>May 3</date></pub-dates></dates><isbn>1095-9203 (Electronic)&#xD;0036-8075 (Linking)</isbn><accession-num>11988563</accession-num><urls><related-urls><url>. While neuronal cell bodies may die via the canonical caspase-3-dependent apoptotic pathway, blockade of this pathway does not prevent axonal degeneration ADDIN EN.CITE <EndNote><Cite><Author>Sagot</Author><Year>1995</Year><RecNum>4318</RecNum><DisplayText><style face="superscript">247</style></DisplayText><record><rec-number>4318</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1540906371">4318</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sagot, Y.</author><author>Dubois-Dauphin, M.</author><author>Tan, S. A.</author><author>de Bilbao, F.</author><author>Aebischer, P.</author><author>Martinou, J. C.</author><author>Kato, A. C.</author></authors></contributors><auth-address>Department of Pharmacology, Centre Medical Universitaire, Geneva, Switzerland.</auth-address><titles><title>Bcl-2 overexpression prevents motoneuron cell body loss but not axonal degeneration in a mouse model of a neurodegenerative disease</title><secondary-title>J Neurosci</secondary-title></titles><periodical><full-title>J Neurosci</full-title></periodical><pages>7727-33</pages><volume>15</volume><number>11</number><edition>1995/11/01</edition><keywords><keyword>Animals</keyword><keyword>Axons/*physiology</keyword><keyword>Cell Death</keyword><keyword>Facial Nerve/pathology</keyword><keyword>Humans</keyword><keyword>Immunohistochemistry</keyword><keyword>Mice</keyword><keyword>Mice, Transgenic</keyword><keyword>Motor Neuron Disease/*metabolism/*pathology</keyword><keyword>Motor Neurons/*pathology</keyword><keyword>*Nerve Degeneration</keyword><keyword>Phrenic Nerve/pathology</keyword><keyword>Pons/pathology</keyword><keyword>Proto-Oncogene Proteins/genetics/*metabolism</keyword><keyword>Proto-Oncogene Proteins c-bcl-2</keyword></keywords><dates><year>1995</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0270-6474 (Print)&#xD;0270-6474 (Linking)</isbn><accession-num>7472523</accession-num><urls><related-urls><url>. Axon degeneration depends on the proapoptotic family member bax and requires caspase-6 ADDIN EN.CITE <EndNote><Cite><Author>Nikolaev</Author><Year>2009</Year><RecNum>4319</RecNum><DisplayText><style face="superscript">248</style></DisplayText><record><rec-number>4319</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1540906458">4319</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nikolaev, A.</author><author>McLaughlin, T.</author><author>O&apos;Leary, D. D.</author><author>Tessier-Lavigne, M.</author></authors></contributors><auth-address>Division of Research, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.</auth-address><titles><title>APP binds DR6 to trigger axon pruning and neuron death via distinct caspases</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title></periodical><pages>981-9</pages><volume>457</volume><number>7232</number><edition>2009/02/20</edition><keywords><keyword>Alzheimer Disease/metabolism</keyword><keyword>Amyloid beta-Protein Precursor/chemistry/*metabolism</keyword><keyword>Animals</keyword><keyword>Axons/*metabolism</keyword><keyword>Caspase 3/metabolism</keyword><keyword>Caspase 6/*metabolism</keyword><keyword>Caspases/*metabolism</keyword><keyword>Cell Death</keyword><keyword>Ligands</keyword><keyword>Mice</keyword><keyword>Neurons/*cytology/*metabolism</keyword><keyword>Peptide Fragments/chemistry/metabolism</keyword><keyword>Protein Binding</keyword><keyword>Receptors, Tumor Necrosis Factor/*metabolism</keyword><keyword>Signal Transduction</keyword><keyword>bcl-2-Associated X Protein/genetics/metabolism</keyword></keywords><dates><year>2009</year><pub-dates><date>Feb 19</date></pub-dates></dates><isbn>1476-4687 (Electronic)&#xD;0028-0836 (Linking)</isbn><accession-num>19225519</accession-num><urls><related-urls><url>. Gut microbiota and ADIn AD subjects, higher levels of pro-inflammatory cytokines have been found, together with reactive microglial cells co-localizing with amyloid plaques. It has been proposed that high levels of inflammation are a consequence of Aβ signaling PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZXBwbmVyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

UmVjTnVtPjM5NjI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4yNDksMjUwPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzk2Mjwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2NzcyNzQxIj4zOTYyPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5IZXBwbmVyLCBGLiBMLjwvYXV0

aG9yPjxhdXRob3I+UmFuc29ob2ZmLCBSLiBNLjwvYXV0aG9yPjxhdXRob3I+QmVjaGVyLCBCLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPjFdIERlcGFydG1l

bnQgb2YgTmV1cm9wYXRob2xvZ3ksIENoYXJpdGVwbGF0eiAxLCBDaGFyaXRlIC0gVW5pdmVyc2l0

YXRzbWVkaXppbiBCZXJsaW4sIEQtMTAxMTcgQmVybGluLCBHZXJtYW55LiBbMl0gQ2x1c3RlciBv

ZiBFeGNlbGxlbmNlLCBOZXVyb0N1cmUsIENoYXJpdGVwbGF0eiAxLCBELTEwMTE3IEJlcmxpbiwg

R2VybWFueS4mI3hEO0Jpb2dlbiwgMjI1IEJpbm5leSBTdHJlZXQsIENhbWJyaWRnZSwgTWFzc2Fj

aHVzZXR0cyAwMjE0MiwgVVNBLiYjeEQ7SW5zdGl0dXRlIG9mIEV4cGVyaW1lbnRhbCBJbW11bm9s

b2d5LCBVbml2ZXJzaXR5IG9mIFp1cmljaCwgV2ludGVydGh1cmVyc3RyYXNzZSAxOTAsIENILTgw

NTcgWnJpY2gsIFN3aXR6ZXJsYW5kLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkltbXVu

ZSBhdHRhY2s6IHRoZSByb2xlIG9mIGluZmxhbW1hdGlvbiBpbiBBbHpoZWltZXIgZGlzZWFzZTwv

dGl0bGU+PHNlY29uZGFyeS10aXRsZT5OYXQgUmV2IE5ldXJvc2NpPC9zZWNvbmRhcnktdGl0bGU+

PC90aXRsZXM+PHBhZ2VzPjM1OC03MjwvcGFnZXM+PHZvbHVtZT4xNjwvdm9sdW1lPjxudW1iZXI+

NjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qaW1tdW5vbG9n

eS8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+

SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1hdGlvbi8qaW1tdW5vbG9neS8qcGF0aG9s

b2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT5KdW48L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDcxLTAwNDggKEVs

ZWN0cm9uaWMpJiN4RDsxNDcxLTAwM1ggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1

OTkxNDQzPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3

Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI1OTkxNDQzPC91cmw+PC9yZWxhdGVkLXVybHM+PC91

cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDM4L25ybjM4ODA8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlpvdG92YTwvQXV0aG9y

PjxZZWFyPjIwMTA8L1llYXI+PFJlY051bT4zOTU1PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJl

cj4zOTU1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndh

MHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzY3NzI3MTIi

PjM5NTU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xl

Ij4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlpvdG92YSwgRS48

L2F1dGhvcj48YXV0aG9yPk5pY29sbCwgSi4gQS48L2F1dGhvcj48YXV0aG9yPkthbGFyaWEsIFIu

PC9hdXRob3I+PGF1dGhvcj5Ib2xtZXMsIEMuPC9hdXRob3I+PGF1dGhvcj5Cb2NoZSwgRC48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EaXZpc2lvbiBvZiBD

bGluaWNhbCBOZXVyb3NjaWVuY2VzLCBTY2hvb2wgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2Yg

U291dGhhbXB0b24sIE1haWxwb2ludCA4MDYsIExldmVsIEQsIFNvdXRoIFBhdGhvbG9neSBCbG9j

aywgU291dGhhbXB0b24gR2VuZXJhbCBIb3NwaXRhbCwgU291dGhhbXB0b24sIFNPMTYgNllELCBV

Sy4gRS5ab3RvdmFAc290b24uYWMudWsuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+SW5m

bGFtbWF0aW9uIGluIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogcmVsZXZhbmNlIHRvIHBhdGhv

Z2VuZXNpcyBhbmQgdGhlcmFweTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbHpoZWltZXJzIFJl

cyBUaGVyPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+

QWx6aGVpbWVycyBSZXMgVGhlcjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjE8L3Bh

Z2VzPjx2b2x1bWU+Mjwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDEw

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SmFuIDIyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGlzYm4+MTc1OC05MTkzIChFbGVjdHJvbmljKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMDEyMjI4

OTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3B1Ym1lZC8yMDEyMjI4OTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48

Y3VzdG9tMj5QTUMyODc0MjYwPC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4x

MTg2L2FsenJ0MjQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0Vu

ZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZXBwbmVyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

UmVjTnVtPjM5NjI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4yNDksMjUwPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzk2Mjwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2NzcyNzQxIj4zOTYyPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5IZXBwbmVyLCBGLiBMLjwvYXV0

aG9yPjxhdXRob3I+UmFuc29ob2ZmLCBSLiBNLjwvYXV0aG9yPjxhdXRob3I+QmVjaGVyLCBCLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPjFdIERlcGFydG1l

bnQgb2YgTmV1cm9wYXRob2xvZ3ksIENoYXJpdGVwbGF0eiAxLCBDaGFyaXRlIC0gVW5pdmVyc2l0

YXRzbWVkaXppbiBCZXJsaW4sIEQtMTAxMTcgQmVybGluLCBHZXJtYW55LiBbMl0gQ2x1c3RlciBv

ZiBFeGNlbGxlbmNlLCBOZXVyb0N1cmUsIENoYXJpdGVwbGF0eiAxLCBELTEwMTE3IEJlcmxpbiwg

R2VybWFueS4mI3hEO0Jpb2dlbiwgMjI1IEJpbm5leSBTdHJlZXQsIENhbWJyaWRnZSwgTWFzc2Fj

aHVzZXR0cyAwMjE0MiwgVVNBLiYjeEQ7SW5zdGl0dXRlIG9mIEV4cGVyaW1lbnRhbCBJbW11bm9s

b2d5LCBVbml2ZXJzaXR5IG9mIFp1cmljaCwgV2ludGVydGh1cmVyc3RyYXNzZSAxOTAsIENILTgw

NTcgWnJpY2gsIFN3aXR6ZXJsYW5kLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkltbXVu

ZSBhdHRhY2s6IHRoZSByb2xlIG9mIGluZmxhbW1hdGlvbiBpbiBBbHpoZWltZXIgZGlzZWFzZTwv

dGl0bGU+PHNlY29uZGFyeS10aXRsZT5OYXQgUmV2IE5ldXJvc2NpPC9zZWNvbmRhcnktdGl0bGU+

PC90aXRsZXM+PHBhZ2VzPjM1OC03MjwvcGFnZXM+PHZvbHVtZT4xNjwvdm9sdW1lPjxudW1iZXI+

NjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qaW1tdW5vbG9n

eS8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+

SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1hdGlvbi8qaW1tdW5vbG9neS8qcGF0aG9s

b2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT5KdW48L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDcxLTAwNDggKEVs

ZWN0cm9uaWMpJiN4RDsxNDcxLTAwM1ggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1

OTkxNDQzPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3

Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI1OTkxNDQzPC91cmw+PC9yZWxhdGVkLXVybHM+PC91

cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDM4L25ybjM4ODA8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlpvdG92YTwvQXV0aG9y

PjxZZWFyPjIwMTA8L1llYXI+PFJlY051bT4zOTU1PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJl

cj4zOTU1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndh

MHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzY3NzI3MTIi

PjM5NTU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xl

Ij4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlpvdG92YSwgRS48

L2F1dGhvcj48YXV0aG9yPk5pY29sbCwgSi4gQS48L2F1dGhvcj48YXV0aG9yPkthbGFyaWEsIFIu

PC9hdXRob3I+PGF1dGhvcj5Ib2xtZXMsIEMuPC9hdXRob3I+PGF1dGhvcj5Cb2NoZSwgRC48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EaXZpc2lvbiBvZiBD

bGluaWNhbCBOZXVyb3NjaWVuY2VzLCBTY2hvb2wgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2Yg

U291dGhhbXB0b24sIE1haWxwb2ludCA4MDYsIExldmVsIEQsIFNvdXRoIFBhdGhvbG9neSBCbG9j

aywgU291dGhhbXB0b24gR2VuZXJhbCBIb3NwaXRhbCwgU291dGhhbXB0b24sIFNPMTYgNllELCBV

Sy4gRS5ab3RvdmFAc290b24uYWMudWsuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+SW5m

bGFtbWF0aW9uIGluIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogcmVsZXZhbmNlIHRvIHBhdGhv

Z2VuZXNpcyBhbmQgdGhlcmFweTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbHpoZWltZXJzIFJl

cyBUaGVyPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+

QWx6aGVpbWVycyBSZXMgVGhlcjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjE8L3Bh

Z2VzPjx2b2x1bWU+Mjwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDEw

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SmFuIDIyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGlzYm4+MTc1OC05MTkzIChFbGVjdHJvbmljKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMDEyMjI4

OTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3B1Ym1lZC8yMDEyMjI4OTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48

Y3VzdG9tMj5QTUMyODc0MjYwPC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4x

MTg2L2FsenJ0MjQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0Vu

ZE5vdGU+

ADDIN EN.CITE.DATA 249,250. However, recently this hypothesis has been revised since the induction of the pro-inflammatory state can promote the amyloid cascade. It is in this context that we look at the role of the microbiota.The gut microbiota has been named our other brain for the functional connections between the two. The microbiota weighs as much as the brain itself (up to 1.5 kg ADDIN EN.CITE <EndNote><Cite><Author>Sommer</Author><Year>2013</Year><RecNum>3969</RecNum><DisplayText><style face="superscript">251</style></DisplayText><record><rec-number>3969</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1536772835">3969</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sommer, F.</author><author>Backhed, F.</author></authors></contributors><auth-address>Wallenberg Laboratory for Cardiovascular and Metabolic Research, Sahlgrenska University Hospital, Department of Molecular and Clinical Medicine, University of Gothenburg, SE-413 45 Gothenburg, Sweden.</auth-address><titles><title>The gut microbiota--masters of host development and physiology</title><secondary-title>Nat Rev Microbiol</secondary-title></titles><pages>227-38</pages><volume>11</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>Gastrointestinal Tract/growth &amp; development/immunology/*microbiology/*physiology</keyword><keyword>Health</keyword><keyword>Homeostasis</keyword><keyword>Host-Pathogen Interactions</keyword><keyword>Humans</keyword><keyword>Immune System/*physiology</keyword><keyword>Immunity, Mucosal/*immunology</keyword><keyword>Metagenome/*physiology</keyword><keyword>Signal Transduction</keyword></keywords><dates><year>2013</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1740-1534 (Electronic)&#xD;1740-1526 (Linking)</isbn><accession-num>23435359</accession-num><urls><related-urls><url>) and is made of bacteria, viruses, and fungi. The number of bacteria in the gut exceeds the number of somatic cells by 10-fold and the number of microbial genes (the microbiome) exceeds the number of human genes by 100-fold PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb21tZXI8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS

ZWNOdW0+Mzk2OTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI1MSwyNTI8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zOTY5PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzY3NzI4MzUiPjM5Njk8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNvbW1lciwgRi48L2F1dGhvcj48

YXV0aG9yPkJhY2toZWQsIEYuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo

LWFkZHJlc3M+V2FsbGVuYmVyZyBMYWJvcmF0b3J5IGZvciBDYXJkaW92YXNjdWxhciBhbmQgTWV0

YWJvbGljIFJlc2VhcmNoLCBTYWhsZ3JlbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBEZXBhcnRt

ZW50IG9mIE1vbGVjdWxhciBhbmQgQ2xpbmljYWwgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgR290

aGVuYnVyZywgU0UtNDEzIDQ1IEdvdGhlbmJ1cmcsIFN3ZWRlbi48L2F1dGgtYWRkcmVzcz48dGl0

bGVzPjx0aXRsZT5UaGUgZ3V0IG1pY3JvYmlvdGEtLW1hc3RlcnMgb2YgaG9zdCBkZXZlbG9wbWVu

dCBhbmQgcGh5c2lvbG9neTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OYXQgUmV2IE1pY3JvYmlv

bDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4yMjctMzg8L3BhZ2VzPjx2b2x1bWU+

MTE8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFsczwv

a2V5d29yZD48a2V5d29yZD5HYXN0cm9pbnRlc3RpbmFsIFRyYWN0L2dyb3d0aCAmYW1wOyBkZXZl

bG9wbWVudC9pbW11bm9sb2d5LyptaWNyb2Jpb2xvZ3kvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+SGVhbHRoPC9rZXl3b3JkPjxrZXl3b3JkPkhvbWVvc3Rhc2lzPC9rZXl3b3JkPjxrZXl3

b3JkPkhvc3QtUGF0aG9nZW4gSW50ZXJhY3Rpb25zPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwv

a2V5d29yZD48a2V5d29yZD5JbW11bmUgU3lzdGVtLypwaHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPkltbXVuaXR5LCBNdWNvc2FsLyppbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1ldGFn

ZW5vbWUvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+U2lnbmFsIFRyYW5zZHVjdGlvbjwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+QXByPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTc0MC0xNTM0IChFbGVjdHJv

bmljKSYjeEQ7MTc0MC0xNTI2IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzQzNTM1

OTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3B1Ym1lZC8yMzQzNTM1OTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9ucm1pY3JvMjk3NDwvZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+VHJlbWFyb2xpPC9BdXRo

b3I+PFllYXI+MjAxMjwvWWVhcj48UmVjTnVtPjM5Nzc8L1JlY051bT48cmVjb3JkPjxyZWMtbnVt

YmVyPjM5Nzc8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJm

d2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjc3Mjkx

NyI+Mzk3Nzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj

bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+VHJlbWFyb2xp

LCBWLjwvYXV0aG9yPjxhdXRob3I+QmFja2hlZCwgRi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5XYWxsZW5iZXJnIExhYm9yYXRvcnkgZm9yIENhcmRpb3Zh

c2N1bGFyIGFuZCBNZXRhYm9saWMgUmVzZWFyY2gsIFNhaGxncmVuc2thIFVuaXZlcnNpdHkgSG9z

cGl0YWwsIDQxMyA0NSBHb3RoZW5idXJnLCBTd2VkZW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48

dGl0bGU+RnVuY3Rpb25hbCBpbnRlcmFjdGlvbnMgYmV0d2VlbiB0aGUgZ3V0IG1pY3JvYmlvdGEg

YW5kIGhvc3QgbWV0YWJvbGlzbTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OYXR1cmU8L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OYXR1cmU8L2Z1bGwt

dGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yNDItOTwvcGFnZXM+PHZvbHVtZT40ODk8L3ZvbHVt

ZT48bnVtYmVyPjc0MTU8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5d29y

ZD48a2V5d29yZD5EaWV0PC9rZXl3b3JkPjxrZXl3b3JkPipFbmVyZ3kgTWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5GZXJtZW50YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3

b3JkPjxrZXl3b3JkPkltbXVuaXR5LCBJbm5hdGU8L2tleXdvcmQ+PGtleXdvcmQ+SW5mbGFtbWF0

aW9uL21ldGFib2xpc20vbWljcm9iaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkludGVzdGluZXMv

aW1tdW5vbG9neS8qbWV0YWJvbGlzbS8qbWljcm9iaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1l

dGFib2xpYyBTeW5kcm9tZS9tZXRhYm9saXNtL21pY3JvYmlvbG9neTwva2V5d29yZD48a2V5d29y

ZD5NZXRhZ2Vub21lL2ltbXVub2xvZ3kvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+T2Jl

c2l0eS9tZXRhYm9saXNtL21pY3JvYmlvbG9neTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4yMDEyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwIDEzPC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PGlzYm4+MTQ3Ni00Njg3IChFbGVjdHJvbmljKSYjeEQ7MDAyOC0wODM2IChMaW5r

aW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMjk3MjI5NzwvYWNjZXNzaW9uLW51bT48dXJscz48

cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMjk3

MjI5NzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

MTAuMTAzOC9uYXR1cmUxMTU1MjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9D

aXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb21tZXI8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS

ZWNOdW0+Mzk2OTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI1MSwyNTI8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zOTY5PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzY3NzI4MzUiPjM5Njk8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNvbW1lciwgRi48L2F1dGhvcj48

YXV0aG9yPkJhY2toZWQsIEYuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo

LWFkZHJlc3M+V2FsbGVuYmVyZyBMYWJvcmF0b3J5IGZvciBDYXJkaW92YXNjdWxhciBhbmQgTWV0

YWJvbGljIFJlc2VhcmNoLCBTYWhsZ3JlbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBEZXBhcnRt

ZW50IG9mIE1vbGVjdWxhciBhbmQgQ2xpbmljYWwgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgR290

aGVuYnVyZywgU0UtNDEzIDQ1IEdvdGhlbmJ1cmcsIFN3ZWRlbi48L2F1dGgtYWRkcmVzcz48dGl0

bGVzPjx0aXRsZT5UaGUgZ3V0IG1pY3JvYmlvdGEtLW1hc3RlcnMgb2YgaG9zdCBkZXZlbG9wbWVu

dCBhbmQgcGh5c2lvbG9neTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OYXQgUmV2IE1pY3JvYmlv

bDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4yMjctMzg8L3BhZ2VzPjx2b2x1bWU+

MTE8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFsczwv

a2V5d29yZD48a2V5d29yZD5HYXN0cm9pbnRlc3RpbmFsIFRyYWN0L2dyb3d0aCAmYW1wOyBkZXZl

bG9wbWVudC9pbW11bm9sb2d5LyptaWNyb2Jpb2xvZ3kvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+SGVhbHRoPC9rZXl3b3JkPjxrZXl3b3JkPkhvbWVvc3Rhc2lzPC9rZXl3b3JkPjxrZXl3

b3JkPkhvc3QtUGF0aG9nZW4gSW50ZXJhY3Rpb25zPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwv

a2V5d29yZD48a2V5d29yZD5JbW11bmUgU3lzdGVtLypwaHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPkltbXVuaXR5LCBNdWNvc2FsLyppbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1ldGFn

ZW5vbWUvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+U2lnbmFsIFRyYW5zZHVjdGlvbjwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+QXByPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTc0MC0xNTM0IChFbGVjdHJv

bmljKSYjeEQ7MTc0MC0xNTI2IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzQzNTM1

OTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3B1Ym1lZC8yMzQzNTM1OTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9ucm1pY3JvMjk3NDwvZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+VHJlbWFyb2xpPC9BdXRo

b3I+PFllYXI+MjAxMjwvWWVhcj48UmVjTnVtPjM5Nzc8L1JlY051bT48cmVjb3JkPjxyZWMtbnVt

YmVyPjM5Nzc8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJm

d2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjc3Mjkx

NyI+Mzk3Nzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj

bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+VHJlbWFyb2xp

LCBWLjwvYXV0aG9yPjxhdXRob3I+QmFja2hlZCwgRi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5XYWxsZW5iZXJnIExhYm9yYXRvcnkgZm9yIENhcmRpb3Zh

c2N1bGFyIGFuZCBNZXRhYm9saWMgUmVzZWFyY2gsIFNhaGxncmVuc2thIFVuaXZlcnNpdHkgSG9z

cGl0YWwsIDQxMyA0NSBHb3RoZW5idXJnLCBTd2VkZW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48

dGl0bGU+RnVuY3Rpb25hbCBpbnRlcmFjdGlvbnMgYmV0d2VlbiB0aGUgZ3V0IG1pY3JvYmlvdGEg

YW5kIGhvc3QgbWV0YWJvbGlzbTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OYXR1cmU8L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OYXR1cmU8L2Z1bGwt

dGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yNDItOTwvcGFnZXM+PHZvbHVtZT40ODk8L3ZvbHVt

ZT48bnVtYmVyPjc0MTU8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5d29y

ZD48a2V5d29yZD5EaWV0PC9rZXl3b3JkPjxrZXl3b3JkPipFbmVyZ3kgTWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5GZXJtZW50YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3

b3JkPjxrZXl3b3JkPkltbXVuaXR5LCBJbm5hdGU8L2tleXdvcmQ+PGtleXdvcmQ+SW5mbGFtbWF0

aW9uL21ldGFib2xpc20vbWljcm9iaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkludGVzdGluZXMv

aW1tdW5vbG9neS8qbWV0YWJvbGlzbS8qbWljcm9iaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1l

dGFib2xpYyBTeW5kcm9tZS9tZXRhYm9saXNtL21pY3JvYmlvbG9neTwva2V5d29yZD48a2V5d29y

ZD5NZXRhZ2Vub21lL2ltbXVub2xvZ3kvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+T2Jl

c2l0eS9tZXRhYm9saXNtL21pY3JvYmlvbG9neTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4yMDEyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwIDEzPC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PGlzYm4+MTQ3Ni00Njg3IChFbGVjdHJvbmljKSYjeEQ7MDAyOC0wODM2IChMaW5r

aW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMjk3MjI5NzwvYWNjZXNzaW9uLW51bT48dXJscz48

cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMjk3

MjI5NzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

MTAuMTAzOC9uYXR1cmUxMTU1MjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9D

aXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 251,252.The human gut has bacteria with pro-inflammatory and others with anti-inflammatory properties, in dynamic homeostatic balance. Different stressors can lead to dysbiosis, i.e. an imbalance between pro-and anti-inflammatory bacteria that has been invoked to explain observations in patients with rheumatoid arthritis, atherosclerosis, obesity and other diseases (Fig. 4) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DbGFlc3NvbjwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+

PFJlY051bT40MDAzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjUzPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDAwMzwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2NzcyOTg3Ij40MDAzPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DbGFlc3NvbiwgTS4gSi48L2F1dGhv

cj48YXV0aG9yPkplZmZlcnksIEkuIEIuPC9hdXRob3I+PGF1dGhvcj5Db25kZSwgUy48L2F1dGhv

cj48YXV0aG9yPlBvd2VyLCBTLiBFLjwvYXV0aG9yPjxhdXRob3I+TyZhcG9zO0Nvbm5vciwgRS4g

TS48L2F1dGhvcj48YXV0aG9yPkN1c2FjaywgUy48L2F1dGhvcj48YXV0aG9yPkhhcnJpcywgSC4g

TS48L2F1dGhvcj48YXV0aG9yPkNvYWtsZXksIE0uPC9hdXRob3I+PGF1dGhvcj5MYWtzaG1pbmFy

YXlhbmFuLCBCLjwvYXV0aG9yPjxhdXRob3I+TyZhcG9zO1N1bGxpdmFuLCBPLjwvYXV0aG9yPjxh

dXRob3I+Rml0emdlcmFsZCwgRy4gRi48L2F1dGhvcj48YXV0aG9yPkRlYW5lLCBKLjwvYXV0aG9y

PjxhdXRob3I+TyZhcG9zO0Nvbm5vciwgTS48L2F1dGhvcj48YXV0aG9yPkhhcm5lZHksIE4uPC9h

dXRob3I+PGF1dGhvcj5PJmFwb3M7Q29ubm9yLCBLLjwvYXV0aG9yPjxhdXRob3I+TyZhcG9zO01h

aG9ueSwgRC48L2F1dGhvcj48YXV0aG9yPnZhbiBTaW5kZXJlbiwgRC48L2F1dGhvcj48YXV0aG9y

PldhbGxhY2UsIE0uPC9hdXRob3I+PGF1dGhvcj5CcmVubmFuLCBMLjwvYXV0aG9yPjxhdXRob3I+

U3RhbnRvbiwgQy48L2F1dGhvcj48YXV0aG9yPk1hcmNoZXNpLCBKLiBSLjwvYXV0aG9yPjxhdXRo

b3I+Rml0emdlcmFsZCwgQS4gUC48L2F1dGhvcj48YXV0aG9yPlNoYW5haGFuLCBGLjwvYXV0aG9y

PjxhdXRob3I+SGlsbCwgQy48L2F1dGhvcj48YXV0aG9yPlJvc3MsIFIuIFAuPC9hdXRob3I+PGF1

dGhvcj5PJmFwb3M7VG9vbGUsIFAuIFcuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

PjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBNaWNyb2Jpb2xvZ3ksIFVuaXZlcnNpdHkgQ29s

bGVnZSBDb3JrLCBJcmVsYW5kLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkd1dCBtaWNy

b2Jpb3RhIGNvbXBvc2l0aW9uIGNvcnJlbGF0ZXMgd2l0aCBkaWV0IGFuZCBoZWFsdGggaW4gdGhl

IGVsZGVybHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0dXJlPC9zZWNvbmRhcnktdGl0bGU+

PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmF0dXJlPC9mdWxsLXRpdGxlPjwvcGVy

aW9kaWNhbD48cGFnZXM+MTc4LTg0PC9wYWdlcz48dm9sdW1lPjQ4ODwvdm9sdW1lPjxudW1iZXI+

NzQxMDwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFn

ZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFnaW5nLypwaHlzaW9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPkNvaG9ydCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkRpZXQvKnN0YXRp

c3RpY3MgJmFtcDsgbnVtZXJpY2FsIGRhdGE8L2tleXdvcmQ+PGtleXdvcmQ+RGlldCBTdXJ2ZXlz

PC9rZXl3b3JkPjxrZXl3b3JkPkZlY2VzLyptaWNyb2Jpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

RnJ1aXQ8L2tleXdvcmQ+PGtleXdvcmQ+R2VyaWF0cmljIEFzc2Vzc21lbnQ8L2tleXdvcmQ+PGtl

eXdvcmQ+SGVhbHRoPC9rZXl3b3JkPjxrZXl3b3JkPipIZWFsdGggU3RhdHVzPC9rZXl3b3JkPjxr

ZXl3b3JkPkhlYWx0aCBTdXJ2ZXlzPC9rZXl3b3JkPjxrZXl3b3JkPkhvbWVzIGZvciB0aGUgQWdl

ZDwva2V5d29yZD48a2V5d29yZD5Ib3NwaXRhbHMsIENvbW11bml0eTwva2V5d29yZD48a2V5d29y

ZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXN0aW5lcy8qbWljcm9iaW9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPk1lYXQ8L2tleXdvcmQ+PGtleXdvcmQ+TWV0YWdlbm9tZS8qcGh5c2lvbG9n

eTwva2V5d29yZD48a2V5d29yZD5SZWhhYmlsaXRhdGlvbiBDZW50ZXJzPC9rZXl3b3JkPjxrZXl3

b3JkPlN1cnZleXMgYW5kIFF1ZXN0aW9ubmFpcmVzPC9rZXl3b3JkPjxrZXl3b3JkPlZlZ2V0YWJs

ZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMjwveWVhcj48cHViLWRhdGVz

PjxkYXRlPkF1ZyA5PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ3Ni00Njg3IChF

bGVjdHJvbmljKSYjeEQ7MDAyOC0wODM2IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4y

Mjc5NzUxODwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3

dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMjc5NzUxODwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9uYXR1cmUxMTMxOTwvZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DbGFlc3NvbjwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+

PFJlY051bT40MDAzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjUzPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDAwMzwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2NzcyOTg3Ij40MDAzPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DbGFlc3NvbiwgTS4gSi48L2F1dGhv

cj48YXV0aG9yPkplZmZlcnksIEkuIEIuPC9hdXRob3I+PGF1dGhvcj5Db25kZSwgUy48L2F1dGhv

cj48YXV0aG9yPlBvd2VyLCBTLiBFLjwvYXV0aG9yPjxhdXRob3I+TyZhcG9zO0Nvbm5vciwgRS4g

TS48L2F1dGhvcj48YXV0aG9yPkN1c2FjaywgUy48L2F1dGhvcj48YXV0aG9yPkhhcnJpcywgSC4g

TS48L2F1dGhvcj48YXV0aG9yPkNvYWtsZXksIE0uPC9hdXRob3I+PGF1dGhvcj5MYWtzaG1pbmFy

YXlhbmFuLCBCLjwvYXV0aG9yPjxhdXRob3I+TyZhcG9zO1N1bGxpdmFuLCBPLjwvYXV0aG9yPjxh

dXRob3I+Rml0emdlcmFsZCwgRy4gRi48L2F1dGhvcj48YXV0aG9yPkRlYW5lLCBKLjwvYXV0aG9y

PjxhdXRob3I+TyZhcG9zO0Nvbm5vciwgTS48L2F1dGhvcj48YXV0aG9yPkhhcm5lZHksIE4uPC9h

dXRob3I+PGF1dGhvcj5PJmFwb3M7Q29ubm9yLCBLLjwvYXV0aG9yPjxhdXRob3I+TyZhcG9zO01h

aG9ueSwgRC48L2F1dGhvcj48YXV0aG9yPnZhbiBTaW5kZXJlbiwgRC48L2F1dGhvcj48YXV0aG9y

PldhbGxhY2UsIE0uPC9hdXRob3I+PGF1dGhvcj5CcmVubmFuLCBMLjwvYXV0aG9yPjxhdXRob3I+

U3RhbnRvbiwgQy48L2F1dGhvcj48YXV0aG9yPk1hcmNoZXNpLCBKLiBSLjwvYXV0aG9yPjxhdXRo

b3I+Rml0emdlcmFsZCwgQS4gUC48L2F1dGhvcj48YXV0aG9yPlNoYW5haGFuLCBGLjwvYXV0aG9y

PjxhdXRob3I+SGlsbCwgQy48L2F1dGhvcj48YXV0aG9yPlJvc3MsIFIuIFAuPC9hdXRob3I+PGF1

dGhvcj5PJmFwb3M7VG9vbGUsIFAuIFcuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

PjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBNaWNyb2Jpb2xvZ3ksIFVuaXZlcnNpdHkgQ29s

bGVnZSBDb3JrLCBJcmVsYW5kLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkd1dCBtaWNy

b2Jpb3RhIGNvbXBvc2l0aW9uIGNvcnJlbGF0ZXMgd2l0aCBkaWV0IGFuZCBoZWFsdGggaW4gdGhl

IGVsZGVybHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0dXJlPC9zZWNvbmRhcnktdGl0bGU+

PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmF0dXJlPC9mdWxsLXRpdGxlPjwvcGVy

aW9kaWNhbD48cGFnZXM+MTc4LTg0PC9wYWdlcz48dm9sdW1lPjQ4ODwvdm9sdW1lPjxudW1iZXI+

NzQxMDwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFn

ZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFnaW5nLypwaHlzaW9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPkNvaG9ydCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkRpZXQvKnN0YXRp

c3RpY3MgJmFtcDsgbnVtZXJpY2FsIGRhdGE8L2tleXdvcmQ+PGtleXdvcmQ+RGlldCBTdXJ2ZXlz

PC9rZXl3b3JkPjxrZXl3b3JkPkZlY2VzLyptaWNyb2Jpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

RnJ1aXQ8L2tleXdvcmQ+PGtleXdvcmQ+R2VyaWF0cmljIEFzc2Vzc21lbnQ8L2tleXdvcmQ+PGtl

eXdvcmQ+SGVhbHRoPC9rZXl3b3JkPjxrZXl3b3JkPipIZWFsdGggU3RhdHVzPC9rZXl3b3JkPjxr

ZXl3b3JkPkhlYWx0aCBTdXJ2ZXlzPC9rZXl3b3JkPjxrZXl3b3JkPkhvbWVzIGZvciB0aGUgQWdl

ZDwva2V5d29yZD48a2V5d29yZD5Ib3NwaXRhbHMsIENvbW11bml0eTwva2V5d29yZD48a2V5d29y

ZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXN0aW5lcy8qbWljcm9iaW9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPk1lYXQ8L2tleXdvcmQ+PGtleXdvcmQ+TWV0YWdlbm9tZS8qcGh5c2lvbG9n

eTwva2V5d29yZD48a2V5d29yZD5SZWhhYmlsaXRhdGlvbiBDZW50ZXJzPC9rZXl3b3JkPjxrZXl3

b3JkPlN1cnZleXMgYW5kIFF1ZXN0aW9ubmFpcmVzPC9rZXl3b3JkPjxrZXl3b3JkPlZlZ2V0YWJs

ZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMjwveWVhcj48cHViLWRhdGVz

PjxkYXRlPkF1ZyA5PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ3Ni00Njg3IChF

bGVjdHJvbmljKSYjeEQ7MDAyOC0wODM2IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4y

Mjc5NzUxODwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3

dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMjc5NzUxODwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9uYXR1cmUxMTMxOTwvZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 253.Gut microbiota and the immune system in ADSeveral studies have been conducted to investigate the role of microbiome in Alzheimer’s disease as well as other neurodegenerative and psychiatric disorders. There is clear evidence of the role of the microbiome in Parkinson’s disease (PD) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdWxhazwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl

Y051bT40MDg0PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MjU0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDA4NDwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2NzczMTM0Ij40MDg0PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5NdWxhaywgQS48L2F1dGhvcj48YXV0aG9y

PkJvbmF6LCBCLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNz

PkFnYXRhIE11bGFrLCBEZXBhcnRtZW50IG9mIEdhc3Ryb2VudGVyb2xvZ3kgYW5kIEhlcGF0b2xv

Z3ksIFdyb2NsYXcgTWVkaWNhbCBVbml2ZXJzaXR5LCA1MC01NTYgV3JvY2xhdywgUG9sYW5kLjwv

YXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkJyYWluLWd1dC1taWNyb2Jpb3RhIGF4aXMgaW4g

UGFya2luc29uJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEog

R2FzdHJvZW50ZXJvbDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMDYwOS0yMDwv

cGFnZXM+PHZvbHVtZT4yMTwvdm9sdW1lPjxudW1iZXI+Mzc8L251bWJlcj48a2V5d29yZHM+PGtl

eXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CaW9tYXJrZXJzL21ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+QnJhaW4vKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5Db2ZmZWU8

L2tleXdvcmQ+PGtleXdvcmQ+RGlldDwva2V5d29yZD48a2V5d29yZD5FbnRlcmljIE5lcnZvdXMg

U3lzdGVtPC9rZXl3b3JkPjxrZXl3b3JkPipHYXN0cm9pbnRlc3RpbmFsIE1pY3JvYmlvbWU8L2tl

eXdvcmQ+PGtleXdvcmQ+R2FzdHJvaW50ZXN0aW5hbCBUcmFjdC8qbWljcm9iaW9sb2d5LypwaHlz

aW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SGVsaWNvYmFjdGVyIHB5bG9yaTwva2V5d29y

ZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5pdHksIElubmF0ZTwva2V5

d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXN0aW5lcy9t

aWNyb2Jpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TXljb2JhY3Rlcml1bSB0dWJlcmN1bG9zaXM8

L2tleXdvcmQ+PGtleXdvcmQ+UGFya2luc29uIERpc2Vhc2UvKm1pY3JvYmlvbG9neS8qcGh5c2lv

cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBlcm1lYWJpbGl0eTwva2V5d29yZD48a2V5d29y

ZD5Qcm90ZWluIEZvbGRpbmc8L2tleXdvcmQ+PGtleXdvcmQ+U21va2luZzwva2V5d29yZD48a2V5

d29yZD5hbHBoYS1TeW51Y2xlaW4vbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5CcmFpbi1n

dXQtbWljcm9iaW90YSBheGlzPC9rZXl3b3JkPjxrZXl3b3JkPkdhc3Ryb2ludGVzdGluYWwgZHlz

ZnVuY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+R3V0IG1pY3JvYmlvdGE8L2tleXdvcmQ+PGtleXdv

cmQ+UGFya2luc29uJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5

ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5PY3QgNzwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjIyMTktMjg0MCAoRWxlY3Ryb25pYykmI3hEOzEwMDctOTMyNyAoTGlua2lu

Zyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjY0NTcwMjE8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJl

bGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjY0NTcw

MjE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNDU4ODA4MzwvY3VzdG9t

Mj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMzc0OC93amcudjIxLmkzNy4xMDYwOTwvZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdWxhazwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl

Y051bT40MDg0PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

MjU0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDA4NDwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2NzczMTM0Ij40MDg0PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5NdWxhaywgQS48L2F1dGhvcj48YXV0aG9y

PkJvbmF6LCBCLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNz

PkFnYXRhIE11bGFrLCBEZXBhcnRtZW50IG9mIEdhc3Ryb2VudGVyb2xvZ3kgYW5kIEhlcGF0b2xv

Z3ksIFdyb2NsYXcgTWVkaWNhbCBVbml2ZXJzaXR5LCA1MC01NTYgV3JvY2xhdywgUG9sYW5kLjwv

YXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkJyYWluLWd1dC1taWNyb2Jpb3RhIGF4aXMgaW4g

UGFya2luc29uJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEog

R2FzdHJvZW50ZXJvbDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMDYwOS0yMDwv

cGFnZXM+PHZvbHVtZT4yMTwvdm9sdW1lPjxudW1iZXI+Mzc8L251bWJlcj48a2V5d29yZHM+PGtl

eXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CaW9tYXJrZXJzL21ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+QnJhaW4vKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5Db2ZmZWU8

L2tleXdvcmQ+PGtleXdvcmQ+RGlldDwva2V5d29yZD48a2V5d29yZD5FbnRlcmljIE5lcnZvdXMg

U3lzdGVtPC9rZXl3b3JkPjxrZXl3b3JkPipHYXN0cm9pbnRlc3RpbmFsIE1pY3JvYmlvbWU8L2tl

eXdvcmQ+PGtleXdvcmQ+R2FzdHJvaW50ZXN0aW5hbCBUcmFjdC8qbWljcm9iaW9sb2d5LypwaHlz

aW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SGVsaWNvYmFjdGVyIHB5bG9yaTwva2V5d29y

ZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5pdHksIElubmF0ZTwva2V5

d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXN0aW5lcy9t

aWNyb2Jpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TXljb2JhY3Rlcml1bSB0dWJlcmN1bG9zaXM8

L2tleXdvcmQ+PGtleXdvcmQ+UGFya2luc29uIERpc2Vhc2UvKm1pY3JvYmlvbG9neS8qcGh5c2lv

cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBlcm1lYWJpbGl0eTwva2V5d29yZD48a2V5d29y

ZD5Qcm90ZWluIEZvbGRpbmc8L2tleXdvcmQ+PGtleXdvcmQ+U21va2luZzwva2V5d29yZD48a2V5

d29yZD5hbHBoYS1TeW51Y2xlaW4vbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5CcmFpbi1n

dXQtbWljcm9iaW90YSBheGlzPC9rZXl3b3JkPjxrZXl3b3JkPkdhc3Ryb2ludGVzdGluYWwgZHlz

ZnVuY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+R3V0IG1pY3JvYmlvdGE8L2tleXdvcmQ+PGtleXdv

cmQ+UGFya2luc29uJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5

ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5PY3QgNzwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjIyMTktMjg0MCAoRWxlY3Ryb25pYykmI3hEOzEwMDctOTMyNyAoTGlua2lu

Zyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjY0NTcwMjE8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJl

bGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjY0NTcw

MjE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNDU4ODA4MzwvY3VzdG9t

Mj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMzc0OC93amcudjIxLmkzNy4xMDYwOTwvZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 254, multiple sclerosis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaXlha2U8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS

ZWNOdW0+NDEyOTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI1NTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQxMjk8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjc3MzE4NSI+NDEyOTwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWl5YWtlLCBTLjwvYXV0aG9yPjxhdXRo

b3I+S2ltLCBTLjwvYXV0aG9yPjxhdXRob3I+U3VkYSwgVy48L2F1dGhvcj48YXV0aG9yPk9zaGlt

YSwgSy48L2F1dGhvcj48YXV0aG9yPk5ha2FtdXJhLCBNLjwvYXV0aG9yPjxhdXRob3I+TWF0c3Vv

a2EsIFQuPC9hdXRob3I+PGF1dGhvcj5DaGloYXJhLCBOLjwvYXV0aG9yPjxhdXRob3I+VG9taXRh

LCBBLjwvYXV0aG9yPjxhdXRob3I+U2F0bywgVy48L2F1dGhvcj48YXV0aG9yPktpbSwgUy4gVy48

L2F1dGhvcj48YXV0aG9yPk1vcml0YSwgSC48L2F1dGhvcj48YXV0aG9yPkhhdHRvcmksIE0uPC9h

dXRob3I+PGF1dGhvcj5ZYW1hbXVyYSwgVC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIEltbXVub2xvZ3ksIE5hdGlvbmFsIEluc3Rp

dHV0ZSBvZiBOZXVyb3NjaWVuY2UsIDQtMS0xLCBPZ2F3YS1IaWdhc2hpLCBLb2RhaXJhLCBUb2t5

byAxODctODUwMiwgSmFwYW47IERlcGFydG1lbnQgb2YgSW1tdW5vbG9neSwgSnVudGVuZG8gVW5p

dmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUsIDItMS0xLCBIb25nbywgQnVua3lvLWt1LCBUb2t5

byAxMTMtODQyMSwgSmFwYW4uJiN4RDtDZW50ZXIgZm9yIE9taWNzIGFuZCBCaW9pbmZvcm1hdGlj

cywgVGhlIERlcGFydG1lbnQgb2YgQ29tcHV0YXRpb25hbCBCaW9sb2d5LCBHcmFkdWF0ZSBTY2hv

b2wgb2YgRnJvbnRpZXIgU2NpZW5jZXMsIFRoZSBVbml2ZXJzaXR5IG9mIFRva3lvLCBLYXNoaXdh

bm9oYSA1LTEtNSwgS2FzaGl3YSwgQ2hpYmEgMjc3LTg1NjEsIEphcGFuLiYjeEQ7RGVwYXJ0bWVu

dCBvZiBJbW11bm9sb2d5LCBOYXRpb25hbCBJbnN0aXR1dGUgb2YgTmV1cm9zY2llbmNlLCA0LTEt

MSwgT2dhd2EtSGlnYXNoaSwgS29kYWlyYSwgVG9reW8gMTg3LTg1MDIsIEphcGFuLiYjeEQ7Q2Vu

dGVyIGZvciBPbWljcyBhbmQgQmlvaW5mb3JtYXRpY3MsIFRoZSBEZXBhcnRtZW50IG9mIENvbXB1

dGF0aW9uYWwgQmlvbG9neSwgR3JhZHVhdGUgU2Nob29sIG9mIEZyb250aWVyIFNjaWVuY2VzLCBU

aGUgVW5pdmVyc2l0eSBvZiBUb2t5bywgS2FzaGl3YW5vaGEgNS0xLTUsIEthc2hpd2EsIENoaWJh

IDI3Ny04NTYxLCBKYXBhbjsgTGFib3JhdG9yeSBmb3IgSW50ZWdyYXRlZCBCaW9pbmZvcm1hdGlj

cywgUklLRU4gQ2VudGVyIGZvciBJbnRlZ3JhdGl2ZSBNZWRpY2FsIFNjaWVuY2VzLCAxLTctMjIg

U3VlaGlyby1jaG8sIFRzdXJ1bWkta3UsIFlva29oYW1hLCBLYW5hZ2F3YSAyMzAtMDA0NSwgSmFw

YW4uJiN4RDtTY2hvb2wgb2YgVmV0ZXJpbmFyeSBNZWRpY2luZSwgQXphYnUgVW5pdmVyc2l0eSwg

MS0xNy03MSBGdWNoaW5vYmUsIENodW8ta3UsIFNhZ2FtaWhhcmEsIEthbmFnYXdhIDIyOS04NTAx

LCBKYXBhbi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5EeXNiaW9zaXMgaW4gdGhlIEd1

dCBNaWNyb2Jpb3RhIG9mIFBhdGllbnRzIHdpdGggTXVsdGlwbGUgU2NsZXJvc2lzLCB3aXRoIGEg

U3RyaWtpbmcgRGVwbGV0aW9uIG9mIFNwZWNpZXMgQmVsb25naW5nIHRvIENsb3N0cmlkaWEgWElW

YSBhbmQgSVYgQ2x1c3RlcnM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UExvUyBPbmU8L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5QTG9TIE9uZTwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPmUwMTM3NDI5PC9wYWdlcz48dm9sdW1lPjEwPC92

b2x1bWU+PG51bWJlcj45PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3Jk

PjxrZXl3b3JkPkJhY3Rlcm9pZGV0ZXMvZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5DbG9zdHJpZGl1bS9jbGFzc2lmaWNhdGlvbi9nZW5ldGljcy8qbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5EeXNiaW9zaXMvKm1ldGFib2xpc20vbWljcm9iaW9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD4qR2FzdHJvaW50ZXN0aW5hbCBNaWNy

b2Jpb21lPC9rZXl3b3JkPjxrZXl3b3JkPkhpZ2gtVGhyb3VnaHB1dCBOdWNsZW90aWRlIFNlcXVl

bmNpbmc8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkphcGFuPC9r

ZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TXVsdGlwbGUgU2NsZXJvc2lz

LyptaWNyb2Jpb2xvZ3kvcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlJOQSwgQmFj

dGVyaWFsL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPlJOQSwgUmlib3NvbWFsLCAxNlMvZ2Vu

ZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+U2VxdWVuY2UgQW5hbHlzaXMsIFJOQTwva2V5d29yZD48

L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE1PC95ZWFyPjwvZGF0ZXM+PGlzYm4+MTkzMi02MjAz

IChFbGVjdHJvbmljKSYjeEQ7MTkzMi02MjAzIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51

bT4yNjM2Nzc3NjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDov

L3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjM2Nzc3NjwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48Y3VzdG9tMj5QTUM0NTY5NDMyPC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNl

LW51bT4xMC4xMzcxL2pvdXJuYWwucG9uZS4wMTM3NDI5PC9lbGVjdHJvbmljLXJlc291cmNlLW51

bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaXlha2U8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS

ZWNOdW0+NDEyOTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI1NTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQxMjk8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjc3MzE4NSI+NDEyOTwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWl5YWtlLCBTLjwvYXV0aG9yPjxhdXRo

b3I+S2ltLCBTLjwvYXV0aG9yPjxhdXRob3I+U3VkYSwgVy48L2F1dGhvcj48YXV0aG9yPk9zaGlt

YSwgSy48L2F1dGhvcj48YXV0aG9yPk5ha2FtdXJhLCBNLjwvYXV0aG9yPjxhdXRob3I+TWF0c3Vv

a2EsIFQuPC9hdXRob3I+PGF1dGhvcj5DaGloYXJhLCBOLjwvYXV0aG9yPjxhdXRob3I+VG9taXRh

LCBBLjwvYXV0aG9yPjxhdXRob3I+U2F0bywgVy48L2F1dGhvcj48YXV0aG9yPktpbSwgUy4gVy48

L2F1dGhvcj48YXV0aG9yPk1vcml0YSwgSC48L2F1dGhvcj48YXV0aG9yPkhhdHRvcmksIE0uPC9h

dXRob3I+PGF1dGhvcj5ZYW1hbXVyYSwgVC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIEltbXVub2xvZ3ksIE5hdGlvbmFsIEluc3Rp

dHV0ZSBvZiBOZXVyb3NjaWVuY2UsIDQtMS0xLCBPZ2F3YS1IaWdhc2hpLCBLb2RhaXJhLCBUb2t5

byAxODctODUwMiwgSmFwYW47IERlcGFydG1lbnQgb2YgSW1tdW5vbG9neSwgSnVudGVuZG8gVW5p

dmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUsIDItMS0xLCBIb25nbywgQnVua3lvLWt1LCBUb2t5

byAxMTMtODQyMSwgSmFwYW4uJiN4RDtDZW50ZXIgZm9yIE9taWNzIGFuZCBCaW9pbmZvcm1hdGlj

cywgVGhlIERlcGFydG1lbnQgb2YgQ29tcHV0YXRpb25hbCBCaW9sb2d5LCBHcmFkdWF0ZSBTY2hv

b2wgb2YgRnJvbnRpZXIgU2NpZW5jZXMsIFRoZSBVbml2ZXJzaXR5IG9mIFRva3lvLCBLYXNoaXdh

bm9oYSA1LTEtNSwgS2FzaGl3YSwgQ2hpYmEgMjc3LTg1NjEsIEphcGFuLiYjeEQ7RGVwYXJ0bWVu

dCBvZiBJbW11bm9sb2d5LCBOYXRpb25hbCBJbnN0aXR1dGUgb2YgTmV1cm9zY2llbmNlLCA0LTEt

MSwgT2dhd2EtSGlnYXNoaSwgS29kYWlyYSwgVG9reW8gMTg3LTg1MDIsIEphcGFuLiYjeEQ7Q2Vu

dGVyIGZvciBPbWljcyBhbmQgQmlvaW5mb3JtYXRpY3MsIFRoZSBEZXBhcnRtZW50IG9mIENvbXB1

dGF0aW9uYWwgQmlvbG9neSwgR3JhZHVhdGUgU2Nob29sIG9mIEZyb250aWVyIFNjaWVuY2VzLCBU

aGUgVW5pdmVyc2l0eSBvZiBUb2t5bywgS2FzaGl3YW5vaGEgNS0xLTUsIEthc2hpd2EsIENoaWJh

IDI3Ny04NTYxLCBKYXBhbjsgTGFib3JhdG9yeSBmb3IgSW50ZWdyYXRlZCBCaW9pbmZvcm1hdGlj

cywgUklLRU4gQ2VudGVyIGZvciBJbnRlZ3JhdGl2ZSBNZWRpY2FsIFNjaWVuY2VzLCAxLTctMjIg

U3VlaGlyby1jaG8sIFRzdXJ1bWkta3UsIFlva29oYW1hLCBLYW5hZ2F3YSAyMzAtMDA0NSwgSmFw

YW4uJiN4RDtTY2hvb2wgb2YgVmV0ZXJpbmFyeSBNZWRpY2luZSwgQXphYnUgVW5pdmVyc2l0eSwg

MS0xNy03MSBGdWNoaW5vYmUsIENodW8ta3UsIFNhZ2FtaWhhcmEsIEthbmFnYXdhIDIyOS04NTAx

LCBKYXBhbi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5EeXNiaW9zaXMgaW4gdGhlIEd1

dCBNaWNyb2Jpb3RhIG9mIFBhdGllbnRzIHdpdGggTXVsdGlwbGUgU2NsZXJvc2lzLCB3aXRoIGEg

U3RyaWtpbmcgRGVwbGV0aW9uIG9mIFNwZWNpZXMgQmVsb25naW5nIHRvIENsb3N0cmlkaWEgWElW

YSBhbmQgSVYgQ2x1c3RlcnM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UExvUyBPbmU8L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5QTG9TIE9uZTwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPmUwMTM3NDI5PC9wYWdlcz48dm9sdW1lPjEwPC92

b2x1bWU+PG51bWJlcj45PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3Jk

PjxrZXl3b3JkPkJhY3Rlcm9pZGV0ZXMvZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5DbG9zdHJpZGl1bS9jbGFzc2lmaWNhdGlvbi9nZW5ldGljcy8qbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5EeXNiaW9zaXMvKm1ldGFib2xpc20vbWljcm9iaW9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD4qR2FzdHJvaW50ZXN0aW5hbCBNaWNy

b2Jpb21lPC9rZXl3b3JkPjxrZXl3b3JkPkhpZ2gtVGhyb3VnaHB1dCBOdWNsZW90aWRlIFNlcXVl

bmNpbmc8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkphcGFuPC9r

ZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TXVsdGlwbGUgU2NsZXJvc2lz

LyptaWNyb2Jpb2xvZ3kvcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlJOQSwgQmFj

dGVyaWFsL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPlJOQSwgUmlib3NvbWFsLCAxNlMvZ2Vu

ZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+U2VxdWVuY2UgQW5hbHlzaXMsIFJOQTwva2V5d29yZD48

L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE1PC95ZWFyPjwvZGF0ZXM+PGlzYm4+MTkzMi02MjAz

IChFbGVjdHJvbmljKSYjeEQ7MTkzMi02MjAzIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51

bT4yNjM2Nzc3NjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDov

L3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjM2Nzc3NjwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48Y3VzdG9tMj5QTUM0NTY5NDMyPC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNl

LW51bT4xMC4xMzcxL2pvdXJuYWwucG9uZS4wMTM3NDI5PC9lbGVjdHJvbmljLXJlc291cmNlLW51

bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 255, sickness behavior PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EJmFwb3M7TWVsbG88L0F1dGhvcj48WWVhcj4yMDE1PC9Z

ZWFyPjxSZWNOdW0+NDEzMTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJz

Y3JpcHQiPjI1Njwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQxMzE8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjc3MzIyMSI+NDEzMTwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RCZhcG9zO01lbGxvLCBDLjwv

YXV0aG9yPjxhdXRob3I+Um9uYWdoYW4sIE4uPC9hdXRob3I+PGF1dGhvcj5aYWhlZXIsIFIuPC9h

dXRob3I+PGF1dGhvcj5EaWNheSwgTS48L2F1dGhvcj48YXV0aG9yPkxlLCBULjwvYXV0aG9yPjxh

dXRob3I+TWFjTmF1Z2h0b24sIFcuIEsuPC9hdXRob3I+PGF1dGhvcj5TdXJyZXR0ZSwgTS4gRy48

L2F1dGhvcj48YXV0aG9yPlN3YWluLCBNLiBHLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkltbXVub2xvZ3kgUmVzZWFyY2ggR3JvdXAgYW5kLiYjeEQ7R2Fz

dHJvaW50ZXN0aW5hbCBSZXNlYXJjaCBHcm91cCBhbmQgSW5mbGFtbWF0aW9uIFJlc2VhcmNoIE5l

dHdvcmssIENhbHZpbiwgUGhvZWJlIGFuZCBKb2FuIFNueWRlciBJbnN0aXR1dGUgZm9yIENocm9u

aWMgRGlzZWFzZXMsIEN1bW1pbmcgU2Nob29sIG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIENh

bGdhcnksIENhbGdhcnksIEFsYmVydGEgVDJOIDROMSwgQ2FuYWRhLCBhbmQuJiN4RDtGYXJuY29t

YmUgRmFtaWx5IERpZ2VzdGl2ZSBIZWFsdGggUmVzZWFyY2ggSW5zdGl0dXRlLCBNY01hc3RlciBV

bml2ZXJzaXR5LCBIYW1pbHRvbiwgT250YXJpbyBMOFMgNEw4LCBDYW5hZGEuJiN4RDtJbW11bm9s

b2d5IFJlc2VhcmNoIEdyb3VwIGFuZCBzd2FpbkB1Y2FsZ2FyeS5jYS48L2F1dGgtYWRkcmVzcz48

dGl0bGVzPjx0aXRsZT5Qcm9iaW90aWNzIEltcHJvdmUgSW5mbGFtbWF0aW9uLUFzc29jaWF0ZWQg

U2lja25lc3MgQmVoYXZpb3IgYnkgQWx0ZXJpbmcgQ29tbXVuaWNhdGlvbiBiZXR3ZWVuIHRoZSBQ

ZXJpcGhlcmFsIEltbXVuZSBTeXN0ZW0gYW5kIHRoZSBCcmFpbjwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5KIE5ldXJvc2NpPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1

bGwtdGl0bGU+SiBOZXVyb3NjaTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjEwODIx

LTMwPC9wYWdlcz48dm9sdW1lPjM1PC92b2x1bWU+PG51bWJlcj4zMDwvbnVtYmVyPjxrZXl3b3Jk

cz48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJlaGF2aW9yLCBBbmltYWw8L2tl

eXdvcmQ+PGtleXdvcmQ+QnJhaW4vKmRydWcgZWZmZWN0cy9pbW11bm9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPkRpc2Vhc2UgTW9kZWxzLCBBbmltYWw8L2tleXdvcmQ+PGtleXdvcmQ+SWxsbmVzcyBC

ZWhhdmlvci8qZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVuZSBTeXN0ZW0vKmRy

dWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb24vY29tcGxpY2F0aW9uczwv

a2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtl

eXdvcmQ+TWljZSwgSW5icmVkIEM1N0JMPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvaW1tdW5vbW9k

dWxhdGlvbi8qZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPlByb2Jpb3RpY3MvKnBoYXJt

YWNvbG9neTwva2V5d29yZD48a2V5d29yZD5UTkYtYWxwaGE8L2tleXdvcmQ+PGtleXdvcmQ+Y2Vy

ZWJyYWwgaW50cmF2aXRhbCBtaWNyb3Njb3B5PC9rZXl3b3JkPjxrZXl3b3JkPm1pY3JvZ2xpYTwv

a2V5d29yZD48a2V5d29yZD5tb25vY3l0ZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bCAyOTwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjE1MjktMjQwMSAoRWxlY3Ryb25pYykmI3hEOzAyNzAtNjQ3NCAoTGlua2lu

Zyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjYyMjQ4NjQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJl

bGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjYyMjQ4

NjQ8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEw

LjE1MjMvSk5FVVJPU0NJLjA1NzUtMTUuMjAxNTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9y

ZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EJmFwb3M7TWVsbG88L0F1dGhvcj48WWVhcj4yMDE1PC9Z

ZWFyPjxSZWNOdW0+NDEzMTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJz

Y3JpcHQiPjI1Njwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQxMzE8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjc3MzIyMSI+NDEzMTwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RCZhcG9zO01lbGxvLCBDLjwv

YXV0aG9yPjxhdXRob3I+Um9uYWdoYW4sIE4uPC9hdXRob3I+PGF1dGhvcj5aYWhlZXIsIFIuPC9h

dXRob3I+PGF1dGhvcj5EaWNheSwgTS48L2F1dGhvcj48YXV0aG9yPkxlLCBULjwvYXV0aG9yPjxh

dXRob3I+TWFjTmF1Z2h0b24sIFcuIEsuPC9hdXRob3I+PGF1dGhvcj5TdXJyZXR0ZSwgTS4gRy48

L2F1dGhvcj48YXV0aG9yPlN3YWluLCBNLiBHLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkltbXVub2xvZ3kgUmVzZWFyY2ggR3JvdXAgYW5kLiYjeEQ7R2Fz

dHJvaW50ZXN0aW5hbCBSZXNlYXJjaCBHcm91cCBhbmQgSW5mbGFtbWF0aW9uIFJlc2VhcmNoIE5l

dHdvcmssIENhbHZpbiwgUGhvZWJlIGFuZCBKb2FuIFNueWRlciBJbnN0aXR1dGUgZm9yIENocm9u

aWMgRGlzZWFzZXMsIEN1bW1pbmcgU2Nob29sIG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIENh

bGdhcnksIENhbGdhcnksIEFsYmVydGEgVDJOIDROMSwgQ2FuYWRhLCBhbmQuJiN4RDtGYXJuY29t

YmUgRmFtaWx5IERpZ2VzdGl2ZSBIZWFsdGggUmVzZWFyY2ggSW5zdGl0dXRlLCBNY01hc3RlciBV

bml2ZXJzaXR5LCBIYW1pbHRvbiwgT250YXJpbyBMOFMgNEw4LCBDYW5hZGEuJiN4RDtJbW11bm9s

b2d5IFJlc2VhcmNoIEdyb3VwIGFuZCBzd2FpbkB1Y2FsZ2FyeS5jYS48L2F1dGgtYWRkcmVzcz48

dGl0bGVzPjx0aXRsZT5Qcm9iaW90aWNzIEltcHJvdmUgSW5mbGFtbWF0aW9uLUFzc29jaWF0ZWQg

U2lja25lc3MgQmVoYXZpb3IgYnkgQWx0ZXJpbmcgQ29tbXVuaWNhdGlvbiBiZXR3ZWVuIHRoZSBQ

ZXJpcGhlcmFsIEltbXVuZSBTeXN0ZW0gYW5kIHRoZSBCcmFpbjwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5KIE5ldXJvc2NpPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1

bGwtdGl0bGU+SiBOZXVyb3NjaTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjEwODIx

LTMwPC9wYWdlcz48dm9sdW1lPjM1PC92b2x1bWU+PG51bWJlcj4zMDwvbnVtYmVyPjxrZXl3b3Jk

cz48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJlaGF2aW9yLCBBbmltYWw8L2tl

eXdvcmQ+PGtleXdvcmQ+QnJhaW4vKmRydWcgZWZmZWN0cy9pbW11bm9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPkRpc2Vhc2UgTW9kZWxzLCBBbmltYWw8L2tleXdvcmQ+PGtleXdvcmQ+SWxsbmVzcyBC

ZWhhdmlvci8qZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVuZSBTeXN0ZW0vKmRy

dWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb24vY29tcGxpY2F0aW9uczwv

a2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtl

eXdvcmQ+TWljZSwgSW5icmVkIEM1N0JMPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvaW1tdW5vbW9k

dWxhdGlvbi8qZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPlByb2Jpb3RpY3MvKnBoYXJt

YWNvbG9neTwva2V5d29yZD48a2V5d29yZD5UTkYtYWxwaGE8L2tleXdvcmQ+PGtleXdvcmQ+Y2Vy

ZWJyYWwgaW50cmF2aXRhbCBtaWNyb3Njb3B5PC9rZXl3b3JkPjxrZXl3b3JkPm1pY3JvZ2xpYTwv

a2V5d29yZD48a2V5d29yZD5tb25vY3l0ZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bCAyOTwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjE1MjktMjQwMSAoRWxlY3Ryb25pYykmI3hEOzAyNzAtNjQ3NCAoTGlua2lu

Zyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjYyMjQ4NjQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJl

bGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjYyMjQ4

NjQ8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEw

LjE1MjMvSk5FVVJPU0NJLjA1NzUtMTUuMjAxNTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9y

ZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 256, major depression ADDIN EN.CITE <EndNote><Cite><Author>Naseribafrouei</Author><Year>2014</Year><RecNum>4134</RecNum><DisplayText><style face="superscript">257</style></DisplayText><record><rec-number>4134</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1536773290">4134</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Naseribafrouei, A.</author><author>Hestad, K.</author><author>Avershina, E.</author><author>Sekelja, M.</author><author>Linlokken, A.</author><author>Wilson, R.</author><author>Rudi, K.</author></authors></contributors><auth-address>Faculty of Education and Science, Hedmark University College, Hamar, Norway.</auth-address><titles><title>Correlation between the human fecal microbiota and depression</title><secondary-title>Neurogastroenterol Motil</secondary-title></titles><pages>1155-62</pages><volume>26</volume><number>8</number><keywords><keyword>Adult</keyword><keyword>Depressive Disorder/*microbiology</keyword><keyword>Feces/*microbiology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>*Microbiota</keyword><keyword>Middle Aged</keyword><keyword>RNA, Ribosomal, 16S/genetics</keyword><keyword>16SrRNA gene</keyword><keyword>Illumina deep sequencing</keyword><keyword>depression</keyword><keyword>gut microbiota</keyword></keywords><dates><year>2014</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1365-2982 (Electronic)&#xD;1350-1925 (Linking)</isbn><accession-num>24888394</accession-num><urls><related-urls><url>, and autism PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYW5nPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj

TnVtPjQyNTY8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4y

NTg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40MjU2PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzcxOTAzODEiPjQyNTY8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkthbmcsIEQuIFcuPC9hdXRob3I+PGF1dGhv

cj5QYXJrLCBKLiBHLjwvYXV0aG9yPjxhdXRob3I+SWxoYW4sIFouIEUuPC9hdXRob3I+PGF1dGhv

cj5XYWxsc3Ryb20sIEcuPC9hdXRob3I+PGF1dGhvcj5MYWJhZXIsIEouPC9hdXRob3I+PGF1dGhv

cj5BZGFtcywgSi4gQi48L2F1dGhvcj48YXV0aG9yPktyYWptYWxuaWstQnJvd24sIFIuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+U3dldHRlIENlbnRlciBm

b3IgRW52aXJvbm1lbnRhbCBCaW90ZWNobm9sb2d5LCBCaW9kZXNpZ24gSW5zdGl0dXRlLCBBcml6

b25hIFN0YXRlIFVuaXZlcnNpdHksIFRlbXBlLCBBcml6b25hLCBVbml0ZWQgU3RhdGVzIG9mIEFt

ZXJpY2EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UmVkdWNlZCBpbmNpZGVuY2Ugb2Yg

UHJldm90ZWxsYSBhbmQgb3RoZXIgZmVybWVudGVycyBpbiBpbnRlc3RpbmFsIG1pY3JvZmxvcmEg

b2YgYXV0aXN0aWMgY2hpbGRyZW48L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UExvUyBPbmU8L3Nl

Y29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5QTG9TIE9uZTwv

ZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPmU2ODMyMjwvcGFnZXM+PHZvbHVtZT44PC92

b2x1bWU+PG51bWJlcj43PC9udW1iZXI+PGVkaXRpb24+MjAxMy8wNy8xMjwvZWRpdGlvbj48a2V5

d29yZHM+PGtleXdvcmQ+QWRvbGVzY2VudDwva2V5d29yZD48a2V5d29yZD5BdXRpc3RpYyBEaXNv

cmRlci8qY29tcGxpY2F0aW9ucy8qZXBpZGVtaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJhY3Rl

cm9pZGFjZWFlIEluZmVjdGlvbnMvKmNvbXBsaWNhdGlvbnMvKmVwaWRlbWlvbG9neTwva2V5d29y

ZD48a2V5d29yZD5CaW9kaXZlcnNpdHk8L2tleXdvcmQ+PGtleXdvcmQ+Q2hpbGQ8L2tleXdvcmQ+

PGtleXdvcmQ+Q2hpbGQsIFByZXNjaG9vbDwva2V5d29yZD48a2V5d29yZD5DbHVzdGVyIEFuYWx5

c2lzPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5HYXN0cm9pbnRl

c3RpbmFsIERpc2Vhc2VzL2NvbXBsaWNhdGlvbnMvZXBpZGVtaW9sb2d5L21pY3JvYmlvbG9neTwv

a2V5d29yZD48a2V5d29yZD5HYXN0cm9pbnRlc3RpbmFsIFRyYWN0LyptaWNyb2Jpb2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkluY2lkZW5jZTwva2V5d29y

ZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1ldGFnZW5vbWU8L2tleXdvcmQ+PGtl

eXdvcmQ+TWljcm9iaW90YTwva2V5d29yZD48a2V5d29yZD5QaHlsb2dlbnk8L2tleXdvcmQ+PGtl

eXdvcmQ+UHJldm90ZWxsYS9jbGFzc2lmaWNhdGlvbi9nZW5ldGljcy8qaXNvbGF0aW9uICZhbXA7

IHB1cmlmaWNhdGlvbjwva2V5d29yZD48a2V5d29yZD5ST0MgQ3VydmU8L2tleXdvcmQ+PC9rZXl3

b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48L2RhdGVzPjxpc2JuPjE5MzItNjIwMyAoRWxl

Y3Ryb25pYykmI3hEOzE5MzItNjIwMyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjM4

NDQxODc8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3

Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODQ0MTg3PC91cmw+PC9yZWxhdGVkLXVybHM+PC91

cmxzPjxjdXN0b20yPlBNQzM3MDA4NTg8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjEwLjEzNzEvam91cm5hbC5wb25lLjAwNjgzMjI8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwv

cmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYW5nPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj

TnVtPjQyNTY8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4y

NTg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40MjU2PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzcxOTAzODEiPjQyNTY8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkthbmcsIEQuIFcuPC9hdXRob3I+PGF1dGhv

cj5QYXJrLCBKLiBHLjwvYXV0aG9yPjxhdXRob3I+SWxoYW4sIFouIEUuPC9hdXRob3I+PGF1dGhv

cj5XYWxsc3Ryb20sIEcuPC9hdXRob3I+PGF1dGhvcj5MYWJhZXIsIEouPC9hdXRob3I+PGF1dGhv

cj5BZGFtcywgSi4gQi48L2F1dGhvcj48YXV0aG9yPktyYWptYWxuaWstQnJvd24sIFIuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+U3dldHRlIENlbnRlciBm

b3IgRW52aXJvbm1lbnRhbCBCaW90ZWNobm9sb2d5LCBCaW9kZXNpZ24gSW5zdGl0dXRlLCBBcml6

b25hIFN0YXRlIFVuaXZlcnNpdHksIFRlbXBlLCBBcml6b25hLCBVbml0ZWQgU3RhdGVzIG9mIEFt

ZXJpY2EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UmVkdWNlZCBpbmNpZGVuY2Ugb2Yg

UHJldm90ZWxsYSBhbmQgb3RoZXIgZmVybWVudGVycyBpbiBpbnRlc3RpbmFsIG1pY3JvZmxvcmEg

b2YgYXV0aXN0aWMgY2hpbGRyZW48L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UExvUyBPbmU8L3Nl

Y29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5QTG9TIE9uZTwv

ZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPmU2ODMyMjwvcGFnZXM+PHZvbHVtZT44PC92

b2x1bWU+PG51bWJlcj43PC9udW1iZXI+PGVkaXRpb24+MjAxMy8wNy8xMjwvZWRpdGlvbj48a2V5

d29yZHM+PGtleXdvcmQ+QWRvbGVzY2VudDwva2V5d29yZD48a2V5d29yZD5BdXRpc3RpYyBEaXNv

cmRlci8qY29tcGxpY2F0aW9ucy8qZXBpZGVtaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJhY3Rl

cm9pZGFjZWFlIEluZmVjdGlvbnMvKmNvbXBsaWNhdGlvbnMvKmVwaWRlbWlvbG9neTwva2V5d29y

ZD48a2V5d29yZD5CaW9kaXZlcnNpdHk8L2tleXdvcmQ+PGtleXdvcmQ+Q2hpbGQ8L2tleXdvcmQ+

PGtleXdvcmQ+Q2hpbGQsIFByZXNjaG9vbDwva2V5d29yZD48a2V5d29yZD5DbHVzdGVyIEFuYWx5

c2lzPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5HYXN0cm9pbnRl

c3RpbmFsIERpc2Vhc2VzL2NvbXBsaWNhdGlvbnMvZXBpZGVtaW9sb2d5L21pY3JvYmlvbG9neTwv

a2V5d29yZD48a2V5d29yZD5HYXN0cm9pbnRlc3RpbmFsIFRyYWN0LyptaWNyb2Jpb2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkluY2lkZW5jZTwva2V5d29y

ZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1ldGFnZW5vbWU8L2tleXdvcmQ+PGtl

eXdvcmQ+TWljcm9iaW90YTwva2V5d29yZD48a2V5d29yZD5QaHlsb2dlbnk8L2tleXdvcmQ+PGtl

eXdvcmQ+UHJldm90ZWxsYS9jbGFzc2lmaWNhdGlvbi9nZW5ldGljcy8qaXNvbGF0aW9uICZhbXA7

IHB1cmlmaWNhdGlvbjwva2V5d29yZD48a2V5d29yZD5ST0MgQ3VydmU8L2tleXdvcmQ+PC9rZXl3

b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48L2RhdGVzPjxpc2JuPjE5MzItNjIwMyAoRWxl

Y3Ryb25pYykmI3hEOzE5MzItNjIwMyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjM4

NDQxODc8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3

Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODQ0MTg3PC91cmw+PC9yZWxhdGVkLXVybHM+PC91

cmxzPjxjdXN0b20yPlBNQzM3MDA4NTg8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjEwLjEzNzEvam91cm5hbC5wb25lLjAwNjgzMjI8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwv

cmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 258 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZSBBbmdlbGlzPC9BdXRob3I+PFllYXI+MjAxMzwvWWVh

cj48UmVjTnVtPjQyNTc8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2Ny

aXB0Ij4yNTk8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40MjU3PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzcxOTA0NTUiPjQyNTc8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkRlIEFuZ2VsaXMsIE0uPC9hdXRo

b3I+PGF1dGhvcj5QaWNjb2xvLCBNLjwvYXV0aG9yPjxhdXRob3I+VmFubmluaSwgTC48L2F1dGhv

cj48YXV0aG9yPlNpcmFndXNhLCBTLjwvYXV0aG9yPjxhdXRob3I+RGUgR2lhY29tbywgQS48L2F1

dGhvcj48YXV0aG9yPlNlcnJhenphbmV0dGksIEQuIEkuPC9hdXRob3I+PGF1dGhvcj5DcmlzdG9m

b3JpLCBGLjwvYXV0aG9yPjxhdXRob3I+R3VlcnpvbmksIE0uIEUuPC9hdXRob3I+PGF1dGhvcj5H

b2JiZXR0aSwgTS48L2F1dGhvcj48YXV0aG9yPkZyYW5jYXZpbGxhLCBSLjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgU29pbCwgUGxh

bnQgYW5kIEZvb2QgU2NpZW5jZXMsIFVuaXZlcnNpdHkgb2YgQmFyaSBBbGRvIE1vcm8sIEJhcmks

IEl0YWx5LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkZlY2FsIG1pY3JvYmlvdGEgYW5k

IG1ldGFib2xvbWUgb2YgY2hpbGRyZW4gd2l0aCBhdXRpc20gYW5kIHBlcnZhc2l2ZSBkZXZlbG9w

bWVudGFsIGRpc29yZGVyIG5vdCBvdGhlcndpc2Ugc3BlY2lmaWVkPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPlBMb1MgT25lPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1

bGwtdGl0bGU+UExvUyBPbmU8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz5lNzY5OTM8

L3BhZ2VzPjx2b2x1bWU+ODwvdm9sdW1lPjxudW1iZXI+MTA8L251bWJlcj48ZWRpdGlvbj4yMDEz

LzEwLzE3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbWlubyBBY2lkcy9tZXRhYm9saXNt

PC9rZXl3b3JkPjxrZXl3b3JkPkF1dGlzdGljIERpc29yZGVyLyptaWNyb2Jpb2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+QmFjdGVyaWEvZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29y

ZD5DaGlsZDwva2V5d29yZD48a2V5d29yZD5DaGlsZCBEZXZlbG9wbWVudCBEaXNvcmRlcnMsIFBl

cnZhc2l2ZS8qbWljcm9iaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNoaWxkLCBQcmVzY2hvb2w8

L2tleXdvcmQ+PGtleXdvcmQ+RmVjZXMvKm1pY3JvYmlvbG9neTwva2V5d29yZD48a2V5d29yZD5G

ZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tl

eXdvcmQ+PGtleXdvcmQ+Kk1ldGFib2xvbWU8L2tleXdvcmQ+PGtleXdvcmQ+TWljcm9iaW90YS8q

Z2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+U2VxdWVuY2UgQW5hbHlzaXM8L2tleXdvcmQ+PGtl

eXdvcmQ+Vm9sYXRpbGUgT3JnYW5pYyBDb21wb3VuZHMvbWV0YWJvbGlzbTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDEzPC95ZWFyPjwvZGF0ZXM+PGlzYm4+MTkzMi02MjAzIChF

bGVjdHJvbmljKSYjeEQ7MTkzMi02MjAzIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4y

NDEzMDgyMjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93

d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjQxMzA4MjI8L3VybD48L3JlbGF0ZWQtdXJscz48

L3VybHM+PGN1c3RvbTI+UE1DMzc5Mzk2NTwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+MTAuMTM3MS9qb3VybmFsLnBvbmUuMDA3Njk5MzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZSBBbmdlbGlzPC9BdXRob3I+PFllYXI+MjAxMzwvWWVh

cj48UmVjTnVtPjQyNTc8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2Ny

aXB0Ij4yNTk8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40MjU3PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzcxOTA0NTUiPjQyNTc8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkRlIEFuZ2VsaXMsIE0uPC9hdXRo

b3I+PGF1dGhvcj5QaWNjb2xvLCBNLjwvYXV0aG9yPjxhdXRob3I+VmFubmluaSwgTC48L2F1dGhv

cj48YXV0aG9yPlNpcmFndXNhLCBTLjwvYXV0aG9yPjxhdXRob3I+RGUgR2lhY29tbywgQS48L2F1

dGhvcj48YXV0aG9yPlNlcnJhenphbmV0dGksIEQuIEkuPC9hdXRob3I+PGF1dGhvcj5DcmlzdG9m

b3JpLCBGLjwvYXV0aG9yPjxhdXRob3I+R3VlcnpvbmksIE0uIEUuPC9hdXRob3I+PGF1dGhvcj5H

b2JiZXR0aSwgTS48L2F1dGhvcj48YXV0aG9yPkZyYW5jYXZpbGxhLCBSLjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgU29pbCwgUGxh

bnQgYW5kIEZvb2QgU2NpZW5jZXMsIFVuaXZlcnNpdHkgb2YgQmFyaSBBbGRvIE1vcm8sIEJhcmks

IEl0YWx5LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkZlY2FsIG1pY3JvYmlvdGEgYW5k

IG1ldGFib2xvbWUgb2YgY2hpbGRyZW4gd2l0aCBhdXRpc20gYW5kIHBlcnZhc2l2ZSBkZXZlbG9w

bWVudGFsIGRpc29yZGVyIG5vdCBvdGhlcndpc2Ugc3BlY2lmaWVkPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPlBMb1MgT25lPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1

bGwtdGl0bGU+UExvUyBPbmU8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz5lNzY5OTM8

L3BhZ2VzPjx2b2x1bWU+ODwvdm9sdW1lPjxudW1iZXI+MTA8L251bWJlcj48ZWRpdGlvbj4yMDEz

LzEwLzE3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbWlubyBBY2lkcy9tZXRhYm9saXNt

PC9rZXl3b3JkPjxrZXl3b3JkPkF1dGlzdGljIERpc29yZGVyLyptaWNyb2Jpb2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+QmFjdGVyaWEvZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29y

ZD5DaGlsZDwva2V5d29yZD48a2V5d29yZD5DaGlsZCBEZXZlbG9wbWVudCBEaXNvcmRlcnMsIFBl

cnZhc2l2ZS8qbWljcm9iaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNoaWxkLCBQcmVzY2hvb2w8

L2tleXdvcmQ+PGtleXdvcmQ+RmVjZXMvKm1pY3JvYmlvbG9neTwva2V5d29yZD48a2V5d29yZD5G

ZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tl

eXdvcmQ+PGtleXdvcmQ+Kk1ldGFib2xvbWU8L2tleXdvcmQ+PGtleXdvcmQ+TWljcm9iaW90YS8q

Z2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+U2VxdWVuY2UgQW5hbHlzaXM8L2tleXdvcmQ+PGtl

eXdvcmQ+Vm9sYXRpbGUgT3JnYW5pYyBDb21wb3VuZHMvbWV0YWJvbGlzbTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDEzPC95ZWFyPjwvZGF0ZXM+PGlzYm4+MTkzMi02MjAzIChF

bGVjdHJvbmljKSYjeEQ7MTkzMi02MjAzIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4y

NDEzMDgyMjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93

d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjQxMzA4MjI8L3VybD48L3JlbGF0ZWQtdXJscz48

L3VybHM+PGN1c3RvbTI+UE1DMzc5Mzk2NTwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+MTAuMTM3MS9qb3VybmFsLnBvbmUuMDA3Njk5MzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 259. It is important to note that one of the common features of these pathologies is the high levels of peripheral and central inflammation.Preclinical research indicates that beta-amyloid exerts antimicrobial properties PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb3NjaWE8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

ZWNOdW0+NDE0NDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI2MCwyNjE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40MTQ0PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzY3NzMzNjQiPjQxNDQ8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNvc2NpYSwgUy4gSi48L2F1dGhv

cj48YXV0aG9yPktpcmJ5LCBKLiBFLjwvYXV0aG9yPjxhdXRob3I+V2FzaGljb3NreSwgSy4gSi48

L2F1dGhvcj48YXV0aG9yPlR1Y2tlciwgUy4gTS48L2F1dGhvcj48YXV0aG9yPkluZ2Vsc3Nvbiwg

TS48L2F1dGhvcj48YXV0aG9yPkh5bWFuLCBCLjwvYXV0aG9yPjxhdXRob3I+QnVydG9uLCBNLiBB

LjwvYXV0aG9yPjxhdXRob3I+R29sZHN0ZWluLCBMLiBFLjwvYXV0aG9yPjxhdXRob3I+RHVvbmcs

IFMuPC9hdXRob3I+PGF1dGhvcj5UYW56aSwgUi4gRS48L2F1dGhvcj48YXV0aG9yPk1vaXIsIFIu

IEQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+R2VuZXRp

Y3MgYW5kIEFnaW5nIFJlc2VhcmNoIFVuaXQsIE1hc3MgR2VuZXJhbCBJbnN0aXR1dGUgZm9yIE5l

dXJvZGVnZW5lcmF0aXZlIERpc2Vhc2UgYW5kIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBNYXNz

YWNodXNldHRzIEdlbmVyYWwgSG9zcGl0YWwsIENoYXJsZXN0b3duLCBNYXNzYWNodXNldHRzLCBV

bml0ZWQgU3RhdGVzIG9mIEFtZXJpY2EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGhl

IEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZS1hc3NvY2lhdGVkIGFteWxvaWQgYmV0YS1wcm90ZWlu

IGlzIGFuIGFudGltaWNyb2JpYWwgcGVwdGlkZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5QTG9T

IE9uZTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlBM

b1MgT25lPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+ZTk1MDU8L3BhZ2VzPjx2b2x1

bWU+NTwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWlt

ZXIgRGlzZWFzZS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVw

dGlkZXMvbWV0YWJvbGlzbS8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5BbnRpbWljcm9i

aWFsIENhdGlvbmljIFBlcHRpZGVzLypwaGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QnJh

aW4vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNhbmRpZGEgYWxiaWNhbnMvbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5DZWxsIFN1cnZpdmFsPC9rZXl3b3JkPjxrZXl3b3JkPkVudmly

b25tZW50PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bml0

eSwgSW5uYXRlPC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29y

ZD5MaWdhbmRzPC9rZXl3b3JkPjxrZXl3b3JkPk1pY3JvYmlhbCBTZW5zaXRpdml0eSBUZXN0czwv

a2V5d29yZD48a2V5d29yZD5PeGF6aW5lcy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

UmVjb21iaW5hbnQgUHJvdGVpbnMvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPlhhbnRoZW5l

cy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMDwveWVh

cj48cHViLWRhdGVzPjxkYXRlPk1hciAzPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+

MTkzMi02MjAzIChFbGVjdHJvbmljKSYjeEQ7MTkzMi02MjAzIChMaW5raW5nKTwvaXNibj48YWNj

ZXNzaW9uLW51bT4yMDIwOTA3OTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1

cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMDIwOTA3OTwvdXJsPjwvcmVs

YXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUMyODMxMDY2PC9jdXN0b20yPjxlbGVjdHJvbmlj

LXJlc291cmNlLW51bT4xMC4xMzcxL2pvdXJuYWwucG9uZS4wMDA5NTA1PC9lbGVjdHJvbmljLXJl

c291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5LdW1hcjwvQXV0aG9yPjxZ

ZWFyPjIwMTY8L1llYXI+PFJlY051bT40MTQ2PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj40

MTQ2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4

NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzY3NzM0NTciPjQx

NDY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x

NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkt1bWFyLCBELiBLLjwv

YXV0aG9yPjxhdXRob3I+Q2hvaSwgUy4gSC48L2F1dGhvcj48YXV0aG9yPldhc2hpY29za3ksIEsu

IEouPC9hdXRob3I+PGF1dGhvcj5FaW1lciwgVy4gQS48L2F1dGhvcj48YXV0aG9yPlR1Y2tlciwg

Uy48L2F1dGhvcj48YXV0aG9yPkdob2ZyYW5pLCBKLjwvYXV0aG9yPjxhdXRob3I+TGVma293aXR6

LCBBLjwvYXV0aG9yPjxhdXRob3I+TWNDb2xsLCBHLjwvYXV0aG9yPjxhdXRob3I+R29sZHN0ZWlu

LCBMLiBFLjwvYXV0aG9yPjxhdXRob3I+VGFuemksIFIuIEUuPC9hdXRob3I+PGF1dGhvcj5Nb2ly

LCBSLiBELjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkdl

bmV0aWNzIGFuZCBBZ2luZyBSZXNlYXJjaCBVbml0LCBNYXNzR2VuZXJhbCBJbnN0aXR1dGUgZm9y

IE5ldXJvZGVnZW5lcmF0aXZlIERpc2Vhc2UsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBNYXNz

YWNodXNldHRzIEdlbmVyYWwgSG9zcGl0YWwgYW5kIEhhcnZhcmQgTWVkaWNhbCBTY2hvb2wsIENo

YXJsZXN0b3duLCBNQSAwMjEyOSwgVVNBLiYjeEQ7VGhlIEZsb3JleSBJbnN0aXR1dGUgb2YgTmV1

cm9zY2llbmNlIGFuZCBNZW50YWwgSGVhbHRoLCBVbml2ZXJzaXR5IG9mIE1lbGJvdXJuZSwgUGFy

a3ZpbGxlLCBWaWN0b3JpYSAzMDUyLCBBdXN0cmFsaWEuJiN4RDtEZXBhcnRtZW50IG9mIFBzeWNo

aWF0cnksIEJvc3RvbiBVbml2ZXJzaXR5LCBCb3N0b24sIE1BIDAyMjE1LCBVU0EuJiN4RDtHZW5l

dGljcyBhbmQgQWdpbmcgUmVzZWFyY2ggVW5pdCwgTWFzc0dlbmVyYWwgSW5zdGl0dXRlIGZvciBO

ZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlLCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgTWFzc2Fj

aHVzZXR0cyBHZW5lcmFsIEhvc3BpdGFsIGFuZCBIYXJ2YXJkIE1lZGljYWwgU2Nob29sLCBDaGFy

bGVzdG93biwgTUEgMDIxMjksIFVTQS4gbW9pckBoZWxpeC5tZ2guaGFydmFyZC5lZHUgdGFuemlA

aGVsaXgubWdoLmhhcnZhcmQuZWR1LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkFteWxv

aWQtYmV0YSBwZXB0aWRlIHByb3RlY3RzIGFnYWluc3QgbWljcm9iaWFsIGluZmVjdGlvbiBpbiBt

b3VzZSBhbmQgd29ybSBtb2RlbHMgb2YgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48

c2Vjb25kYXJ5LXRpdGxlPlNjaSBUcmFuc2wgTWVkPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+U2NpIFRyYW5zbCBNZWQ8L2Z1bGwtdGl0bGU+PC9wZXJp

b2RpY2FsPjxwYWdlcz4zNDByYTcyPC9wYWdlcz48dm9sdW1lPjg8L3ZvbHVtZT48bnVtYmVyPjM0

MDwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9nZW5ldGljcy8q

bWV0YWJvbGlzbS8qbWljcm9iaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1Q

ZXB0aWRlcy9nZW5ldGljcy8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9r

ZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHMsIEdlbmV0aWNhbGx5IE1vZGlmaWVkPC9rZXl3b3JkPjxr

ZXl3b3JkPkNhZW5vcmhhYmRpdGlzIGVsZWdhbnMvZ2VuZXRpY3MvKm1ldGFib2xpc20vKm1pY3Jv

YmlvbG9neTwva2V5d29yZD48a2V5d29yZD5EaXNlYXNlIE1vZGVscywgQW5pbWFsPC9rZXl3b3Jk

PjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdv

cmQ+SW1tdW5pdHksIElubmF0ZS9nZW5ldGljcy9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

Pk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgVHJhbnNnZW5pYzwva2V5d29yZD48a2V5d29y

ZD5TYWxtb25lbGxhIHR5cGhpbXVyaXVtL3BhdGhvZ2VuaWNpdHk8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1heSAyNTwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE5NDYtNjI0MiAoRWxlY3Ryb25pYykmI3hEOzE5NDYt

NjIzNCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjcyMjUxODI8L2FjY2Vzc2lvbi1u

dW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9w

dWJtZWQvMjcyMjUxODI8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNTUw

NTU2NTwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTEyNi9zY2l0cmFuc2xt

ZWQuYWFmMTA1OTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5k

Tm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb3NjaWE8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

ZWNOdW0+NDE0NDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI2MCwyNjE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40MTQ0PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzY3NzMzNjQiPjQxNDQ8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNvc2NpYSwgUy4gSi48L2F1dGhv

cj48YXV0aG9yPktpcmJ5LCBKLiBFLjwvYXV0aG9yPjxhdXRob3I+V2FzaGljb3NreSwgSy4gSi48

L2F1dGhvcj48YXV0aG9yPlR1Y2tlciwgUy4gTS48L2F1dGhvcj48YXV0aG9yPkluZ2Vsc3Nvbiwg

TS48L2F1dGhvcj48YXV0aG9yPkh5bWFuLCBCLjwvYXV0aG9yPjxhdXRob3I+QnVydG9uLCBNLiBB

LjwvYXV0aG9yPjxhdXRob3I+R29sZHN0ZWluLCBMLiBFLjwvYXV0aG9yPjxhdXRob3I+RHVvbmcs

IFMuPC9hdXRob3I+PGF1dGhvcj5UYW56aSwgUi4gRS48L2F1dGhvcj48YXV0aG9yPk1vaXIsIFIu

IEQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+R2VuZXRp

Y3MgYW5kIEFnaW5nIFJlc2VhcmNoIFVuaXQsIE1hc3MgR2VuZXJhbCBJbnN0aXR1dGUgZm9yIE5l

dXJvZGVnZW5lcmF0aXZlIERpc2Vhc2UgYW5kIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBNYXNz

YWNodXNldHRzIEdlbmVyYWwgSG9zcGl0YWwsIENoYXJsZXN0b3duLCBNYXNzYWNodXNldHRzLCBV

bml0ZWQgU3RhdGVzIG9mIEFtZXJpY2EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGhl

IEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZS1hc3NvY2lhdGVkIGFteWxvaWQgYmV0YS1wcm90ZWlu

IGlzIGFuIGFudGltaWNyb2JpYWwgcGVwdGlkZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5QTG9T

IE9uZTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlBM

b1MgT25lPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+ZTk1MDU8L3BhZ2VzPjx2b2x1

bWU+NTwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWlt

ZXIgRGlzZWFzZS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVw

dGlkZXMvbWV0YWJvbGlzbS8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5BbnRpbWljcm9i

aWFsIENhdGlvbmljIFBlcHRpZGVzLypwaGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QnJh

aW4vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNhbmRpZGEgYWxiaWNhbnMvbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5DZWxsIFN1cnZpdmFsPC9rZXl3b3JkPjxrZXl3b3JkPkVudmly

b25tZW50PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bml0

eSwgSW5uYXRlPC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29y

ZD5MaWdhbmRzPC9rZXl3b3JkPjxrZXl3b3JkPk1pY3JvYmlhbCBTZW5zaXRpdml0eSBUZXN0czwv

a2V5d29yZD48a2V5d29yZD5PeGF6aW5lcy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

UmVjb21iaW5hbnQgUHJvdGVpbnMvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPlhhbnRoZW5l

cy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMDwveWVh

cj48cHViLWRhdGVzPjxkYXRlPk1hciAzPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+

MTkzMi02MjAzIChFbGVjdHJvbmljKSYjeEQ7MTkzMi02MjAzIChMaW5raW5nKTwvaXNibj48YWNj

ZXNzaW9uLW51bT4yMDIwOTA3OTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1

cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMDIwOTA3OTwvdXJsPjwvcmVs

YXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUMyODMxMDY2PC9jdXN0b20yPjxlbGVjdHJvbmlj

LXJlc291cmNlLW51bT4xMC4xMzcxL2pvdXJuYWwucG9uZS4wMDA5NTA1PC9lbGVjdHJvbmljLXJl

c291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5LdW1hcjwvQXV0aG9yPjxZ

ZWFyPjIwMTY8L1llYXI+PFJlY051bT40MTQ2PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj40

MTQ2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4

NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzY3NzM0NTciPjQx

NDY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x

NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkt1bWFyLCBELiBLLjwv

YXV0aG9yPjxhdXRob3I+Q2hvaSwgUy4gSC48L2F1dGhvcj48YXV0aG9yPldhc2hpY29za3ksIEsu

IEouPC9hdXRob3I+PGF1dGhvcj5FaW1lciwgVy4gQS48L2F1dGhvcj48YXV0aG9yPlR1Y2tlciwg

Uy48L2F1dGhvcj48YXV0aG9yPkdob2ZyYW5pLCBKLjwvYXV0aG9yPjxhdXRob3I+TGVma293aXR6

LCBBLjwvYXV0aG9yPjxhdXRob3I+TWNDb2xsLCBHLjwvYXV0aG9yPjxhdXRob3I+R29sZHN0ZWlu

LCBMLiBFLjwvYXV0aG9yPjxhdXRob3I+VGFuemksIFIuIEUuPC9hdXRob3I+PGF1dGhvcj5Nb2ly

LCBSLiBELjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkdl

bmV0aWNzIGFuZCBBZ2luZyBSZXNlYXJjaCBVbml0LCBNYXNzR2VuZXJhbCBJbnN0aXR1dGUgZm9y

IE5ldXJvZGVnZW5lcmF0aXZlIERpc2Vhc2UsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBNYXNz

YWNodXNldHRzIEdlbmVyYWwgSG9zcGl0YWwgYW5kIEhhcnZhcmQgTWVkaWNhbCBTY2hvb2wsIENo

YXJsZXN0b3duLCBNQSAwMjEyOSwgVVNBLiYjeEQ7VGhlIEZsb3JleSBJbnN0aXR1dGUgb2YgTmV1

cm9zY2llbmNlIGFuZCBNZW50YWwgSGVhbHRoLCBVbml2ZXJzaXR5IG9mIE1lbGJvdXJuZSwgUGFy

a3ZpbGxlLCBWaWN0b3JpYSAzMDUyLCBBdXN0cmFsaWEuJiN4RDtEZXBhcnRtZW50IG9mIFBzeWNo

aWF0cnksIEJvc3RvbiBVbml2ZXJzaXR5LCBCb3N0b24sIE1BIDAyMjE1LCBVU0EuJiN4RDtHZW5l

dGljcyBhbmQgQWdpbmcgUmVzZWFyY2ggVW5pdCwgTWFzc0dlbmVyYWwgSW5zdGl0dXRlIGZvciBO

ZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlLCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgTWFzc2Fj

aHVzZXR0cyBHZW5lcmFsIEhvc3BpdGFsIGFuZCBIYXJ2YXJkIE1lZGljYWwgU2Nob29sLCBDaGFy

bGVzdG93biwgTUEgMDIxMjksIFVTQS4gbW9pckBoZWxpeC5tZ2guaGFydmFyZC5lZHUgdGFuemlA

aGVsaXgubWdoLmhhcnZhcmQuZWR1LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkFteWxv

aWQtYmV0YSBwZXB0aWRlIHByb3RlY3RzIGFnYWluc3QgbWljcm9iaWFsIGluZmVjdGlvbiBpbiBt

b3VzZSBhbmQgd29ybSBtb2RlbHMgb2YgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48

c2Vjb25kYXJ5LXRpdGxlPlNjaSBUcmFuc2wgTWVkPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+U2NpIFRyYW5zbCBNZWQ8L2Z1bGwtdGl0bGU+PC9wZXJp

b2RpY2FsPjxwYWdlcz4zNDByYTcyPC9wYWdlcz48dm9sdW1lPjg8L3ZvbHVtZT48bnVtYmVyPjM0

MDwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9nZW5ldGljcy8q

bWV0YWJvbGlzbS8qbWljcm9iaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1Q

ZXB0aWRlcy9nZW5ldGljcy8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9r

ZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHMsIEdlbmV0aWNhbGx5IE1vZGlmaWVkPC9rZXl3b3JkPjxr

ZXl3b3JkPkNhZW5vcmhhYmRpdGlzIGVsZWdhbnMvZ2VuZXRpY3MvKm1ldGFib2xpc20vKm1pY3Jv

YmlvbG9neTwva2V5d29yZD48a2V5d29yZD5EaXNlYXNlIE1vZGVscywgQW5pbWFsPC9rZXl3b3Jk

PjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdv

cmQ+SW1tdW5pdHksIElubmF0ZS9nZW5ldGljcy9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

Pk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgVHJhbnNnZW5pYzwva2V5d29yZD48a2V5d29y

ZD5TYWxtb25lbGxhIHR5cGhpbXVyaXVtL3BhdGhvZ2VuaWNpdHk8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1heSAyNTwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE5NDYtNjI0MiAoRWxlY3Ryb25pYykmI3hEOzE5NDYt

NjIzNCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjcyMjUxODI8L2FjY2Vzc2lvbi1u

dW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9w

dWJtZWQvMjcyMjUxODI8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNTUw

NTU2NTwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTEyNi9zY2l0cmFuc2xt

ZWQuYWFmMTA1OTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5k

Tm90ZT5=

ADDIN EN.CITE.DATA 260,261 similar to those of a known anti-microbial agent (LL-37). Temporal lobes homogenates from AD patients inhibit Candida albicans growth, in a dose-dependent manner; supporting the idea that beta amyloid can have these antimicrobial properties. And, fungi have been found in the brain of Alzheimer’s disease patients, especially in the area where the beta-amyloid plaques are present ADDIN EN.CITE <EndNote><Cite><Author>Pisa</Author><Year>2015</Year><RecNum>4147</RecNum><DisplayText><style face="superscript">262</style></DisplayText><record><rec-number>4147</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1536773548">4147</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pisa, D.</author><author>Alonso, R.</author><author>Rabano, A.</author><author>Rodal, I.</author><author>Carrasco, L.</author></authors></contributors><auth-address>Centro de Biologia Molecular &quot;Severo Ochoa&quot;. c/Nicolas Cabrera, 1. Universidad Autonoma de Madrid. Cantoblanco. 28049 Madrid. Spain.&#xD;Department of Neuropathology and Tissue Bank, Unidad de Investigacion Proyecto Alzheimer, Fundacion CIEN, Instituto de Salud Carlos III, Madrid. Spain.</auth-address><titles><title>Different Brain Regions are Infected with Fungi in Alzheimer&apos;s Disease</title><secondary-title>Sci Rep</secondary-title></titles><periodical><full-title>Sci Rep</full-title></periodical><pages>15015</pages><volume>5</volume><keywords><keyword>Alzheimer Disease/*etiology/metabolism/*pathology</keyword><keyword>Brain/blood supply/metabolism/*microbiology/*pathology</keyword><keyword>Candida glabrata</keyword><keyword>Central Nervous System Fungal Infections/*complications/*microbiology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Hyphae</keyword><keyword>Immunohistochemistry</keyword><keyword>Male</keyword></keywords><dates><year>2015</year><pub-dates><date>Oct 15</date></pub-dates></dates><isbn>2045-2322 (Electronic)&#xD;2045-2322 (Linking)</isbn><accession-num>26468932</accession-num><urls><related-urls><url>. In a preclinical study, AD transgenic APP-PS1 mice have been shown not to deposit Aβ if raised germ-free, and the transfer of the gut microbiome from conventionally raised AD into germ-free mice re-instated brain Aβ accumulation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJhY2g8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS

ZWNOdW0+NDE0OTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI2Mzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQxNDk8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjc3MzU4MyI+NDE0OTwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SGFyYWNoLCBULjwvYXV0aG9yPjxhdXRo

b3I+TWFydW5ncnVhbmcsIE4uPC9hdXRob3I+PGF1dGhvcj5EdXRoaWxsZXVsLCBOLjwvYXV0aG9y

PjxhdXRob3I+Q2hlYXRoYW0sIFYuPC9hdXRob3I+PGF1dGhvcj5NYyBDb3ksIEsuIEQuPC9hdXRo

b3I+PGF1dGhvcj5Gcmlzb25pLCBHLjwvYXV0aG9yPjxhdXRob3I+TmVoZXIsIEouIEouPC9hdXRo

b3I+PGF1dGhvcj5GYWssIEYuPC9hdXRob3I+PGF1dGhvcj5KdWNrZXIsIE0uPC9hdXRob3I+PGF1

dGhvcj5MYXNzZXIsIFQuPC9hdXRob3I+PGF1dGhvcj5Cb2xtb250LCBULjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkxhYm9yYXRvaXJlIGQmYXBvcztPcHRp

cXVlIGJpb21lZGljYWxlLCBJbnN0aXR1dGUgb2YgTWljcm9lbmdpbmVlcmluZywgU2Nob29sIG9m

IEVuZ2luZWVyaW5nLCBFY29sZSBQb2x5dGVjaG5pcXVlIEZlZGVyYWxlIGRlIExhdXNhbm5lLCBD

SDEwMTUgTGF1c2FubmUsIFN3aXR6ZXJsYW5kLiYjeEQ7Rm9vZCBmb3IgSGVhbHRoIFNjaWVuY2Ug

Q2VudHJlLCBMdW5kIFVuaXZlcnNpdHksIE1lZGljb24gVmlsbGFnZSwgMjIzODEgTHVuZCwgU3dl

ZGVuLiYjeEQ7TXVjb3NhbCBJbW11bm9sb2d5IExhYiwgRGVwYXJ0bWVudCBvZiBDbGluaWNhbCBS

ZXNlYXJjaCwgVW5pdmVyc2l0eSBvZiBCZXJuLCBNdXJ0ZW5zdHJhc3NlLCAzNSBDSCAtIDMwMTAg

QmVybiwgU3dpdHplcmxhbmQuJiN4RDtNZW1vcnkgQ2xpbmljIGFuZCBMQU5WSUUgLSBMYWJvcmF0

b3J5IG9mIE5ldXJvaW1hZ2luZyBvZiBBZ2luZywgVW5pdmVyc2l0eSBIb3NwaXRhbHMgYW5kIFVu

aXZlcnNpdHkgb2YgR2VuZXZhLCBHZW5ldmEsIFN3aXR6ZXJsYW5kLiYjeEQ7R2VybWFuIENlbnRy

ZSBmb3IgTmV1cm9kZWdlbmVyYXRpdmUgRGlzZWFzZXMgKERaTkUpLCBUdWJpbmdlbiwgRC03MjA3

NiBUdWJpbmdlbiwgR2VybWFueS4mI3hEO0RlcGFydG1lbnQgb2YgQ2VsbHVsYXIgTmV1cm9sb2d5

LCBIZXJ0aWUgSW5zdGl0dXRlIGZvciBDbGluaWNhbCBCcmFpbiBSZXNlYXJjaCwgVW5pdmVyc2l0

eSBvZiBUdWJpbmdlbiwgRC03MjA3NiBUdWJpbmdlbiwgR2VybWFueS4mI3hEO1N0ZW1lZGljYSBJ

bnRlcm5hdGlvbmFsLCBBdmVudWUgZGUgU2V2ZWxpbiAyMCwgQ0gxMDA0IExhdXNhbm5lLCBTd2l0

emVybGFuZC48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5SZWR1Y3Rpb24gb2YgQWJldGEg

YW15bG9pZCBwYXRob2xvZ3kgaW4gQVBQUFMxIHRyYW5zZ2VuaWMgbWljZSBpbiB0aGUgYWJzZW5j

ZSBvZiBndXQgbWljcm9iaW90YTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5TY2kgUmVwPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+U2NpIFJlcDwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjQxODAyPC9wYWdlcz48dm9sdW1lPjc8L3ZvbHVt

ZT48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkZlYiA4PC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MjA0NS0yMzIyIChFbGVjdHJvbmljKSYjeEQ7MjA0NS0y

MzIyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yODE3NjgxOTwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8yODE3NjgxOTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM1Mjk3

MjQ3PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDM4L3NyZXA0MTgwMjwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJhY2g8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS

ZWNOdW0+NDE0OTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI2Mzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQxNDk8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjc3MzU4MyI+NDE0OTwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SGFyYWNoLCBULjwvYXV0aG9yPjxhdXRo

b3I+TWFydW5ncnVhbmcsIE4uPC9hdXRob3I+PGF1dGhvcj5EdXRoaWxsZXVsLCBOLjwvYXV0aG9y

PjxhdXRob3I+Q2hlYXRoYW0sIFYuPC9hdXRob3I+PGF1dGhvcj5NYyBDb3ksIEsuIEQuPC9hdXRo

b3I+PGF1dGhvcj5Gcmlzb25pLCBHLjwvYXV0aG9yPjxhdXRob3I+TmVoZXIsIEouIEouPC9hdXRo

b3I+PGF1dGhvcj5GYWssIEYuPC9hdXRob3I+PGF1dGhvcj5KdWNrZXIsIE0uPC9hdXRob3I+PGF1

dGhvcj5MYXNzZXIsIFQuPC9hdXRob3I+PGF1dGhvcj5Cb2xtb250LCBULjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkxhYm9yYXRvaXJlIGQmYXBvcztPcHRp

cXVlIGJpb21lZGljYWxlLCBJbnN0aXR1dGUgb2YgTWljcm9lbmdpbmVlcmluZywgU2Nob29sIG9m

IEVuZ2luZWVyaW5nLCBFY29sZSBQb2x5dGVjaG5pcXVlIEZlZGVyYWxlIGRlIExhdXNhbm5lLCBD

SDEwMTUgTGF1c2FubmUsIFN3aXR6ZXJsYW5kLiYjeEQ7Rm9vZCBmb3IgSGVhbHRoIFNjaWVuY2Ug

Q2VudHJlLCBMdW5kIFVuaXZlcnNpdHksIE1lZGljb24gVmlsbGFnZSwgMjIzODEgTHVuZCwgU3dl

ZGVuLiYjeEQ7TXVjb3NhbCBJbW11bm9sb2d5IExhYiwgRGVwYXJ0bWVudCBvZiBDbGluaWNhbCBS

ZXNlYXJjaCwgVW5pdmVyc2l0eSBvZiBCZXJuLCBNdXJ0ZW5zdHJhc3NlLCAzNSBDSCAtIDMwMTAg

QmVybiwgU3dpdHplcmxhbmQuJiN4RDtNZW1vcnkgQ2xpbmljIGFuZCBMQU5WSUUgLSBMYWJvcmF0

b3J5IG9mIE5ldXJvaW1hZ2luZyBvZiBBZ2luZywgVW5pdmVyc2l0eSBIb3NwaXRhbHMgYW5kIFVu

aXZlcnNpdHkgb2YgR2VuZXZhLCBHZW5ldmEsIFN3aXR6ZXJsYW5kLiYjeEQ7R2VybWFuIENlbnRy

ZSBmb3IgTmV1cm9kZWdlbmVyYXRpdmUgRGlzZWFzZXMgKERaTkUpLCBUdWJpbmdlbiwgRC03MjA3

NiBUdWJpbmdlbiwgR2VybWFueS4mI3hEO0RlcGFydG1lbnQgb2YgQ2VsbHVsYXIgTmV1cm9sb2d5

LCBIZXJ0aWUgSW5zdGl0dXRlIGZvciBDbGluaWNhbCBCcmFpbiBSZXNlYXJjaCwgVW5pdmVyc2l0

eSBvZiBUdWJpbmdlbiwgRC03MjA3NiBUdWJpbmdlbiwgR2VybWFueS4mI3hEO1N0ZW1lZGljYSBJ

bnRlcm5hdGlvbmFsLCBBdmVudWUgZGUgU2V2ZWxpbiAyMCwgQ0gxMDA0IExhdXNhbm5lLCBTd2l0

emVybGFuZC48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5SZWR1Y3Rpb24gb2YgQWJldGEg

YW15bG9pZCBwYXRob2xvZ3kgaW4gQVBQUFMxIHRyYW5zZ2VuaWMgbWljZSBpbiB0aGUgYWJzZW5j

ZSBvZiBndXQgbWljcm9iaW90YTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5TY2kgUmVwPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+U2NpIFJlcDwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjQxODAyPC9wYWdlcz48dm9sdW1lPjc8L3ZvbHVt

ZT48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkZlYiA4PC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MjA0NS0yMzIyIChFbGVjdHJvbmljKSYjeEQ7MjA0NS0y

MzIyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yODE3NjgxOTwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8yODE3NjgxOTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM1Mjk3

MjQ3PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDM4L3NyZXA0MTgwMjwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 263.A theoretical framework integrating the current hypotheses in AD and microbiota-mediated inflammation would look as follows: Intestinal lumen is sensible to signals coming from microorganisms and directly from the diet. These signals activate inflammatory mediators in the gut mucosa and submucosal layers, which can generate adaptive responses through antimicrobial and active peptides. The generated peptides can be secreted into the lumen to help maintain homeostasis. Simultaneously, effector cells will secrete chemokines to the blood stream that are able to communicate to the central nervous system (CNS) by and/or through the BBB. In response to the gut signaling, inflammatory cells in the brain can activate the complement C1q, activate inflammatory receptors such as RAGE and modulate deposition of Aβ. Nevertheless, the presence of gut metabolites and miocrobiota-induced inflammation in the brain of man require more research for confirmation and further characterization (Fig. 4).The landscape of a specific AD microbiomeIn a group of patients with Alzheimer’s disease, bacteria with known pro-inflammatory properties and anti-inflammatory properties were analyzed PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXR0YW5lbzwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+

PFJlY051bT40MTY2PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjY0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDE2NjwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2NzczODEwIj40MTY2PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DYXR0YW5lbywgQS48L2F1dGhvcj48

YXV0aG9yPkNhdHRhbmUsIE4uPC9hdXRob3I+PGF1dGhvcj5HYWxsdXp6aSwgUy48L2F1dGhvcj48

YXV0aG9yPlByb3Zhc2ksIFMuPC9hdXRob3I+PGF1dGhvcj5Mb3BpenpvLCBOLjwvYXV0aG9yPjxh

dXRob3I+RmVzdGFyaSwgQy48L2F1dGhvcj48YXV0aG9yPkZlcnJhcmksIEMuPC9hdXRob3I+PGF1

dGhvcj5HdWVycmEsIFUuIFAuPC9hdXRob3I+PGF1dGhvcj5QYWdoZXJhLCBCLjwvYXV0aG9yPjxh

dXRob3I+TXVzY2lvLCBDLjwvYXV0aG9yPjxhdXRob3I+QmlhbmNoZXR0aSwgQS48L2F1dGhvcj48

YXV0aG9yPlZvbHRhLCBHLiBELjwvYXV0aG9yPjxhdXRob3I+VHVybGEsIE0uPC9hdXRob3I+PGF1

dGhvcj5Db3RlbGxpLCBNLiBTLjwvYXV0aG9yPjxhdXRob3I+R2VubnVzbywgTS48L2F1dGhvcj48

YXV0aG9yPlByZWxsZSwgQS48L2F1dGhvcj48YXV0aG9yPlphbmV0dGksIE8uPC9hdXRob3I+PGF1

dGhvcj5MdXNzaWdub2xpLCBHLjwvYXV0aG9yPjxhdXRob3I+TWlyYWJpbGUsIEQuPC9hdXRob3I+

PGF1dGhvcj5CZWxsYW5kaSwgRC48L2F1dGhvcj48YXV0aG9yPkdlbnRpbGUsIFMuPC9hdXRob3I+

PGF1dGhvcj5CZWxvdHRpLCBHLjwvYXV0aG9yPjxhdXRob3I+VmlsbGFuaSwgRC48L2F1dGhvcj48

YXV0aG9yPkhhcmFjaCwgVC48L2F1dGhvcj48YXV0aG9yPkJvbG1vbnQsIFQuPC9hdXRob3I+PGF1

dGhvcj5QYWRvdmFuaSwgQS48L2F1dGhvcj48YXV0aG9yPkJvY2NhcmRpLCBNLjwvYXV0aG9yPjxh

dXRob3I+RnJpc29uaSwgRy4gQi48L2F1dGhvcj48YXV0aG9yPkluZGlhLUZicCBHcm91cDwvYXV0

aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkJpb2xvZ2ljYWwgUHN5

Y2hpYXRyeSBMYWJvcmF0b3J5LCBJUkNDUyBGYXRlYmVuZWZyYXRlbGxpLCBCcmVzY2lhLCBJdGFs

eTsgS2luZyZhcG9zO3MgQ29sbGVnZSBMb25kb24sIEluc3RpdHV0ZSBvZiBQc3ljaGlhdHJ5LCBM

b25kb24sIFVLLiBFbGVjdHJvbmljIGFkZHJlc3M6IGFjYXR0YW5lb0BmYXRlYmVuZWZyYXRlbGxp

LmV1LiYjeEQ7QmlvbG9naWNhbCBQc3ljaGlhdHJ5IExhYm9yYXRvcnksIElSQ0NTIEZhdGViZW5l

ZnJhdGVsbGksIEJyZXNjaWEsIEl0YWx5LiYjeEQ7TGFib3JhdG9yeSBvZiBOZXVyb2ltYWdpbmcg

YW5kIEFsemhlaW1lciZhcG9zO3MgRXBpZGVtaW9sb2d5LCBJUkNDUyBDZW50cm8gU2FuIEdpb3Zh

bm5pIGRpIERpbyBGYXRlYmVuZWZyYXRlbGxpLCBCcmVzY2lhLCBJdGFseS4mI3hEO051Y2xlYXIg

TWVkaWNpbmUsIFBvbGlhbWJ1bGFuemEgRm91bmRhdGlvbiwgSXN0aXR1dG8gT3NwZWRhbGllcm8s

IEJyZXNjaWEsIEl0YWx5LiYjeEQ7TnVjbGVhciBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBCcmVz

Y2lhIGFuZCBTcGVkYWxpIENpdmlsaSBkaSBCcmVzY2lhLCBCcmVzY2lhLCBJdGFseS4mI3hEO0Jp

b2xvZ2ljYWwgUHN5Y2hpYXRyeSBMYWJvcmF0b3J5LCBJUkNDUyBGYXRlYmVuZWZyYXRlbGxpLCBC

cmVzY2lhLCBJdGFseTsgRXVyb3BlYW4gRm91bmRhdGlvbiBCaW9tZWRpY2FsIFJlc2VhcmNoIChG

RVJCKSwgQ2VudGVyIG9mIEV4Y2VsbGVuY2UgQWx6aGVpbWVyLCBPc3BlZGFsZSBCcmlvbGluaSwg

R2F6emFuaWdhLCBCZXJnYW1vLCBJdGFseS4mI3hEO0RlcGFydG1lbnQgb2YgTWVkaWNpbmUgYW5k

IFJlaGFiaWxpdGF0aW9uLCBJc3RpdHV0byBDbGluaWNvIFNhbnQmYXBvcztBbm5hLCBCcmVzY2lh

LCBJdGFseS4mI3hEO05ldXJvbG9neSBVbml0LCBJc3RpdHV0byBDbGluaWNvIENpdHRhIGRpIEJy

ZXNjaWEsIEJyZXNjaWEsIEl0YWx5LiYjeEQ7TmV1cm9sb2d5IFVuaXQsIE9zcGVkYWxlIGRpIFZh

bGxlY2Ftb25pY2EgRXNpbmUsIEJyZXNjaWEsIEl0YWx5LiYjeEQ7TmV1cm9sb2d5IFVuaXQsIE9z

cGVkYWxlIE1hZ2dpb3JlIGRpIENyZW1hLCBDcmVtb25hLCBJdGFseS4mI3hEO0V1cm9wZWFuIEZv

dW5kYXRpb24gQmlvbWVkaWNhbCBSZXNlYXJjaCAoRkVSQiksIENlbnRlciBvZiBFeGNlbGxlbmNl

IEFsemhlaW1lciwgT3NwZWRhbGUgQnJpb2xpbmksIEdhenphbmlnYSwgQmVyZ2FtbywgSXRhbHku

JiN4RDtBbHpoZWltZXIgRXZhbHVhdGlvbiBVbml0LCBJc3RpdHV0byBPc3BlZGFsaWVybyBkaSBT

b3NwaXJvIE9OTFVTIEZvdW5kYXRpb24sIENyZW1vbmEsIEl0YWx5LiYjeEQ7RGVwYXJ0bWVudCBv

ZiBSZWhhYmlsaXRhdGlvbiwgQ2FzYSBkaSBDdXJhIEFuY2VsbGUgZGVsbGEgQ2FyaXRhLCBDcmVt

b25hLCBJdGFseS4mI3hEO0FsemhlaW1lciBFdmFsdWF0aW9uIFVuaXQsIEhvc3BpY2UgU2FudGEg

TWFyaWEgQXVzaWxpYXRyaWNlIE9OTFVTIEZvdW5kYXRpb24sIEJlcmdhbW8sIEl0YWx5LiYjeEQ7

QWx6aGVpbWVyIEV2YWx1YXRpb24gVW5pdCwgQ2FzYSBkaSBDdXJhIEZpZ2xpZSBkaSBTLiBDYW1p

bGxvLCBDcmVtb25hLCBJdGFseS4mI3hEO0Vjb2xlIFBvbHl0ZWNobmlxdWUgRmVkZXJhbGUgZGUg

TGF1c2FubmUsIExhdXNhbm5lLCBTd2l0emVybGFuZC4mI3hEO1N0ZW1lZGljYSBJbnRlcm5hdGlv

bmFsIFNBLCBMYXVzYW5uZSwgU3dpdHplcmxhbmQuJiN4RDtOZXVyb2xvZ3kgVW5pdCwgRGVwYXJ0

bWVudCBvZiBNZWRpY2FsIGFuZCBFeHBlcmltZW50YWwgU2NpZW5jZXMsIFVuaXZlcnNpdHkgb2Yg

QnJlc2NpYSwgQnJlc2NpYSwgSXRhbHkuJiN4RDtMYWJvcmF0b3J5IG9mIE5ldXJvaW1hZ2luZyBh

bmQgQWx6aGVpbWVyJmFwb3M7cyBFcGlkZW1pb2xvZ3ksIElSQ0NTIENlbnRybyBTYW4gR2lvdmFu

bmkgZGkgRGlvIEZhdGViZW5lZnJhdGVsbGksIEJyZXNjaWEsIEl0YWx5OyBMQU5WSUUtTGFib3Jh

dG9yeSBvZiBOZXVyb2ltYWdpbmcgb2YgQWdpbmcsIFVuaXZlcnNpdHkgSG9zcGl0YWxzLCBHZW5l

dmEsIFN3aXR6ZXJsYW5kOyBNZW1vcnkgQ2xpbmljLCBVbml2ZXJzaXR5IEhvc3BpdGFscyBhbmQg

VW5pdmVyc2l0eSBvZiBHZW5ldmEsIEdlbmV2YSwgU3dpdHplcmxhbmQuPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+QXNzb2NpYXRpb24gb2YgYnJhaW4gYW15bG9pZG9zaXMgd2l0aCBwcm8t

aW5mbGFtbWF0b3J5IGd1dCBiYWN0ZXJpYWwgdGF4YSBhbmQgcGVyaXBoZXJhbCBpbmZsYW1tYXRp

b24gbWFya2VycyBpbiBjb2duaXRpdmVseSBpbXBhaXJlZCBlbGRlcmx5PC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPk5ldXJvYmlvbCBBZ2luZzwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJp

b2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvYmlvbCBBZ2luZzwvZnVsbC10aXRsZT48L3BlcmlvZGlj

YWw+PHBhZ2VzPjYwLTY4PC9wYWdlcz48dm9sdW1lPjQ5PC92b2x1bWU+PGtleXdvcmRzPjxrZXl3

b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmV0aW9sb2d5L21l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL21ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5D

b2duaXRpb24gRGlzb3JkZXJzLypldGlvbG9neS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

PkN5dG9raW5lcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48

a2V5d29yZD5HYXN0cm9pbnRlc3RpbmFsIE1pY3JvYmlvbWUvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1hdGlvbi8qZXRpb2xvZ3kv

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb24gTWVkaWF0b3JzL21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXN0aW5lcy8qbWljcm9iaW9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+UGxhcXVlLCBBbXlsb2lkL2V0aW9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+KkJyYWluIGFteWxvaWRvc2lzPC9rZXl3b3JkPjxrZXl3b3JkPipDb2duaXRpdmUgaW1wYWly

bWVudDwva2V5d29yZD48a2V5d29yZD4qR3V0IG1pY3JvYmlvdGE8L2tleXdvcmQ+PGtleXdvcmQ+

KkluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD4qTmV1cm9kZWdlbmVyYXRpb248L2tleXdv

cmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkph

bjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTgtMTQ5NyAoRWxlY3Ryb25pYykm

I3hEOzAxOTctNDU4MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjc3NzYyNjM8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMjc3NzYyNjM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb2Jpb2xhZ2luZy4yMDE2LjA4LjAxOTwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXR0YW5lbzwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+

PFJlY051bT40MTY2PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjY0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDE2NjwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2NzczODEwIj40MTY2PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DYXR0YW5lbywgQS48L2F1dGhvcj48

YXV0aG9yPkNhdHRhbmUsIE4uPC9hdXRob3I+PGF1dGhvcj5HYWxsdXp6aSwgUy48L2F1dGhvcj48

YXV0aG9yPlByb3Zhc2ksIFMuPC9hdXRob3I+PGF1dGhvcj5Mb3BpenpvLCBOLjwvYXV0aG9yPjxh

dXRob3I+RmVzdGFyaSwgQy48L2F1dGhvcj48YXV0aG9yPkZlcnJhcmksIEMuPC9hdXRob3I+PGF1

dGhvcj5HdWVycmEsIFUuIFAuPC9hdXRob3I+PGF1dGhvcj5QYWdoZXJhLCBCLjwvYXV0aG9yPjxh

dXRob3I+TXVzY2lvLCBDLjwvYXV0aG9yPjxhdXRob3I+QmlhbmNoZXR0aSwgQS48L2F1dGhvcj48

YXV0aG9yPlZvbHRhLCBHLiBELjwvYXV0aG9yPjxhdXRob3I+VHVybGEsIE0uPC9hdXRob3I+PGF1

dGhvcj5Db3RlbGxpLCBNLiBTLjwvYXV0aG9yPjxhdXRob3I+R2VubnVzbywgTS48L2F1dGhvcj48

YXV0aG9yPlByZWxsZSwgQS48L2F1dGhvcj48YXV0aG9yPlphbmV0dGksIE8uPC9hdXRob3I+PGF1

dGhvcj5MdXNzaWdub2xpLCBHLjwvYXV0aG9yPjxhdXRob3I+TWlyYWJpbGUsIEQuPC9hdXRob3I+

PGF1dGhvcj5CZWxsYW5kaSwgRC48L2F1dGhvcj48YXV0aG9yPkdlbnRpbGUsIFMuPC9hdXRob3I+

PGF1dGhvcj5CZWxvdHRpLCBHLjwvYXV0aG9yPjxhdXRob3I+VmlsbGFuaSwgRC48L2F1dGhvcj48

YXV0aG9yPkhhcmFjaCwgVC48L2F1dGhvcj48YXV0aG9yPkJvbG1vbnQsIFQuPC9hdXRob3I+PGF1

dGhvcj5QYWRvdmFuaSwgQS48L2F1dGhvcj48YXV0aG9yPkJvY2NhcmRpLCBNLjwvYXV0aG9yPjxh

dXRob3I+RnJpc29uaSwgRy4gQi48L2F1dGhvcj48YXV0aG9yPkluZGlhLUZicCBHcm91cDwvYXV0

aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkJpb2xvZ2ljYWwgUHN5

Y2hpYXRyeSBMYWJvcmF0b3J5LCBJUkNDUyBGYXRlYmVuZWZyYXRlbGxpLCBCcmVzY2lhLCBJdGFs

eTsgS2luZyZhcG9zO3MgQ29sbGVnZSBMb25kb24sIEluc3RpdHV0ZSBvZiBQc3ljaGlhdHJ5LCBM

b25kb24sIFVLLiBFbGVjdHJvbmljIGFkZHJlc3M6IGFjYXR0YW5lb0BmYXRlYmVuZWZyYXRlbGxp

LmV1LiYjeEQ7QmlvbG9naWNhbCBQc3ljaGlhdHJ5IExhYm9yYXRvcnksIElSQ0NTIEZhdGViZW5l

ZnJhdGVsbGksIEJyZXNjaWEsIEl0YWx5LiYjeEQ7TGFib3JhdG9yeSBvZiBOZXVyb2ltYWdpbmcg

YW5kIEFsemhlaW1lciZhcG9zO3MgRXBpZGVtaW9sb2d5LCBJUkNDUyBDZW50cm8gU2FuIEdpb3Zh

bm5pIGRpIERpbyBGYXRlYmVuZWZyYXRlbGxpLCBCcmVzY2lhLCBJdGFseS4mI3hEO051Y2xlYXIg

TWVkaWNpbmUsIFBvbGlhbWJ1bGFuemEgRm91bmRhdGlvbiwgSXN0aXR1dG8gT3NwZWRhbGllcm8s

IEJyZXNjaWEsIEl0YWx5LiYjeEQ7TnVjbGVhciBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBCcmVz

Y2lhIGFuZCBTcGVkYWxpIENpdmlsaSBkaSBCcmVzY2lhLCBCcmVzY2lhLCBJdGFseS4mI3hEO0Jp

b2xvZ2ljYWwgUHN5Y2hpYXRyeSBMYWJvcmF0b3J5LCBJUkNDUyBGYXRlYmVuZWZyYXRlbGxpLCBC

cmVzY2lhLCBJdGFseTsgRXVyb3BlYW4gRm91bmRhdGlvbiBCaW9tZWRpY2FsIFJlc2VhcmNoIChG

RVJCKSwgQ2VudGVyIG9mIEV4Y2VsbGVuY2UgQWx6aGVpbWVyLCBPc3BlZGFsZSBCcmlvbGluaSwg

R2F6emFuaWdhLCBCZXJnYW1vLCBJdGFseS4mI3hEO0RlcGFydG1lbnQgb2YgTWVkaWNpbmUgYW5k

IFJlaGFiaWxpdGF0aW9uLCBJc3RpdHV0byBDbGluaWNvIFNhbnQmYXBvcztBbm5hLCBCcmVzY2lh

LCBJdGFseS4mI3hEO05ldXJvbG9neSBVbml0LCBJc3RpdHV0byBDbGluaWNvIENpdHRhIGRpIEJy

ZXNjaWEsIEJyZXNjaWEsIEl0YWx5LiYjeEQ7TmV1cm9sb2d5IFVuaXQsIE9zcGVkYWxlIGRpIFZh

bGxlY2Ftb25pY2EgRXNpbmUsIEJyZXNjaWEsIEl0YWx5LiYjeEQ7TmV1cm9sb2d5IFVuaXQsIE9z

cGVkYWxlIE1hZ2dpb3JlIGRpIENyZW1hLCBDcmVtb25hLCBJdGFseS4mI3hEO0V1cm9wZWFuIEZv

dW5kYXRpb24gQmlvbWVkaWNhbCBSZXNlYXJjaCAoRkVSQiksIENlbnRlciBvZiBFeGNlbGxlbmNl

IEFsemhlaW1lciwgT3NwZWRhbGUgQnJpb2xpbmksIEdhenphbmlnYSwgQmVyZ2FtbywgSXRhbHku

JiN4RDtBbHpoZWltZXIgRXZhbHVhdGlvbiBVbml0LCBJc3RpdHV0byBPc3BlZGFsaWVybyBkaSBT

b3NwaXJvIE9OTFVTIEZvdW5kYXRpb24sIENyZW1vbmEsIEl0YWx5LiYjeEQ7RGVwYXJ0bWVudCBv

ZiBSZWhhYmlsaXRhdGlvbiwgQ2FzYSBkaSBDdXJhIEFuY2VsbGUgZGVsbGEgQ2FyaXRhLCBDcmVt

b25hLCBJdGFseS4mI3hEO0FsemhlaW1lciBFdmFsdWF0aW9uIFVuaXQsIEhvc3BpY2UgU2FudGEg

TWFyaWEgQXVzaWxpYXRyaWNlIE9OTFVTIEZvdW5kYXRpb24sIEJlcmdhbW8sIEl0YWx5LiYjeEQ7

QWx6aGVpbWVyIEV2YWx1YXRpb24gVW5pdCwgQ2FzYSBkaSBDdXJhIEZpZ2xpZSBkaSBTLiBDYW1p

bGxvLCBDcmVtb25hLCBJdGFseS4mI3hEO0Vjb2xlIFBvbHl0ZWNobmlxdWUgRmVkZXJhbGUgZGUg

TGF1c2FubmUsIExhdXNhbm5lLCBTd2l0emVybGFuZC4mI3hEO1N0ZW1lZGljYSBJbnRlcm5hdGlv

bmFsIFNBLCBMYXVzYW5uZSwgU3dpdHplcmxhbmQuJiN4RDtOZXVyb2xvZ3kgVW5pdCwgRGVwYXJ0

bWVudCBvZiBNZWRpY2FsIGFuZCBFeHBlcmltZW50YWwgU2NpZW5jZXMsIFVuaXZlcnNpdHkgb2Yg

QnJlc2NpYSwgQnJlc2NpYSwgSXRhbHkuJiN4RDtMYWJvcmF0b3J5IG9mIE5ldXJvaW1hZ2luZyBh

bmQgQWx6aGVpbWVyJmFwb3M7cyBFcGlkZW1pb2xvZ3ksIElSQ0NTIENlbnRybyBTYW4gR2lvdmFu

bmkgZGkgRGlvIEZhdGViZW5lZnJhdGVsbGksIEJyZXNjaWEsIEl0YWx5OyBMQU5WSUUtTGFib3Jh

dG9yeSBvZiBOZXVyb2ltYWdpbmcgb2YgQWdpbmcsIFVuaXZlcnNpdHkgSG9zcGl0YWxzLCBHZW5l

dmEsIFN3aXR6ZXJsYW5kOyBNZW1vcnkgQ2xpbmljLCBVbml2ZXJzaXR5IEhvc3BpdGFscyBhbmQg

VW5pdmVyc2l0eSBvZiBHZW5ldmEsIEdlbmV2YSwgU3dpdHplcmxhbmQuPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+QXNzb2NpYXRpb24gb2YgYnJhaW4gYW15bG9pZG9zaXMgd2l0aCBwcm8t

aW5mbGFtbWF0b3J5IGd1dCBiYWN0ZXJpYWwgdGF4YSBhbmQgcGVyaXBoZXJhbCBpbmZsYW1tYXRp

b24gbWFya2VycyBpbiBjb2duaXRpdmVseSBpbXBhaXJlZCBlbGRlcmx5PC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPk5ldXJvYmlvbCBBZ2luZzwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJp

b2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvYmlvbCBBZ2luZzwvZnVsbC10aXRsZT48L3BlcmlvZGlj

YWw+PHBhZ2VzPjYwLTY4PC9wYWdlcz48dm9sdW1lPjQ5PC92b2x1bWU+PGtleXdvcmRzPjxrZXl3

b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmV0aW9sb2d5L21l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL21ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5D

b2duaXRpb24gRGlzb3JkZXJzLypldGlvbG9neS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

PkN5dG9raW5lcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48

a2V5d29yZD5HYXN0cm9pbnRlc3RpbmFsIE1pY3JvYmlvbWUvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1hdGlvbi8qZXRpb2xvZ3kv

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb24gTWVkaWF0b3JzL21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXN0aW5lcy8qbWljcm9iaW9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+UGxhcXVlLCBBbXlsb2lkL2V0aW9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+KkJyYWluIGFteWxvaWRvc2lzPC9rZXl3b3JkPjxrZXl3b3JkPipDb2duaXRpdmUgaW1wYWly

bWVudDwva2V5d29yZD48a2V5d29yZD4qR3V0IG1pY3JvYmlvdGE8L2tleXdvcmQ+PGtleXdvcmQ+

KkluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD4qTmV1cm9kZWdlbmVyYXRpb248L2tleXdv

cmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkph

bjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTgtMTQ5NyAoRWxlY3Ryb25pYykm

I3hEOzAxOTctNDU4MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjc3NzYyNjM8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMjc3NzYyNjM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb2Jpb2xhZ2luZy4yMDE2LjA4LjAxOTwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 264. In parallel, cytokines with known pro- and anti-inflammatory properties were assayed in the blood. Moreover, by using a hypothesis-free approach, the composition of the entire microbiome of these patients and controls was investigated. The results showed and imbalance between proinflammatory and anti-inflammatory bacteria species. AD patients had greater abundance of the pro-inflammatory Escherichia/Shigella and lower abundance of the anti-inflammatory B. fragilis and E. rectale. Blood analysis revealed higher levels of pro-inflammatory cytokines and factors in AD patients (NLRP3, CXCL2, IL-6, IL-1beta), and lower levels of the anti-inflammatory cytokine IL-10. Interestingly, higher levels of blood pro-inflammatory cytokines were associated with greater gut abundance of pro-inflammatory bacteria, and vice versa for anti-inflammatory cytokines and bacteriaPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXR0YW5lbzwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+

PFJlY051bT40MTY2PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjY0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDE2NjwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2NzczODEwIj40MTY2PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DYXR0YW5lbywgQS48L2F1dGhvcj48

YXV0aG9yPkNhdHRhbmUsIE4uPC9hdXRob3I+PGF1dGhvcj5HYWxsdXp6aSwgUy48L2F1dGhvcj48

YXV0aG9yPlByb3Zhc2ksIFMuPC9hdXRob3I+PGF1dGhvcj5Mb3BpenpvLCBOLjwvYXV0aG9yPjxh

dXRob3I+RmVzdGFyaSwgQy48L2F1dGhvcj48YXV0aG9yPkZlcnJhcmksIEMuPC9hdXRob3I+PGF1

dGhvcj5HdWVycmEsIFUuIFAuPC9hdXRob3I+PGF1dGhvcj5QYWdoZXJhLCBCLjwvYXV0aG9yPjxh

dXRob3I+TXVzY2lvLCBDLjwvYXV0aG9yPjxhdXRob3I+QmlhbmNoZXR0aSwgQS48L2F1dGhvcj48

YXV0aG9yPlZvbHRhLCBHLiBELjwvYXV0aG9yPjxhdXRob3I+VHVybGEsIE0uPC9hdXRob3I+PGF1

dGhvcj5Db3RlbGxpLCBNLiBTLjwvYXV0aG9yPjxhdXRob3I+R2VubnVzbywgTS48L2F1dGhvcj48

YXV0aG9yPlByZWxsZSwgQS48L2F1dGhvcj48YXV0aG9yPlphbmV0dGksIE8uPC9hdXRob3I+PGF1

dGhvcj5MdXNzaWdub2xpLCBHLjwvYXV0aG9yPjxhdXRob3I+TWlyYWJpbGUsIEQuPC9hdXRob3I+

PGF1dGhvcj5CZWxsYW5kaSwgRC48L2F1dGhvcj48YXV0aG9yPkdlbnRpbGUsIFMuPC9hdXRob3I+

PGF1dGhvcj5CZWxvdHRpLCBHLjwvYXV0aG9yPjxhdXRob3I+VmlsbGFuaSwgRC48L2F1dGhvcj48

YXV0aG9yPkhhcmFjaCwgVC48L2F1dGhvcj48YXV0aG9yPkJvbG1vbnQsIFQuPC9hdXRob3I+PGF1

dGhvcj5QYWRvdmFuaSwgQS48L2F1dGhvcj48YXV0aG9yPkJvY2NhcmRpLCBNLjwvYXV0aG9yPjxh

dXRob3I+RnJpc29uaSwgRy4gQi48L2F1dGhvcj48YXV0aG9yPkluZGlhLUZicCBHcm91cDwvYXV0

aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkJpb2xvZ2ljYWwgUHN5

Y2hpYXRyeSBMYWJvcmF0b3J5LCBJUkNDUyBGYXRlYmVuZWZyYXRlbGxpLCBCcmVzY2lhLCBJdGFs

eTsgS2luZyZhcG9zO3MgQ29sbGVnZSBMb25kb24sIEluc3RpdHV0ZSBvZiBQc3ljaGlhdHJ5LCBM

b25kb24sIFVLLiBFbGVjdHJvbmljIGFkZHJlc3M6IGFjYXR0YW5lb0BmYXRlYmVuZWZyYXRlbGxp

LmV1LiYjeEQ7QmlvbG9naWNhbCBQc3ljaGlhdHJ5IExhYm9yYXRvcnksIElSQ0NTIEZhdGViZW5l

ZnJhdGVsbGksIEJyZXNjaWEsIEl0YWx5LiYjeEQ7TGFib3JhdG9yeSBvZiBOZXVyb2ltYWdpbmcg

YW5kIEFsemhlaW1lciZhcG9zO3MgRXBpZGVtaW9sb2d5LCBJUkNDUyBDZW50cm8gU2FuIEdpb3Zh

bm5pIGRpIERpbyBGYXRlYmVuZWZyYXRlbGxpLCBCcmVzY2lhLCBJdGFseS4mI3hEO051Y2xlYXIg

TWVkaWNpbmUsIFBvbGlhbWJ1bGFuemEgRm91bmRhdGlvbiwgSXN0aXR1dG8gT3NwZWRhbGllcm8s

IEJyZXNjaWEsIEl0YWx5LiYjeEQ7TnVjbGVhciBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBCcmVz

Y2lhIGFuZCBTcGVkYWxpIENpdmlsaSBkaSBCcmVzY2lhLCBCcmVzY2lhLCBJdGFseS4mI3hEO0Jp

b2xvZ2ljYWwgUHN5Y2hpYXRyeSBMYWJvcmF0b3J5LCBJUkNDUyBGYXRlYmVuZWZyYXRlbGxpLCBC

cmVzY2lhLCBJdGFseTsgRXVyb3BlYW4gRm91bmRhdGlvbiBCaW9tZWRpY2FsIFJlc2VhcmNoIChG

RVJCKSwgQ2VudGVyIG9mIEV4Y2VsbGVuY2UgQWx6aGVpbWVyLCBPc3BlZGFsZSBCcmlvbGluaSwg

R2F6emFuaWdhLCBCZXJnYW1vLCBJdGFseS4mI3hEO0RlcGFydG1lbnQgb2YgTWVkaWNpbmUgYW5k

IFJlaGFiaWxpdGF0aW9uLCBJc3RpdHV0byBDbGluaWNvIFNhbnQmYXBvcztBbm5hLCBCcmVzY2lh

LCBJdGFseS4mI3hEO05ldXJvbG9neSBVbml0LCBJc3RpdHV0byBDbGluaWNvIENpdHRhIGRpIEJy

ZXNjaWEsIEJyZXNjaWEsIEl0YWx5LiYjeEQ7TmV1cm9sb2d5IFVuaXQsIE9zcGVkYWxlIGRpIFZh

bGxlY2Ftb25pY2EgRXNpbmUsIEJyZXNjaWEsIEl0YWx5LiYjeEQ7TmV1cm9sb2d5IFVuaXQsIE9z

cGVkYWxlIE1hZ2dpb3JlIGRpIENyZW1hLCBDcmVtb25hLCBJdGFseS4mI3hEO0V1cm9wZWFuIEZv

dW5kYXRpb24gQmlvbWVkaWNhbCBSZXNlYXJjaCAoRkVSQiksIENlbnRlciBvZiBFeGNlbGxlbmNl

IEFsemhlaW1lciwgT3NwZWRhbGUgQnJpb2xpbmksIEdhenphbmlnYSwgQmVyZ2FtbywgSXRhbHku

JiN4RDtBbHpoZWltZXIgRXZhbHVhdGlvbiBVbml0LCBJc3RpdHV0byBPc3BlZGFsaWVybyBkaSBT

b3NwaXJvIE9OTFVTIEZvdW5kYXRpb24sIENyZW1vbmEsIEl0YWx5LiYjeEQ7RGVwYXJ0bWVudCBv

ZiBSZWhhYmlsaXRhdGlvbiwgQ2FzYSBkaSBDdXJhIEFuY2VsbGUgZGVsbGEgQ2FyaXRhLCBDcmVt

b25hLCBJdGFseS4mI3hEO0FsemhlaW1lciBFdmFsdWF0aW9uIFVuaXQsIEhvc3BpY2UgU2FudGEg

TWFyaWEgQXVzaWxpYXRyaWNlIE9OTFVTIEZvdW5kYXRpb24sIEJlcmdhbW8sIEl0YWx5LiYjeEQ7

QWx6aGVpbWVyIEV2YWx1YXRpb24gVW5pdCwgQ2FzYSBkaSBDdXJhIEZpZ2xpZSBkaSBTLiBDYW1p

bGxvLCBDcmVtb25hLCBJdGFseS4mI3hEO0Vjb2xlIFBvbHl0ZWNobmlxdWUgRmVkZXJhbGUgZGUg

TGF1c2FubmUsIExhdXNhbm5lLCBTd2l0emVybGFuZC4mI3hEO1N0ZW1lZGljYSBJbnRlcm5hdGlv

bmFsIFNBLCBMYXVzYW5uZSwgU3dpdHplcmxhbmQuJiN4RDtOZXVyb2xvZ3kgVW5pdCwgRGVwYXJ0

bWVudCBvZiBNZWRpY2FsIGFuZCBFeHBlcmltZW50YWwgU2NpZW5jZXMsIFVuaXZlcnNpdHkgb2Yg

QnJlc2NpYSwgQnJlc2NpYSwgSXRhbHkuJiN4RDtMYWJvcmF0b3J5IG9mIE5ldXJvaW1hZ2luZyBh

bmQgQWx6aGVpbWVyJmFwb3M7cyBFcGlkZW1pb2xvZ3ksIElSQ0NTIENlbnRybyBTYW4gR2lvdmFu

bmkgZGkgRGlvIEZhdGViZW5lZnJhdGVsbGksIEJyZXNjaWEsIEl0YWx5OyBMQU5WSUUtTGFib3Jh

dG9yeSBvZiBOZXVyb2ltYWdpbmcgb2YgQWdpbmcsIFVuaXZlcnNpdHkgSG9zcGl0YWxzLCBHZW5l

dmEsIFN3aXR6ZXJsYW5kOyBNZW1vcnkgQ2xpbmljLCBVbml2ZXJzaXR5IEhvc3BpdGFscyBhbmQg

VW5pdmVyc2l0eSBvZiBHZW5ldmEsIEdlbmV2YSwgU3dpdHplcmxhbmQuPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+QXNzb2NpYXRpb24gb2YgYnJhaW4gYW15bG9pZG9zaXMgd2l0aCBwcm8t

aW5mbGFtbWF0b3J5IGd1dCBiYWN0ZXJpYWwgdGF4YSBhbmQgcGVyaXBoZXJhbCBpbmZsYW1tYXRp

b24gbWFya2VycyBpbiBjb2duaXRpdmVseSBpbXBhaXJlZCBlbGRlcmx5PC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPk5ldXJvYmlvbCBBZ2luZzwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJp

b2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvYmlvbCBBZ2luZzwvZnVsbC10aXRsZT48L3BlcmlvZGlj

YWw+PHBhZ2VzPjYwLTY4PC9wYWdlcz48dm9sdW1lPjQ5PC92b2x1bWU+PGtleXdvcmRzPjxrZXl3

b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmV0aW9sb2d5L21l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL21ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5D

b2duaXRpb24gRGlzb3JkZXJzLypldGlvbG9neS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

PkN5dG9raW5lcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48

a2V5d29yZD5HYXN0cm9pbnRlc3RpbmFsIE1pY3JvYmlvbWUvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1hdGlvbi8qZXRpb2xvZ3kv

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb24gTWVkaWF0b3JzL21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXN0aW5lcy8qbWljcm9iaW9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+UGxhcXVlLCBBbXlsb2lkL2V0aW9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+KkJyYWluIGFteWxvaWRvc2lzPC9rZXl3b3JkPjxrZXl3b3JkPipDb2duaXRpdmUgaW1wYWly

bWVudDwva2V5d29yZD48a2V5d29yZD4qR3V0IG1pY3JvYmlvdGE8L2tleXdvcmQ+PGtleXdvcmQ+

KkluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD4qTmV1cm9kZWdlbmVyYXRpb248L2tleXdv

cmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkph

bjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTgtMTQ5NyAoRWxlY3Ryb25pYykm

I3hEOzAxOTctNDU4MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjc3NzYyNjM8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMjc3NzYyNjM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb2Jpb2xhZ2luZy4yMDE2LjA4LjAxOTwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXR0YW5lbzwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+

PFJlY051bT40MTY2PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjY0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDE2NjwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2NzczODEwIj40MTY2PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DYXR0YW5lbywgQS48L2F1dGhvcj48

YXV0aG9yPkNhdHRhbmUsIE4uPC9hdXRob3I+PGF1dGhvcj5HYWxsdXp6aSwgUy48L2F1dGhvcj48

YXV0aG9yPlByb3Zhc2ksIFMuPC9hdXRob3I+PGF1dGhvcj5Mb3BpenpvLCBOLjwvYXV0aG9yPjxh

dXRob3I+RmVzdGFyaSwgQy48L2F1dGhvcj48YXV0aG9yPkZlcnJhcmksIEMuPC9hdXRob3I+PGF1

dGhvcj5HdWVycmEsIFUuIFAuPC9hdXRob3I+PGF1dGhvcj5QYWdoZXJhLCBCLjwvYXV0aG9yPjxh

dXRob3I+TXVzY2lvLCBDLjwvYXV0aG9yPjxhdXRob3I+QmlhbmNoZXR0aSwgQS48L2F1dGhvcj48

YXV0aG9yPlZvbHRhLCBHLiBELjwvYXV0aG9yPjxhdXRob3I+VHVybGEsIE0uPC9hdXRob3I+PGF1

dGhvcj5Db3RlbGxpLCBNLiBTLjwvYXV0aG9yPjxhdXRob3I+R2VubnVzbywgTS48L2F1dGhvcj48

YXV0aG9yPlByZWxsZSwgQS48L2F1dGhvcj48YXV0aG9yPlphbmV0dGksIE8uPC9hdXRob3I+PGF1

dGhvcj5MdXNzaWdub2xpLCBHLjwvYXV0aG9yPjxhdXRob3I+TWlyYWJpbGUsIEQuPC9hdXRob3I+

PGF1dGhvcj5CZWxsYW5kaSwgRC48L2F1dGhvcj48YXV0aG9yPkdlbnRpbGUsIFMuPC9hdXRob3I+

PGF1dGhvcj5CZWxvdHRpLCBHLjwvYXV0aG9yPjxhdXRob3I+VmlsbGFuaSwgRC48L2F1dGhvcj48

YXV0aG9yPkhhcmFjaCwgVC48L2F1dGhvcj48YXV0aG9yPkJvbG1vbnQsIFQuPC9hdXRob3I+PGF1

dGhvcj5QYWRvdmFuaSwgQS48L2F1dGhvcj48YXV0aG9yPkJvY2NhcmRpLCBNLjwvYXV0aG9yPjxh

dXRob3I+RnJpc29uaSwgRy4gQi48L2F1dGhvcj48YXV0aG9yPkluZGlhLUZicCBHcm91cDwvYXV0

aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkJpb2xvZ2ljYWwgUHN5

Y2hpYXRyeSBMYWJvcmF0b3J5LCBJUkNDUyBGYXRlYmVuZWZyYXRlbGxpLCBCcmVzY2lhLCBJdGFs

eTsgS2luZyZhcG9zO3MgQ29sbGVnZSBMb25kb24sIEluc3RpdHV0ZSBvZiBQc3ljaGlhdHJ5LCBM

b25kb24sIFVLLiBFbGVjdHJvbmljIGFkZHJlc3M6IGFjYXR0YW5lb0BmYXRlYmVuZWZyYXRlbGxp

LmV1LiYjeEQ7QmlvbG9naWNhbCBQc3ljaGlhdHJ5IExhYm9yYXRvcnksIElSQ0NTIEZhdGViZW5l

ZnJhdGVsbGksIEJyZXNjaWEsIEl0YWx5LiYjeEQ7TGFib3JhdG9yeSBvZiBOZXVyb2ltYWdpbmcg

YW5kIEFsemhlaW1lciZhcG9zO3MgRXBpZGVtaW9sb2d5LCBJUkNDUyBDZW50cm8gU2FuIEdpb3Zh

bm5pIGRpIERpbyBGYXRlYmVuZWZyYXRlbGxpLCBCcmVzY2lhLCBJdGFseS4mI3hEO051Y2xlYXIg

TWVkaWNpbmUsIFBvbGlhbWJ1bGFuemEgRm91bmRhdGlvbiwgSXN0aXR1dG8gT3NwZWRhbGllcm8s

IEJyZXNjaWEsIEl0YWx5LiYjeEQ7TnVjbGVhciBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBCcmVz

Y2lhIGFuZCBTcGVkYWxpIENpdmlsaSBkaSBCcmVzY2lhLCBCcmVzY2lhLCBJdGFseS4mI3hEO0Jp

b2xvZ2ljYWwgUHN5Y2hpYXRyeSBMYWJvcmF0b3J5LCBJUkNDUyBGYXRlYmVuZWZyYXRlbGxpLCBC

cmVzY2lhLCBJdGFseTsgRXVyb3BlYW4gRm91bmRhdGlvbiBCaW9tZWRpY2FsIFJlc2VhcmNoIChG

RVJCKSwgQ2VudGVyIG9mIEV4Y2VsbGVuY2UgQWx6aGVpbWVyLCBPc3BlZGFsZSBCcmlvbGluaSwg

R2F6emFuaWdhLCBCZXJnYW1vLCBJdGFseS4mI3hEO0RlcGFydG1lbnQgb2YgTWVkaWNpbmUgYW5k

IFJlaGFiaWxpdGF0aW9uLCBJc3RpdHV0byBDbGluaWNvIFNhbnQmYXBvcztBbm5hLCBCcmVzY2lh

LCBJdGFseS4mI3hEO05ldXJvbG9neSBVbml0LCBJc3RpdHV0byBDbGluaWNvIENpdHRhIGRpIEJy

ZXNjaWEsIEJyZXNjaWEsIEl0YWx5LiYjeEQ7TmV1cm9sb2d5IFVuaXQsIE9zcGVkYWxlIGRpIFZh

bGxlY2Ftb25pY2EgRXNpbmUsIEJyZXNjaWEsIEl0YWx5LiYjeEQ7TmV1cm9sb2d5IFVuaXQsIE9z

cGVkYWxlIE1hZ2dpb3JlIGRpIENyZW1hLCBDcmVtb25hLCBJdGFseS4mI3hEO0V1cm9wZWFuIEZv

dW5kYXRpb24gQmlvbWVkaWNhbCBSZXNlYXJjaCAoRkVSQiksIENlbnRlciBvZiBFeGNlbGxlbmNl

IEFsemhlaW1lciwgT3NwZWRhbGUgQnJpb2xpbmksIEdhenphbmlnYSwgQmVyZ2FtbywgSXRhbHku

JiN4RDtBbHpoZWltZXIgRXZhbHVhdGlvbiBVbml0LCBJc3RpdHV0byBPc3BlZGFsaWVybyBkaSBT

b3NwaXJvIE9OTFVTIEZvdW5kYXRpb24sIENyZW1vbmEsIEl0YWx5LiYjeEQ7RGVwYXJ0bWVudCBv

ZiBSZWhhYmlsaXRhdGlvbiwgQ2FzYSBkaSBDdXJhIEFuY2VsbGUgZGVsbGEgQ2FyaXRhLCBDcmVt

b25hLCBJdGFseS4mI3hEO0FsemhlaW1lciBFdmFsdWF0aW9uIFVuaXQsIEhvc3BpY2UgU2FudGEg

TWFyaWEgQXVzaWxpYXRyaWNlIE9OTFVTIEZvdW5kYXRpb24sIEJlcmdhbW8sIEl0YWx5LiYjeEQ7

QWx6aGVpbWVyIEV2YWx1YXRpb24gVW5pdCwgQ2FzYSBkaSBDdXJhIEZpZ2xpZSBkaSBTLiBDYW1p

bGxvLCBDcmVtb25hLCBJdGFseS4mI3hEO0Vjb2xlIFBvbHl0ZWNobmlxdWUgRmVkZXJhbGUgZGUg

TGF1c2FubmUsIExhdXNhbm5lLCBTd2l0emVybGFuZC4mI3hEO1N0ZW1lZGljYSBJbnRlcm5hdGlv

bmFsIFNBLCBMYXVzYW5uZSwgU3dpdHplcmxhbmQuJiN4RDtOZXVyb2xvZ3kgVW5pdCwgRGVwYXJ0

bWVudCBvZiBNZWRpY2FsIGFuZCBFeHBlcmltZW50YWwgU2NpZW5jZXMsIFVuaXZlcnNpdHkgb2Yg

QnJlc2NpYSwgQnJlc2NpYSwgSXRhbHkuJiN4RDtMYWJvcmF0b3J5IG9mIE5ldXJvaW1hZ2luZyBh

bmQgQWx6aGVpbWVyJmFwb3M7cyBFcGlkZW1pb2xvZ3ksIElSQ0NTIENlbnRybyBTYW4gR2lvdmFu

bmkgZGkgRGlvIEZhdGViZW5lZnJhdGVsbGksIEJyZXNjaWEsIEl0YWx5OyBMQU5WSUUtTGFib3Jh

dG9yeSBvZiBOZXVyb2ltYWdpbmcgb2YgQWdpbmcsIFVuaXZlcnNpdHkgSG9zcGl0YWxzLCBHZW5l

dmEsIFN3aXR6ZXJsYW5kOyBNZW1vcnkgQ2xpbmljLCBVbml2ZXJzaXR5IEhvc3BpdGFscyBhbmQg

VW5pdmVyc2l0eSBvZiBHZW5ldmEsIEdlbmV2YSwgU3dpdHplcmxhbmQuPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+QXNzb2NpYXRpb24gb2YgYnJhaW4gYW15bG9pZG9zaXMgd2l0aCBwcm8t

aW5mbGFtbWF0b3J5IGd1dCBiYWN0ZXJpYWwgdGF4YSBhbmQgcGVyaXBoZXJhbCBpbmZsYW1tYXRp

b24gbWFya2VycyBpbiBjb2duaXRpdmVseSBpbXBhaXJlZCBlbGRlcmx5PC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPk5ldXJvYmlvbCBBZ2luZzwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJp

b2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvYmlvbCBBZ2luZzwvZnVsbC10aXRsZT48L3BlcmlvZGlj

YWw+PHBhZ2VzPjYwLTY4PC9wYWdlcz48dm9sdW1lPjQ5PC92b2x1bWU+PGtleXdvcmRzPjxrZXl3

b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmV0aW9sb2d5L21l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL21ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5D

b2duaXRpb24gRGlzb3JkZXJzLypldGlvbG9neS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

PkN5dG9raW5lcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48

a2V5d29yZD5HYXN0cm9pbnRlc3RpbmFsIE1pY3JvYmlvbWUvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1hdGlvbi8qZXRpb2xvZ3kv

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb24gTWVkaWF0b3JzL21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXN0aW5lcy8qbWljcm9iaW9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+UGxhcXVlLCBBbXlsb2lkL2V0aW9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+KkJyYWluIGFteWxvaWRvc2lzPC9rZXl3b3JkPjxrZXl3b3JkPipDb2duaXRpdmUgaW1wYWly

bWVudDwva2V5d29yZD48a2V5d29yZD4qR3V0IG1pY3JvYmlvdGE8L2tleXdvcmQ+PGtleXdvcmQ+

KkluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD4qTmV1cm9kZWdlbmVyYXRpb248L2tleXdv

cmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkph

bjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTgtMTQ5NyAoRWxlY3Ryb25pYykm

I3hEOzAxOTctNDU4MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjc3NzYyNjM8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMjc3NzYyNjM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb2Jpb2xhZ2luZy4yMDE2LjA4LjAxOTwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 264. In addition, in this cohort, metagenomics analysis showed that AD patients have an increase of Firmicutes (Blautia, Ruminococcus, and others), and a reduction of Verrucomicrobia and Bacteroidetes compared to healthy controls. Furthermore, higher levels of bacterial lipopolysaccharides in AD patients was found compared to controls. It is possible to conclude that AD patients have a pro-inflammatory status in the gut and in the blood, with a participation of bacterial metabolites. It is paramount to investigate the causality behind the increase of these metabolites and some other bacterial components, not only in the blood of the same patients but also in the CSF, as well as the role of the microbiota in other sites such as the oral cavity (Fig. 4) ADDIN EN.CITE <EndNote><Cite><Author>Kamer</Author><Year>2008</Year><RecNum>4260</RecNum><DisplayText><style face="superscript">265</style></DisplayText><record><rec-number>4260</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1537190638">4260</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kamer, A. R.</author><author>Craig, R. G.</author><author>Dasanayake, A. P.</author><author>Brys, M.</author><author>Glodzik-Sobanska, L.</author><author>de Leon, M. J.</author></authors></contributors><auth-address>Department of Periodontology and Implant Dentistry, College of Dentistry, New York University, New York, NY, USA. ark5@nyu.edu</auth-address><titles><title>Inflammation and Alzheimer&apos;s disease: possible role of periodontal diseases</title><secondary-title>Alzheimers Dement</secondary-title></titles><pages>242-50</pages><volume>4</volume><number>4</number><edition>2008/07/18</edition><keywords><keyword>Alzheimer Disease/*etiology/pathology</keyword><keyword>Disease Progression</keyword><keyword>Humans</keyword><keyword>Inflammation/*complications/microbiology/pathology</keyword><keyword>Periodontal Diseases/*complications/pathology</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2008</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1552-5279 (Electronic)&#xD;1552-5260 (Linking)</isbn><accession-num>18631974</accession-num><urls><related-urls><url>. This is because the association between the microbiomes of AD and control patients does not clarify the triggers promoting this imbalance. The microbiome is changing frequently, influenced by factors such as environment, the diet but also the season of the year. All these parameters can be used to improve the power of these studies to find signatures that are more specific from patients. Moreover, stable microbiota signatures have been identified that can be as unique to individuals as fingerprints PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GcmFuem9zYTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+

PFJlY051bT40MjYzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjY2PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDI2MzwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM3MTkwODAzIj40MjYzPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5GcmFuem9zYSwgRS4gQS48L2F1dGhv

cj48YXV0aG9yPkh1YW5nLCBLLjwvYXV0aG9yPjxhdXRob3I+TWVhZG93LCBKLiBGLjwvYXV0aG9y

PjxhdXRob3I+R2V2ZXJzLCBELjwvYXV0aG9yPjxhdXRob3I+TGVtb24sIEsuIFAuPC9hdXRob3I+

PGF1dGhvcj5Cb2hhbm5hbiwgQi4gSi48L2F1dGhvcj48YXV0aG9yPkh1dHRlbmhvd2VyLCBDLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkJpb3N0YXRpc3Rp

Y3MgRGVwYXJ0bWVudCwgSGFydmFyZCBTY2hvb2wgb2YgUHVibGljIEhlYWx0aCwgQm9zdG9uLCBN

QSAwMjExNTsgTWljcm9iaWFsIFN5c3RlbXMgYW5kIENvbW11bml0aWVzLCBHZW5vbWUgU2VxdWVu

Y2luZyBhbmQgQW5hbHlzaXMgUHJvZ3JhbSwgVGhlIEJyb2FkIEluc3RpdHV0ZSwgQ2FtYnJpZGdl

LCBNQSAwMjE0MjsmI3hEO01pY3JvYmlhbCBTeXN0ZW1zIGFuZCBDb21tdW5pdGllcywgR2Vub21l

IFNlcXVlbmNpbmcgYW5kIEFuYWx5c2lzIFByb2dyYW0sIFRoZSBCcm9hZCBJbnN0aXR1dGUsIENh

bWJyaWRnZSwgTUEgMDIxNDI7JiN4RDtJbnN0aXR1dGUgb2YgRWNvbG9neSBhbmQgRXZvbHV0aW9u

LCBVbml2ZXJzaXR5IG9mIE9yZWdvbiwgRXVnZW5lLCBPUiA5NzQwMzsmI3hEO0RlcGFydG1lbnQg

b2YgTWljcm9iaW9sb2d5LCBUaGUgRm9yc3l0aCBJbnN0aXR1dGUsIENhbWJyaWRnZSwgTUEgMDIx

NDI7IGFuZCBEaXZpc2lvbiBvZiBJbmZlY3Rpb3VzIERpc2Vhc2VzLCBCb3N0b24gQ2hpbGRyZW4m

YXBvcztzIEhvc3BpdGFsLCBIYXJ2YXJkIE1lZGljYWwgU2Nob29sLCBCb3N0b24sIE1BIDAyMTE1

LiYjeEQ7Qmlvc3RhdGlzdGljcyBEZXBhcnRtZW50LCBIYXJ2YXJkIFNjaG9vbCBvZiBQdWJsaWMg

SGVhbHRoLCBCb3N0b24sIE1BIDAyMTE1OyBNaWNyb2JpYWwgU3lzdGVtcyBhbmQgQ29tbXVuaXRp

ZXMsIEdlbm9tZSBTZXF1ZW5jaW5nIGFuZCBBbmFseXNpcyBQcm9ncmFtLCBUaGUgQnJvYWQgSW5z

dGl0dXRlLCBDYW1icmlkZ2UsIE1BIDAyMTQyOyBjaHV0dGVuaEBoc3BoLmhhcnZhcmQuZWR1Ljwv

YXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPklkZW50aWZ5aW5nIHBlcnNvbmFsIG1pY3JvYmlv

bWVzIHVzaW5nIG1ldGFnZW5vbWljIGNvZGVzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlByb2Mg

TmF0bCBBY2FkIFNjaSBVIFMgQTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPlByb2MgTmF0bCBBY2FkIFNjaSBVIFMgQTwvZnVsbC10aXRsZT48L3Blcmlv

ZGljYWw+PHBhZ2VzPkUyOTMwLTg8L3BhZ2VzPjx2b2x1bWU+MTEyPC92b2x1bWU+PG51bWJlcj4y

MjwvbnVtYmVyPjxlZGl0aW9uPjIwMTUvMDUvMTM8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PkNvbmZpZGVudGlhbGl0eS9zdGFuZGFyZHMvdHJlbmRzPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmV0

aWMgTWFya2Vycy8qZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+KkdlbmV0aWMgVmFyaWF0aW9u

PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NZXRhZ2Vub21pY3Mv

Km1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWljcm9iaW90YS8qZ2VuZXRpY3M8L2tleXdvcmQ+

PGtleXdvcmQ+TW9kZWxzLCBHZW5ldGljPC9rZXl3b3JkPjxrZXl3b3JkPlByZWNpc2lvbiBNZWRp

Y2luZS8qbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5mb3JlbnNpYyBnZW5ldGljczwva2V5d29y

ZD48a2V5d29yZD5odW1hbiBtaWNyb2Jpb21lPC9rZXl3b3JkPjxrZXl3b3JkPm1ldGFnZW5vbWlj

czwva2V5d29yZD48a2V5d29yZD5taWNyb2JpYWwgZWNvbG9neTwva2V5d29yZD48a2V5d29yZD5z

dHJhaW4gdmFyaWF0aW9uPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3ll

YXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdW4gMjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju

PjEwOTEtNjQ5MCAoRWxlY3Ryb25pYykmI3hEOzAwMjctODQyNCAoTGlua2luZyk8L2lzYm4+PGFj

Y2Vzc2lvbi1udW0+MjU5NjQzNDE8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48

dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI1OTY0MzQxPC91cmw+PC9y

ZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQ0NjA1MDc8L2N1c3RvbTI+PGVsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjEwLjEwNzMvcG5hcy4xNDIzODU0MTEyPC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GcmFuem9zYTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+

PFJlY051bT40MjYzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjY2PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDI2MzwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM3MTkwODAzIj40MjYzPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5GcmFuem9zYSwgRS4gQS48L2F1dGhv

cj48YXV0aG9yPkh1YW5nLCBLLjwvYXV0aG9yPjxhdXRob3I+TWVhZG93LCBKLiBGLjwvYXV0aG9y

PjxhdXRob3I+R2V2ZXJzLCBELjwvYXV0aG9yPjxhdXRob3I+TGVtb24sIEsuIFAuPC9hdXRob3I+

PGF1dGhvcj5Cb2hhbm5hbiwgQi4gSi48L2F1dGhvcj48YXV0aG9yPkh1dHRlbmhvd2VyLCBDLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkJpb3N0YXRpc3Rp

Y3MgRGVwYXJ0bWVudCwgSGFydmFyZCBTY2hvb2wgb2YgUHVibGljIEhlYWx0aCwgQm9zdG9uLCBN

QSAwMjExNTsgTWljcm9iaWFsIFN5c3RlbXMgYW5kIENvbW11bml0aWVzLCBHZW5vbWUgU2VxdWVu

Y2luZyBhbmQgQW5hbHlzaXMgUHJvZ3JhbSwgVGhlIEJyb2FkIEluc3RpdHV0ZSwgQ2FtYnJpZGdl

LCBNQSAwMjE0MjsmI3hEO01pY3JvYmlhbCBTeXN0ZW1zIGFuZCBDb21tdW5pdGllcywgR2Vub21l

IFNlcXVlbmNpbmcgYW5kIEFuYWx5c2lzIFByb2dyYW0sIFRoZSBCcm9hZCBJbnN0aXR1dGUsIENh

bWJyaWRnZSwgTUEgMDIxNDI7JiN4RDtJbnN0aXR1dGUgb2YgRWNvbG9neSBhbmQgRXZvbHV0aW9u

LCBVbml2ZXJzaXR5IG9mIE9yZWdvbiwgRXVnZW5lLCBPUiA5NzQwMzsmI3hEO0RlcGFydG1lbnQg

b2YgTWljcm9iaW9sb2d5LCBUaGUgRm9yc3l0aCBJbnN0aXR1dGUsIENhbWJyaWRnZSwgTUEgMDIx

NDI7IGFuZCBEaXZpc2lvbiBvZiBJbmZlY3Rpb3VzIERpc2Vhc2VzLCBCb3N0b24gQ2hpbGRyZW4m

YXBvcztzIEhvc3BpdGFsLCBIYXJ2YXJkIE1lZGljYWwgU2Nob29sLCBCb3N0b24sIE1BIDAyMTE1

LiYjeEQ7Qmlvc3RhdGlzdGljcyBEZXBhcnRtZW50LCBIYXJ2YXJkIFNjaG9vbCBvZiBQdWJsaWMg

SGVhbHRoLCBCb3N0b24sIE1BIDAyMTE1OyBNaWNyb2JpYWwgU3lzdGVtcyBhbmQgQ29tbXVuaXRp

ZXMsIEdlbm9tZSBTZXF1ZW5jaW5nIGFuZCBBbmFseXNpcyBQcm9ncmFtLCBUaGUgQnJvYWQgSW5z

dGl0dXRlLCBDYW1icmlkZ2UsIE1BIDAyMTQyOyBjaHV0dGVuaEBoc3BoLmhhcnZhcmQuZWR1Ljwv

YXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPklkZW50aWZ5aW5nIHBlcnNvbmFsIG1pY3JvYmlv

bWVzIHVzaW5nIG1ldGFnZW5vbWljIGNvZGVzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlByb2Mg

TmF0bCBBY2FkIFNjaSBVIFMgQTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPlByb2MgTmF0bCBBY2FkIFNjaSBVIFMgQTwvZnVsbC10aXRsZT48L3Blcmlv

ZGljYWw+PHBhZ2VzPkUyOTMwLTg8L3BhZ2VzPjx2b2x1bWU+MTEyPC92b2x1bWU+PG51bWJlcj4y

MjwvbnVtYmVyPjxlZGl0aW9uPjIwMTUvMDUvMTM8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PkNvbmZpZGVudGlhbGl0eS9zdGFuZGFyZHMvdHJlbmRzPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmV0

aWMgTWFya2Vycy8qZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+KkdlbmV0aWMgVmFyaWF0aW9u

PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NZXRhZ2Vub21pY3Mv

Km1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWljcm9iaW90YS8qZ2VuZXRpY3M8L2tleXdvcmQ+

PGtleXdvcmQ+TW9kZWxzLCBHZW5ldGljPC9rZXl3b3JkPjxrZXl3b3JkPlByZWNpc2lvbiBNZWRp

Y2luZS8qbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5mb3JlbnNpYyBnZW5ldGljczwva2V5d29y

ZD48a2V5d29yZD5odW1hbiBtaWNyb2Jpb21lPC9rZXl3b3JkPjxrZXl3b3JkPm1ldGFnZW5vbWlj

czwva2V5d29yZD48a2V5d29yZD5taWNyb2JpYWwgZWNvbG9neTwva2V5d29yZD48a2V5d29yZD5z

dHJhaW4gdmFyaWF0aW9uPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3ll

YXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdW4gMjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju

PjEwOTEtNjQ5MCAoRWxlY3Ryb25pYykmI3hEOzAwMjctODQyNCAoTGlua2luZyk8L2lzYm4+PGFj

Y2Vzc2lvbi1udW0+MjU5NjQzNDE8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48

dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI1OTY0MzQxPC91cmw+PC9y

ZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQ0NjA1MDc8L2N1c3RvbTI+PGVsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjEwLjEwNzMvcG5hcy4xNDIzODU0MTEyPC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 266.Regarding therapeutic opportunities, it is possible to modify the composition of the gut microbiota to prevent or improve cognitive symptoms in AD. An early clinical trial carried out in Iran using commercial probiotics produced by a local company has shown that diet supplementation can affect cognitive performance in older severely demented patients. Baseline MMSE increased from 8.7 to 10.6 in the treated and decreased from 8.5 to 8.0 in the untreated patients over 12 weeks. An impact was reported not only in MMSE scores but also in blood markers of insulin and lipid metabolism ADDIN EN.CITE <EndNote><Cite><Author>Akbari</Author><Year>2016</Year><RecNum>3949</RecNum><DisplayText><style face="superscript">267</style></DisplayText><record><rec-number>3949</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1536762070">3949</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Akbari, E.</author><author>Asemi, Z.</author><author>Daneshvar Kakhaki, R.</author><author>Bahmani, F.</author><author>Kouchaki, E.</author><author>Tamtaji, O. R.</author><author>Hamidi, G. A.</author><author>Salami, M.</author></authors></contributors><auth-address>Physiology Research Center, Kashan University of Medical Sciences Kashan, Iran.&#xD;Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences Kashan, Iran.&#xD;Department of Neurology, School of Medicine, Kashan University of Medical Sciences Kashan, Iran.</auth-address><titles><title>Effect of Probiotic Supplementation on Cognitive Function and Metabolic Status in Alzheimer&apos;s Disease: A Randomized, Double-Blind and Controlled Trial</title><secondary-title>Front Aging Neurosci</secondary-title></titles><pages>256</pages><volume>8</volume><keywords><keyword>Alzheimer&apos;s disease</keyword><keyword>clinical trial</keyword><keyword>cognitive function</keyword><keyword>metabolic status</keyword><keyword>probiotic</keyword></keywords><dates><year>2016</year></dates><isbn>1663-4365 (Print)&#xD;1663-4365 (Linking)</isbn><accession-num>27891089</accession-num><urls><related-urls><url>. Nevertheless, from gut microbiome metagenomics, it has become evident that it is challenging to identify a universal therapeutic composition of microorganisms for therapies. Therefore, novel mediators of gut-induced inflammation in blood and CSF are key to develop therapeutic strategies.Figure 4. Possible pathophysiologic role of microbiota in Alzheimer’s disease. BBB, blood–brain barrier; BMAA, b-Nmethylamino-L-alanine; HSV-1, herpes simplex virus type 1; LPS, lipopolysaccharide. From: Marizzoni et al., Microbiota and neurodegenerative diseases. Curr Opin Neurol 2017, 30:630-8.AD as a metabolic syndrome:Restoring Insulin Action & Glucose Metabolism in AD: Our Short-Term PerspectivesRationaleBesides the known effects of amyloid-β (Aβ) and hyperphosphorylated Tau protein in the central nervous system (CNS) in AD, they may be also important at the periphery ADDIN EN.CITE <EndNote><Cite><Author>Jarosz-Griffiths</Author><Year>2015</Year><RecNum>984</RecNum><DisplayText><style face="superscript">268</style></DisplayText><record><rec-number>984</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865640">984</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jarosz-Griffiths, Heledd H.</author><author>Noble, Elizabeth</author><author>Rushworth, Jo V.</author><author>Hooper, Nigel M.</author></authors></contributors><titles><title>Amyloid-β Receptors: The Good, the Bad, and the Prion Protein</title><secondary-title>Journal of Biological Chemistry</secondary-title></titles><pages>3174-3183</pages><volume>291</volume><number>7</number><dates><year>2015</year><pub-dates><date>2015/12/30</date></pub-dates></dates><publisher>American Society for Biochemistry &amp; Molecular Biology (ASBMB)</publisher><isbn>0021-9258&#xD;1083-351X</isbn><urls><related-urls><url>. For instance, Aβ may compete with insulin and bind to its receptors at the periphery, impairing pancreatic β-cells and leading to insulin resistance and glucose dysmetabolism PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWtsb3NzeTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+

PFJlY051bT45ODU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4yNjksMjcwPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+OTg1PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU2NDAiPjk4NTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWlrbG9zc3ksIEp1ZGl0aDwvYXV0

aG9yPjxhdXRob3I+UWluZywgSG9uZzwvYXV0aG9yPjxhdXRob3I+UmFkZW5vdmljLCBBbGVrc2Fu

ZHJhPC9hdXRob3I+PGF1dGhvcj5LaXMsIEFuZHJhczwvYXV0aG9yPjxhdXRob3I+VmlsZW5vLCBC

ZXJ0cmFuZDwvYXV0aG9yPjxhdXRob3I+TMOgc3psw7MsIEZvcnLDszwvYXV0aG9yPjxhdXRob3I+

TWlsbGVyLCBMaXNhPC9hdXRob3I+PGF1dGhvcj5NYXJ0aW5zLCBSYWxwaCBOLjwvYXV0aG9yPjxh

dXRob3I+V2FlYmVyLCBHZXJhcmQ8L2F1dGhvcj48YXV0aG9yPk1vb3NlciwgVmluY2VudDwvYXV0

aG9yPjxhdXRob3I+Qm9zbWFuLCBGcmVkPC9hdXRob3I+PGF1dGhvcj5LaGFsaWxpLCBLYW1lbDwv

YXV0aG9yPjxhdXRob3I+RGFyYmluaWFuLCBOdW5lPC9hdXRob3I+PGF1dGhvcj5NY0dlZXIsIFBh

dHJpY2sgTC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+

QmV0YSBhbXlsb2lkIGFuZCBoeXBlcnBob3NwaG9yeWxhdGVkIHRhdSBkZXBvc2l0cyBpbiB0aGUg

cGFuY3JlYXMgaW4gdHlwZSAyIGRpYWJldGVzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5ldXJv

YmlvbG9neSBvZiBBZ2luZzwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xNTAzLTE1

MTU8L3BhZ2VzPjx2b2x1bWU+MzE8L3ZvbHVtZT48bnVtYmVyPjk8L251bWJlcj48ZGF0ZXM+PHll

YXI+MjAxMDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTAvMDk8L2RhdGU+PC9wdWItZGF0ZXM+

PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MDE5Ny00NTgw

PC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2

L2oubmV1cm9iaW9sYWdpbmcuMjAwOC4wOC4wMTk8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb2Jpb2xhZ2luZy4yMDA4LjA4

LjAxOTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRo

b3I+Um9oZXI8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNOdW0+MjE0MzwvUmVjTnVtPjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MjE0MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0

YW1wPSIxNTM0ODYzNzk5Ij4yMTQzPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5Sb2hlciwgQS4gRS48L2F1dGhvcj48YXV0aG9yPkNyaWJicywgRC4gSC48L2F1dGhvcj48

YXV0aG9yPktpbSwgUi4gQy48L2F1dGhvcj48YXV0aG9yPk1hYXJvdWYsIEMuIEwuPC9hdXRob3I+

PGF1dGhvcj5XaGl0ZXNpZGUsIEMuIE0uPC9hdXRob3I+PGF1dGhvcj5Lb2tqb2huLCBULiBBLjwv

YXV0aG9yPjxhdXRob3I+RGF1Z3MsIEkuIEQuPC9hdXRob3I+PGF1dGhvcj5IZWFkLCBFLjwvYXV0

aG9yPjxhdXRob3I+TGllYnNhY2ssIEMuPC9hdXRob3I+PGF1dGhvcj5TZXJyYW5vLCBHLjwvYXV0

aG9yPjxhdXRob3I+QmVsZGVuLCBDLjwvYXV0aG9yPjxhdXRob3I+U2FiYmFnaCwgTS4gTi48L2F1

dGhvcj48YXV0aG9yPkJlYWNoLCBULiBHLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48YXV0aC1hZGRyZXNzPlRoZSBMb25ndGluZSBDZW50ZXIgZm9yIE5ldXJvZGVnZW5lcmF0aXZl

IEJpb2NoZW1pc3RyeSwgQmFubmVyIFN1biBIZWFsdGggUmVzZWFyY2ggSW5zdGl0dXRlLCBTdW4g

Q2l0eSwgQXJpem9uYSwgVW5pdGVkIFN0YXRlcyBvZiBBbWVyaWNhLiBhbGV4LnJvaGVyQGJhbm5l

cmhlYWx0aC5jb208L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5CYXBpbmV1enVtYWIgYWx0

ZXJzIGFiZXRhIGNvbXBvc2l0aW9uOiBpbXBsaWNhdGlvbnMgZm9yIHRoZSBhbXlsb2lkIGNhc2Nh

ZGUgaHlwb3RoZXNpcyBhbmQgYW50aS1hbXlsb2lkIGltbXVub3RoZXJhcHk8L3RpdGxlPjxzZWNv

bmRhcnktdGl0bGU+UExvUyBPbmU8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh

bD48ZnVsbC10aXRsZT5QTG9TIE9uZTwvZnVsbC10aXRsZT48YWJici0xPlBsb1Mgb25lPC9hYmJy

LTE+PC9wZXJpb2RpY2FsPjxwYWdlcz5lNTk3MzU8L3BhZ2VzPjx2b2x1bWU+ODwvdm9sdW1lPjxu

dW1iZXI+MzwvbnVtYmVyPjxlZGl0aW9uPjIwMTMvMDQvMDU8L2VkaXRpb24+PGtleXdvcmRzPjxr

ZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+

PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvaW1tdW5vbG9neS9tZXRhYm9saXNtL3RoZXJhcHk8

L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzLypjaGVtaXN0cnk8L2tleXdv

cmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW4gUHJlY3Vyc29yL2NoZW1pc3RyeTwva2V5

d29yZD48a2V5d29yZD5BbnRpYm9kaWVzLCBNb25vY2xvbmFsLCBIdW1hbml6ZWQvY2hlbWlzdHJ5

LypwaGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vcGF0aG9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeS9tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPkNvZ25pdGlvbiBEaXNvcmRlcnMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29y

ZD5Fbnp5bWUtTGlua2VkIEltbXVub3NvcmJlbnQgQXNzYXk8L2tleXdvcmQ+PGtleXdvcmQ+RmVt

YWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm90aGVy

YXB5LyptZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+UGVw

dGlkZSBGcmFnbWVudHMvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPlRvbW9ncmFwaHksIFgt

UmF5IENvbXB1dGVkPC9rZXl3b3JkPjxrZXl3b3JkPnRhdSBQcm90ZWlucy9jaGVtaXN0cnk8L2tl

eXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48L2RhdGVzPjxpc2JuPjE5

MzItNjIwMyAoRWxlY3Ryb25pYykmI3hEOzE5MzItNjIwMyAoTGlua2luZyk8L2lzYm4+PGFjY2Vz

c2lvbi1udW0+MjM1NTU3NjQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJs

Pmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzNTU1NzY0PC91cmw+PC9yZWxh

dGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzM2MDU0MDg8L2N1c3RvbTI+PGVsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjEwLjEzNzEvam91cm5hbC5wb25lLjAwNTk3MzU8L2VsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWtsb3NzeTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+

PFJlY051bT45ODU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4yNjksMjcwPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+OTg1PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU2NDAiPjk4NTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWlrbG9zc3ksIEp1ZGl0aDwvYXV0

aG9yPjxhdXRob3I+UWluZywgSG9uZzwvYXV0aG9yPjxhdXRob3I+UmFkZW5vdmljLCBBbGVrc2Fu

ZHJhPC9hdXRob3I+PGF1dGhvcj5LaXMsIEFuZHJhczwvYXV0aG9yPjxhdXRob3I+VmlsZW5vLCBC

ZXJ0cmFuZDwvYXV0aG9yPjxhdXRob3I+TMOgc3psw7MsIEZvcnLDszwvYXV0aG9yPjxhdXRob3I+

TWlsbGVyLCBMaXNhPC9hdXRob3I+PGF1dGhvcj5NYXJ0aW5zLCBSYWxwaCBOLjwvYXV0aG9yPjxh

dXRob3I+V2FlYmVyLCBHZXJhcmQ8L2F1dGhvcj48YXV0aG9yPk1vb3NlciwgVmluY2VudDwvYXV0

aG9yPjxhdXRob3I+Qm9zbWFuLCBGcmVkPC9hdXRob3I+PGF1dGhvcj5LaGFsaWxpLCBLYW1lbDwv

YXV0aG9yPjxhdXRob3I+RGFyYmluaWFuLCBOdW5lPC9hdXRob3I+PGF1dGhvcj5NY0dlZXIsIFBh

dHJpY2sgTC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+

QmV0YSBhbXlsb2lkIGFuZCBoeXBlcnBob3NwaG9yeWxhdGVkIHRhdSBkZXBvc2l0cyBpbiB0aGUg

cGFuY3JlYXMgaW4gdHlwZSAyIGRpYWJldGVzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5ldXJv

YmlvbG9neSBvZiBBZ2luZzwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xNTAzLTE1

MTU8L3BhZ2VzPjx2b2x1bWU+MzE8L3ZvbHVtZT48bnVtYmVyPjk8L251bWJlcj48ZGF0ZXM+PHll

YXI+MjAxMDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTAvMDk8L2RhdGU+PC9wdWItZGF0ZXM+

PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MDE5Ny00NTgw

PC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2

L2oubmV1cm9iaW9sYWdpbmcuMjAwOC4wOC4wMTk8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb2Jpb2xhZ2luZy4yMDA4LjA4

LjAxOTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRo

b3I+Um9oZXI8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNOdW0+MjE0MzwvUmVjTnVtPjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MjE0MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0

YW1wPSIxNTM0ODYzNzk5Ij4yMTQzPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5Sb2hlciwgQS4gRS48L2F1dGhvcj48YXV0aG9yPkNyaWJicywgRC4gSC48L2F1dGhvcj48

YXV0aG9yPktpbSwgUi4gQy48L2F1dGhvcj48YXV0aG9yPk1hYXJvdWYsIEMuIEwuPC9hdXRob3I+

PGF1dGhvcj5XaGl0ZXNpZGUsIEMuIE0uPC9hdXRob3I+PGF1dGhvcj5Lb2tqb2huLCBULiBBLjwv

YXV0aG9yPjxhdXRob3I+RGF1Z3MsIEkuIEQuPC9hdXRob3I+PGF1dGhvcj5IZWFkLCBFLjwvYXV0

aG9yPjxhdXRob3I+TGllYnNhY2ssIEMuPC9hdXRob3I+PGF1dGhvcj5TZXJyYW5vLCBHLjwvYXV0

aG9yPjxhdXRob3I+QmVsZGVuLCBDLjwvYXV0aG9yPjxhdXRob3I+U2FiYmFnaCwgTS4gTi48L2F1

dGhvcj48YXV0aG9yPkJlYWNoLCBULiBHLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48YXV0aC1hZGRyZXNzPlRoZSBMb25ndGluZSBDZW50ZXIgZm9yIE5ldXJvZGVnZW5lcmF0aXZl

IEJpb2NoZW1pc3RyeSwgQmFubmVyIFN1biBIZWFsdGggUmVzZWFyY2ggSW5zdGl0dXRlLCBTdW4g

Q2l0eSwgQXJpem9uYSwgVW5pdGVkIFN0YXRlcyBvZiBBbWVyaWNhLiBhbGV4LnJvaGVyQGJhbm5l

cmhlYWx0aC5jb208L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5CYXBpbmV1enVtYWIgYWx0

ZXJzIGFiZXRhIGNvbXBvc2l0aW9uOiBpbXBsaWNhdGlvbnMgZm9yIHRoZSBhbXlsb2lkIGNhc2Nh

ZGUgaHlwb3RoZXNpcyBhbmQgYW50aS1hbXlsb2lkIGltbXVub3RoZXJhcHk8L3RpdGxlPjxzZWNv

bmRhcnktdGl0bGU+UExvUyBPbmU8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh

bD48ZnVsbC10aXRsZT5QTG9TIE9uZTwvZnVsbC10aXRsZT48YWJici0xPlBsb1Mgb25lPC9hYmJy

LTE+PC9wZXJpb2RpY2FsPjxwYWdlcz5lNTk3MzU8L3BhZ2VzPjx2b2x1bWU+ODwvdm9sdW1lPjxu

dW1iZXI+MzwvbnVtYmVyPjxlZGl0aW9uPjIwMTMvMDQvMDU8L2VkaXRpb24+PGtleXdvcmRzPjxr

ZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+

PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvaW1tdW5vbG9neS9tZXRhYm9saXNtL3RoZXJhcHk8

L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzLypjaGVtaXN0cnk8L2tleXdv

cmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW4gUHJlY3Vyc29yL2NoZW1pc3RyeTwva2V5

d29yZD48a2V5d29yZD5BbnRpYm9kaWVzLCBNb25vY2xvbmFsLCBIdW1hbml6ZWQvY2hlbWlzdHJ5

LypwaGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vcGF0aG9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeS9tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPkNvZ25pdGlvbiBEaXNvcmRlcnMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29y

ZD5Fbnp5bWUtTGlua2VkIEltbXVub3NvcmJlbnQgQXNzYXk8L2tleXdvcmQ+PGtleXdvcmQ+RmVt

YWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm90aGVy

YXB5LyptZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+UGVw

dGlkZSBGcmFnbWVudHMvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPlRvbW9ncmFwaHksIFgt

UmF5IENvbXB1dGVkPC9rZXl3b3JkPjxrZXl3b3JkPnRhdSBQcm90ZWlucy9jaGVtaXN0cnk8L2tl

eXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48L2RhdGVzPjxpc2JuPjE5

MzItNjIwMyAoRWxlY3Ryb25pYykmI3hEOzE5MzItNjIwMyAoTGlua2luZyk8L2lzYm4+PGFjY2Vz

c2lvbi1udW0+MjM1NTU3NjQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJs

Pmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzNTU1NzY0PC91cmw+PC9yZWxh

dGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzM2MDU0MDg8L2N1c3RvbTI+PGVsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjEwLjEzNzEvam91cm5hbC5wb25lLjAwNTk3MzU8L2VsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 269,270. This may in turn exacerbate Aβ deposition PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZYW5nPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj

TnVtPjk4NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjI3

MSwyNzI8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj45ODc8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY0MCI+OTg3PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5ZYW5nLCBZaTwvYXV0aG9yPjxhdXRob3I+

V3UsIFlpbGk8L2F1dGhvcj48YXV0aG9yPlpoYW5nLCBTaHV0aW5nPC9hdXRob3I+PGF1dGhvcj5T

b25nLCBXZWlob25nPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRp

dGxlPkhpZ2ggR2x1Y29zZSBQcm9tb3RlcyBBzrIgUHJvZHVjdGlvbiBieSBJbmhpYml0aW5nIEFQ

UCBEZWdyYWRhdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5QTG9TIE9ORTwvc2Vjb25kYXJ5

LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlBMb1MgT25lPC9mdWxsLXRp

dGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+ZTY5ODI0PC9wYWdlcz48dm9sdW1lPjg8L3ZvbHVtZT48

bnVtYmVyPjc8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRl

PjIwMTMvMDcvMjM8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPlB1YmxpYyBM

aWJyYXJ5IG9mIFNjaWVuY2UgKFBMb1MpPC9wdWJsaXNoZXI+PGlzYm4+MTkzMi02MjAzPC9pc2Ju

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMzcxL2pvdXJu

YWwucG9uZS4wMDY5ODI0PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4xMzcxL2pvdXJuYWwucG9uZS4wMDY5ODI0PC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5UYWtlZGE8L0F1dGhvcj48WWVh

cj4yMDEwPC9ZZWFyPjxSZWNOdW0+MzI4ODwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MzI4

ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUy

cHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTA2MTAyIj4zMjg4

PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8

L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5UYWtlZGEsIFMuPC9hdXRo

b3I+PGF1dGhvcj5TYXRvLCBOLjwvYXV0aG9yPjxhdXRob3I+VWNoaW8tWWFtYWRhLCBLLjwvYXV0

aG9yPjxhdXRob3I+U2F3YWRhLCBLLjwvYXV0aG9yPjxhdXRob3I+S3VuaWVkYSwgVC48L2F1dGhv

cj48YXV0aG9yPlRha2V1Y2hpLCBELjwvYXV0aG9yPjxhdXRob3I+S3VyaW5hbWksIEguPC9hdXRo

b3I+PGF1dGhvcj5TaGlub2hhcmEsIE0uPC9hdXRob3I+PGF1dGhvcj5SYWt1Z2ksIEguPC9hdXRo

b3I+PGF1dGhvcj5Nb3Jpc2hpdGEsIFIuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

PjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBDbGluaWNhbCBHZW5lIFRoZXJhcHksIEdyYWR1

YXRlIFNjaG9vbCBvZiBNZWRpY2luZSwgT3Nha2EgVW5pdmVyc2l0eSwgT3Nha2EgNTY1LTA4NzEs

IEphcGFuLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkRpYWJldGVzLWFjY2VsZXJhdGVk

IG1lbW9yeSBkeXNmdW5jdGlvbiB2aWEgY2VyZWJyb3Zhc2N1bGFyIGluZmxhbW1hdGlvbiBhbmQg

QWJldGEgZGVwb3NpdGlvbiBpbiBhbiBBbHpoZWltZXIgbW91c2UgbW9kZWwgd2l0aCBkaWFiZXRl

czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Qcm9jIE5hdGwgQWNhZCBTY2kgVSBTIEE8L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Qcm9jIE5hdGwgQWNh

ZCBTY2kgVSBTIEE8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz43MDM2LTQxPC9wYWdl

cz48dm9sdW1lPjEwNzwvdm9sdW1lPjxudW1iZXI+MTU8L251bWJlcj48a2V5d29yZHM+PGtleXdv

cmQ+QWx6aGVpbWVyIERpc2Vhc2UvY29tcGxpY2F0aW9ucy8qcGh5c2lvcGF0aG9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy8qYmlvc3ludGhlc2lzPC9rZXl3b3Jk

PjxrZXl3b3JkPkFuaW1hbCBGZWVkPC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+

PGtleXdvcmQ+Q2VyZWJyb3Zhc2N1bGFyIENpcmN1bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkNy

b3NzZXMsIEdlbmV0aWM8L2tleXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgTWVsbGl0dXMsIEV4cGVy

aW1lbnRhbC8qcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkRpc2Vhc2UgTW9kZWxz

LCBBbmltYWw8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkluZmxh

bW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5JbnN1bGluL21ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NZW1vcnkgRGlzb3JkZXJzL2NvbXBsaWNhdGlv

bnMvKnBoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3

b3JkPk1pY2UsIEluYnJlZCBDNTdCTDwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFuc2dlbmlj

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTA8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5BcHIgMTM8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMDkxLTY0OTAgKEVs

ZWN0cm9uaWMpJiN4RDswMDI3LTg0MjQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIw

MjMxNDY4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3

Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIwMjMxNDY4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91

cmxzPjxjdXN0b20yPlBNQzI4NzI0NDk8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjEwLjEwNzMvcG5hcy4xMDAwNjQ1MTA3PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29y

ZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZYW5nPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj

TnVtPjk4NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjI3

MSwyNzI8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj45ODc8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY0MCI+OTg3PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5ZYW5nLCBZaTwvYXV0aG9yPjxhdXRob3I+

V3UsIFlpbGk8L2F1dGhvcj48YXV0aG9yPlpoYW5nLCBTaHV0aW5nPC9hdXRob3I+PGF1dGhvcj5T

b25nLCBXZWlob25nPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRp

dGxlPkhpZ2ggR2x1Y29zZSBQcm9tb3RlcyBBzrIgUHJvZHVjdGlvbiBieSBJbmhpYml0aW5nIEFQ

UCBEZWdyYWRhdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5QTG9TIE9ORTwvc2Vjb25kYXJ5

LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlBMb1MgT25lPC9mdWxsLXRp

dGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+ZTY5ODI0PC9wYWdlcz48dm9sdW1lPjg8L3ZvbHVtZT48

bnVtYmVyPjc8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRl

PjIwMTMvMDcvMjM8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPlB1YmxpYyBM

aWJyYXJ5IG9mIFNjaWVuY2UgKFBMb1MpPC9wdWJsaXNoZXI+PGlzYm4+MTkzMi02MjAzPC9pc2Ju

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMzcxL2pvdXJu

YWwucG9uZS4wMDY5ODI0PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4xMzcxL2pvdXJuYWwucG9uZS4wMDY5ODI0PC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5UYWtlZGE8L0F1dGhvcj48WWVh

cj4yMDEwPC9ZZWFyPjxSZWNOdW0+MzI4ODwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MzI4

ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUy

cHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTA2MTAyIj4zMjg4

PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8

L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5UYWtlZGEsIFMuPC9hdXRo

b3I+PGF1dGhvcj5TYXRvLCBOLjwvYXV0aG9yPjxhdXRob3I+VWNoaW8tWWFtYWRhLCBLLjwvYXV0

aG9yPjxhdXRob3I+U2F3YWRhLCBLLjwvYXV0aG9yPjxhdXRob3I+S3VuaWVkYSwgVC48L2F1dGhv

cj48YXV0aG9yPlRha2V1Y2hpLCBELjwvYXV0aG9yPjxhdXRob3I+S3VyaW5hbWksIEguPC9hdXRo

b3I+PGF1dGhvcj5TaGlub2hhcmEsIE0uPC9hdXRob3I+PGF1dGhvcj5SYWt1Z2ksIEguPC9hdXRo

b3I+PGF1dGhvcj5Nb3Jpc2hpdGEsIFIuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

PjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBDbGluaWNhbCBHZW5lIFRoZXJhcHksIEdyYWR1

YXRlIFNjaG9vbCBvZiBNZWRpY2luZSwgT3Nha2EgVW5pdmVyc2l0eSwgT3Nha2EgNTY1LTA4NzEs

IEphcGFuLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkRpYWJldGVzLWFjY2VsZXJhdGVk

IG1lbW9yeSBkeXNmdW5jdGlvbiB2aWEgY2VyZWJyb3Zhc2N1bGFyIGluZmxhbW1hdGlvbiBhbmQg

QWJldGEgZGVwb3NpdGlvbiBpbiBhbiBBbHpoZWltZXIgbW91c2UgbW9kZWwgd2l0aCBkaWFiZXRl

czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Qcm9jIE5hdGwgQWNhZCBTY2kgVSBTIEE8L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Qcm9jIE5hdGwgQWNh

ZCBTY2kgVSBTIEE8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz43MDM2LTQxPC9wYWdl

cz48dm9sdW1lPjEwNzwvdm9sdW1lPjxudW1iZXI+MTU8L251bWJlcj48a2V5d29yZHM+PGtleXdv

cmQ+QWx6aGVpbWVyIERpc2Vhc2UvY29tcGxpY2F0aW9ucy8qcGh5c2lvcGF0aG9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy8qYmlvc3ludGhlc2lzPC9rZXl3b3Jk

PjxrZXl3b3JkPkFuaW1hbCBGZWVkPC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+

PGtleXdvcmQ+Q2VyZWJyb3Zhc2N1bGFyIENpcmN1bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkNy

b3NzZXMsIEdlbmV0aWM8L2tleXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgTWVsbGl0dXMsIEV4cGVy

aW1lbnRhbC8qcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkRpc2Vhc2UgTW9kZWxz

LCBBbmltYWw8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkluZmxh

bW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5JbnN1bGluL21ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NZW1vcnkgRGlzb3JkZXJzL2NvbXBsaWNhdGlv

bnMvKnBoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3

b3JkPk1pY2UsIEluYnJlZCBDNTdCTDwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFuc2dlbmlj

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTA8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5BcHIgMTM8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMDkxLTY0OTAgKEVs

ZWN0cm9uaWMpJiN4RDswMDI3LTg0MjQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIw

MjMxNDY4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3

Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIwMjMxNDY4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91

cmxzPjxjdXN0b20yPlBNQzI4NzI0NDk8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjEwLjEwNzMvcG5hcy4xMDAwNjQ1MTA3PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29y

ZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 271,272, creating a vicious cycle of dysfunctional CNS insulin signaling, oxidative stress and neuroinflammation, culminating in cognitive deficits PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaGFyYWR3YWo8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFy

PjxSZWNOdW0+MjExMTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjI3Mzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjIxMTE8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDg2MzUyNCI+MjExMTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QmhhcmFkd2FqLCBQLjwvYXV0aG9y

PjxhdXRob3I+U29sb21vbiwgVC48L2F1dGhvcj48YXV0aG9yPk1hbGFqY3p1aywgQy4gSi48L2F1

dGhvcj48YXV0aG9yPk1hbmNlcmEsIFIuIEwuPC9hdXRob3I+PGF1dGhvcj5Ib3dhcmQsIE0uPC9h

dXRob3I+PGF1dGhvcj5BcnJpZ2FuLCBELiBXLiBNLjwvYXV0aG9yPjxhdXRob3I+TmV3c2hvbG1l

LCBQLjwvYXV0aG9yPjxhdXRob3I+TWFydGlucywgUi4gTi48L2F1dGhvcj48L2F1dGhvcnM+PC9j

b250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DZW50cmUgb2YgRXhjZWxsZW5jZSBmb3IgQWx6aGVp

bWVyJmFwb3M7cyBEaXNlYXNlIFJlc2VhcmNoIGFuZCBDYXJlLCBTY2hvb2wgb2YgTWVkaWNhbCBh

bmQgSGVhbHRoIFNjaWVuY2VzLCBFZGl0aCBDb3dhbiBVbml2ZXJzaXR5LCBBdXN0cmFsaWE7IFNj

aG9vbCBvZiBQaGFybWFjeSBhbmQgQmlvbWVkaWNhbCBTY2llbmNlcyBhbmQgQ3VydGluIEhlYWx0

aCBJbm5vdmF0aW9uIFJlc2VhcmNoIEluc3RpdHV0ZSwgQ3VydGluIFVuaXZlcnNpdHksIEdQTyBC

b3ggVTE5ODcsIFBlcnRoLCBXZXN0ZXJuIEF1c3RyYWxpYSA2ODQ1LCBBdXN0cmFsaWEuIEVsZWN0

cm9uaWMgYWRkcmVzczogcC5iaGFyYWR3YWpAZWN1LmVkdS5hdS4mI3hEO1NjaG9vbCBvZiBQaGFy

bWFjeSBhbmQgQmlvbWVkaWNhbCBTY2llbmNlcyBhbmQgQ3VydGluIEhlYWx0aCBJbm5vdmF0aW9u

IFJlc2VhcmNoIEluc3RpdHV0ZSwgQ3VydGluIFVuaXZlcnNpdHksIEdQTyBCb3ggVTE5ODcsIFBl

cnRoLCBXZXN0ZXJuIEF1c3RyYWxpYSA2ODQ1LCBBdXN0cmFsaWEuJiN4RDtDZW50cmUgZm9yIE1p

Y3Jvc2NvcHksIENoYXJhY3RlcmlzYXRpb24gYW5kIEFuYWx5c2lzIChDTUNBKSwgVGhlIFVuaXZl

cnNpdHkgb2YgV2VzdGVybiwgQXVzdHJhbGlhLiYjeEQ7U2Nob29sIG9mIE1vbGVjdWxhciBhbmQg

TGlmZSBTY2llbmNlcywgQ3VydGluIEluc3RpdHV0ZSBmb3IgRnVuY3Rpb25hbCBNb2xlY3VsZXMg

YW5kIEludGVyZmFjZXMsIEN1cnRpbiBVbml2ZXJzaXR5LCBHUE8gQm94IFUxOTg3LCBQZXJ0aCwg

V2VzdGVybiBBdXN0cmFsaWEgNjg0NSwgQXVzdHJhbGlhLiYjeEQ7Q2VudHJlIG9mIEV4Y2VsbGVu

Y2UgZm9yIEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZSBSZXNlYXJjaCBhbmQgQ2FyZSwgU2Nob29s

IG9mIE1lZGljYWwgYW5kIEhlYWx0aCBTY2llbmNlcywgRWRpdGggQ293YW4gVW5pdmVyc2l0eSwg

QXVzdHJhbGlhOyBTY2hvb2wgb2YgQmlvbWVkaWNhbCBTY2llbmNlLCBNYWNxdWFyaWUgVW5pdmVy

c2l0eSwgQXVzdHJhbGlhOyBTY2hvb2wgb2YgUHN5Y2hpYXRyeSBhbmQgQ2xpbmljYWwgTmV1cm9z

Y2llbmNlcywgVW5pdmVyc2l0eSBvZiBXZXN0ZXJuIEF1c3RyYWxpYSwgQXVzdHJhbGlhLjwvYXV0

aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlJvbGUgb2YgdGhlIGNlbGwgbWVtYnJhbmUgaW50ZXJm

YWNlIGluIG1vZHVsYXRpbmcgcHJvZHVjdGlvbiBhbmQgdXB0YWtlIG9mIEFsemhlaW1lciZhcG9z

O3MgYmV0YSBhbXlsb2lkIHByb3RlaW48L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QmlvY2hpbSBC

aW9waHlzIEFjdGE8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10

aXRsZT5CaW9jaGltIEJpb3BoeXMgQWN0YTwvZnVsbC10aXRsZT48YWJici0xPkJpb2NoaW1pY2Eg

ZXQgYmlvcGh5c2ljYSBhY3RhPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxlZGl0aW9uPjIwMTgvMDMv

MjU8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFQUCBwcm90ZW9seXNpczwva2V5d29yZD48

a2V5d29yZD5NZW1icmFuZSBmbHVpZGl0eTwva2V5d29yZD48a2V5d29yZD5NZW1icmFuZSBwZXJt

ZWFiaWxpemF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlJlY2VwdG9yIG1lZGlhdGVkIHVwdGFrZSBv

ZiBiZXRhIGFteWxvaWQ8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxODwveWVh

cj48cHViLWRhdGVzPjxkYXRlPk1hciAyMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju

PjAwMDYtMzAwMiAoUHJpbnQpJiN4RDswMDA2LTMwMDIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI5NTcyMDMzPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yOTU3MjAzMzwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmJiYW1lbS4y

MDE4LjAzLjAxNTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5k

Tm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaGFyYWR3YWo8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFy

PjxSZWNOdW0+MjExMTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjI3Mzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjIxMTE8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDg2MzUyNCI+MjExMTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QmhhcmFkd2FqLCBQLjwvYXV0aG9y

PjxhdXRob3I+U29sb21vbiwgVC48L2F1dGhvcj48YXV0aG9yPk1hbGFqY3p1aywgQy4gSi48L2F1

dGhvcj48YXV0aG9yPk1hbmNlcmEsIFIuIEwuPC9hdXRob3I+PGF1dGhvcj5Ib3dhcmQsIE0uPC9h

dXRob3I+PGF1dGhvcj5BcnJpZ2FuLCBELiBXLiBNLjwvYXV0aG9yPjxhdXRob3I+TmV3c2hvbG1l

LCBQLjwvYXV0aG9yPjxhdXRob3I+TWFydGlucywgUi4gTi48L2F1dGhvcj48L2F1dGhvcnM+PC9j

b250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DZW50cmUgb2YgRXhjZWxsZW5jZSBmb3IgQWx6aGVp

bWVyJmFwb3M7cyBEaXNlYXNlIFJlc2VhcmNoIGFuZCBDYXJlLCBTY2hvb2wgb2YgTWVkaWNhbCBh

bmQgSGVhbHRoIFNjaWVuY2VzLCBFZGl0aCBDb3dhbiBVbml2ZXJzaXR5LCBBdXN0cmFsaWE7IFNj

aG9vbCBvZiBQaGFybWFjeSBhbmQgQmlvbWVkaWNhbCBTY2llbmNlcyBhbmQgQ3VydGluIEhlYWx0

aCBJbm5vdmF0aW9uIFJlc2VhcmNoIEluc3RpdHV0ZSwgQ3VydGluIFVuaXZlcnNpdHksIEdQTyBC

b3ggVTE5ODcsIFBlcnRoLCBXZXN0ZXJuIEF1c3RyYWxpYSA2ODQ1LCBBdXN0cmFsaWEuIEVsZWN0

cm9uaWMgYWRkcmVzczogcC5iaGFyYWR3YWpAZWN1LmVkdS5hdS4mI3hEO1NjaG9vbCBvZiBQaGFy

bWFjeSBhbmQgQmlvbWVkaWNhbCBTY2llbmNlcyBhbmQgQ3VydGluIEhlYWx0aCBJbm5vdmF0aW9u

IFJlc2VhcmNoIEluc3RpdHV0ZSwgQ3VydGluIFVuaXZlcnNpdHksIEdQTyBCb3ggVTE5ODcsIFBl

cnRoLCBXZXN0ZXJuIEF1c3RyYWxpYSA2ODQ1LCBBdXN0cmFsaWEuJiN4RDtDZW50cmUgZm9yIE1p

Y3Jvc2NvcHksIENoYXJhY3RlcmlzYXRpb24gYW5kIEFuYWx5c2lzIChDTUNBKSwgVGhlIFVuaXZl

cnNpdHkgb2YgV2VzdGVybiwgQXVzdHJhbGlhLiYjeEQ7U2Nob29sIG9mIE1vbGVjdWxhciBhbmQg

TGlmZSBTY2llbmNlcywgQ3VydGluIEluc3RpdHV0ZSBmb3IgRnVuY3Rpb25hbCBNb2xlY3VsZXMg

YW5kIEludGVyZmFjZXMsIEN1cnRpbiBVbml2ZXJzaXR5LCBHUE8gQm94IFUxOTg3LCBQZXJ0aCwg

V2VzdGVybiBBdXN0cmFsaWEgNjg0NSwgQXVzdHJhbGlhLiYjeEQ7Q2VudHJlIG9mIEV4Y2VsbGVu

Y2UgZm9yIEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZSBSZXNlYXJjaCBhbmQgQ2FyZSwgU2Nob29s

IG9mIE1lZGljYWwgYW5kIEhlYWx0aCBTY2llbmNlcywgRWRpdGggQ293YW4gVW5pdmVyc2l0eSwg

QXVzdHJhbGlhOyBTY2hvb2wgb2YgQmlvbWVkaWNhbCBTY2llbmNlLCBNYWNxdWFyaWUgVW5pdmVy

c2l0eSwgQXVzdHJhbGlhOyBTY2hvb2wgb2YgUHN5Y2hpYXRyeSBhbmQgQ2xpbmljYWwgTmV1cm9z

Y2llbmNlcywgVW5pdmVyc2l0eSBvZiBXZXN0ZXJuIEF1c3RyYWxpYSwgQXVzdHJhbGlhLjwvYXV0

aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlJvbGUgb2YgdGhlIGNlbGwgbWVtYnJhbmUgaW50ZXJm

YWNlIGluIG1vZHVsYXRpbmcgcHJvZHVjdGlvbiBhbmQgdXB0YWtlIG9mIEFsemhlaW1lciZhcG9z

O3MgYmV0YSBhbXlsb2lkIHByb3RlaW48L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QmlvY2hpbSBC

aW9waHlzIEFjdGE8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10

aXRsZT5CaW9jaGltIEJpb3BoeXMgQWN0YTwvZnVsbC10aXRsZT48YWJici0xPkJpb2NoaW1pY2Eg

ZXQgYmlvcGh5c2ljYSBhY3RhPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxlZGl0aW9uPjIwMTgvMDMv

MjU8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFQUCBwcm90ZW9seXNpczwva2V5d29yZD48

a2V5d29yZD5NZW1icmFuZSBmbHVpZGl0eTwva2V5d29yZD48a2V5d29yZD5NZW1icmFuZSBwZXJt

ZWFiaWxpemF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlJlY2VwdG9yIG1lZGlhdGVkIHVwdGFrZSBv

ZiBiZXRhIGFteWxvaWQ8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxODwveWVh

cj48cHViLWRhdGVzPjxkYXRlPk1hciAyMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju

PjAwMDYtMzAwMiAoUHJpbnQpJiN4RDswMDA2LTMwMDIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI5NTcyMDMzPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yOTU3MjAzMzwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmJiYW1lbS4y

MDE4LjAzLjAxNTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5k

Tm90ZT5=

ADDIN EN.CITE.DATA 273. Despite controversial, this may also involve the hyperphosphorylated Tau-induced destabilization of microtubules in β-cells, blunting insulin secretion ADDIN EN.CITE <EndNote><Cite><Author>Balczon</Author><Year>1992</Year><RecNum>991</RecNum><DisplayText><style face="superscript">274</style></DisplayText><record><rec-number>991</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865640">991</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Balczon, R.</author></authors></contributors><titles><title>The identification, purification, and characterization of a pancreatic beta-cell form of the microtubule adenosine triphosphatase kinesin</title><secondary-title>Endocrinology</secondary-title></titles><periodical><full-title>Endocrinology</full-title></periodical><pages>331-336</pages><volume>131</volume><number>1</number><dates><year>1992</year><pub-dates><date>1992/07/01</date></pub-dates></dates><publisher>The Endocrine Society</publisher><isbn>0013-7227</isbn><urls><related-urls><url> and insulin-mediated trafficking of glucose transporter-4 (GLUT4)-containing vesicles to the plasma membrane. Hence, glucose uptake into skeletal muscle and adipocytes is inhibited and type 2 diabetes (T2D) may arise PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbHZpbTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl

Y051bT45OTI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4y

NzUtMjc3PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+OTkyPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU2NDAiPjk5Mjwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QWx2aW0sIFJhZmFlbCBPLjwvYXV0aG9y

PjxhdXRob3I+Q2hldWhlbiwgTWFyY2VsIFIuPC9hdXRob3I+PGF1dGhvcj5NYWNoYWRvLCBTaWxt

YXJhIFIuPC9hdXRob3I+PGF1dGhvcj5Tb3VzYSwgQW5kcsOJIEd1c3Rhdm8gUC48L2F1dGhvcj48

YXV0aG9yPlNhbnRvcywgUGF1bG8gQy4gSi4gTC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli

dXRvcnM+PHRpdGxlcz48dGl0bGU+R2VuZXJhbCBhc3BlY3RzIG9mIG11c2NsZSBnbHVjb3NlIHVw

dGFrZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbmFpcyBkYSBBY2FkZW1pYSBCcmFzaWxlaXJh

IGRlIENpw6puY2lhczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4zNTEtMzY4PC9w

YWdlcz48dm9sdW1lPjg3PC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIw

MTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDE1LzAzLzA2PC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PHB1Ymxpc2hlcj5GYXBVTklGRVNQIChTY2lFTE8pPC9wdWJsaXNoZXI+PGlzYm4+MTY3

OC0yNjkwJiN4RDswMDAxLTM3NjU8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6

Ly9keC5kb2kub3JnLzEwLjE1OTAvMDAwMS0zNzY1MjAxNTIwMTQwMjI1PC91cmw+PC9yZWxhdGVk

LXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTkwLzAwMDEtMzc2NTIw

MTUyMDE0MDIyNTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRl

PjxBdXRob3I+RW1vdG88L0F1dGhvcj48WWVhcj4yMDAxPC9ZZWFyPjxSZWNOdW0+OTkzPC9SZWNO

dW0+PHJlY29yZD48cmVjLW51bWJlcj45OTM8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5

IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRp

bWVzdGFtcD0iMTUzMjg2NTY0MCI+OTkzPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5FbW90bywgTWFzYWhpcm88L2F1dGhvcj48YXV0aG9yPkxhbmdpbGxlLCBTdGVwaGVu

IEUuPC9hdXRob3I+PGF1dGhvcj5DemVjaCwgTWljaGFlbCBQLjwvYXV0aG9yPjwvYXV0aG9ycz48

L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5BIFJvbGUgZm9yIEtpbmVzaW4gaW4gSW5zdWxp

bi1zdGltdWxhdGVkIEdMVVQ0IEdsdWNvc2UgVHJhbnNwb3J0ZXIgVHJhbnNsb2NhdGlvbiBpbiAz

VDMtTDEgQWRpcG9jeXRlczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Kb3VybmFsIG9mIEJpb2xv

Z2ljYWwgQ2hlbWlzdHJ5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEwNjc3LTEw

NjgyPC9wYWdlcz48dm9sdW1lPjI3Njwvdm9sdW1lPjxudW1iZXI+MTQ8L251bWJlcj48ZGF0ZXM+

PHllYXI+MjAwMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMDEvMDEvMDU8L2RhdGU+PC9wdWIt

ZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkFtZXJpY2FuIFNvY2lldHkgZm9yIEJpb2NoZW1pc3Ry

eSAmYW1wOyBNb2xlY3VsYXIgQmlvbG9neSAoQVNCTUIpPC9wdWJsaXNoZXI+PGlzYm4+MDAyMS05

MjU4JiN4RDsxMDgzLTM1MVg8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9k

eC5kb2kub3JnLzEwLjEwNzQvamJjLm0wMTA3ODUyMDA8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwNzQvamJjLm0wMTA3ODUyMDA8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk9sc29uPC9B

dXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVjTnVtPjk5NDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1u

dW1iZXI+OTk0PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0i

ZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU2

NDAiPjk5NDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj

bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+T2xzb24sIEFu

biBMb3Vpc2U8L2F1dGhvcj48YXV0aG9yPlRydW1ibHksIEFsYW4gUi48L2F1dGhvcj48YXV0aG9y

PkdpYnNvbiwgR2VvcmdlIFYuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRs

ZXM+PHRpdGxlPkluc3VsaW4tbWVkaWF0ZWQgR0xVVDQgVHJhbnNsb2NhdGlvbiBJcyBEZXBlbmRl

bnQgb24gdGhlIE1pY3JvdHVidWxlIE5ldHdvcms8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Sm91

cm5hbCBvZiBCaW9sb2dpY2FsIENoZW1pc3RyeTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxw

YWdlcz4xMDcwNi0xMDcxNDwvcGFnZXM+PHZvbHVtZT4yNzY8L3ZvbHVtZT48bnVtYmVyPjE0PC9u

dW1iZXI+PGRhdGVzPjx5ZWFyPjIwMDE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDAxLzAxLzEy

PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5BbWVyaWNhbiBTb2NpZXR5IGZv

ciBCaW9jaGVtaXN0cnkgJmFtcDsgTW9sZWN1bGFyIEJpb2xvZ3kgKEFTQk1CKTwvcHVibGlzaGVy

Pjxpc2JuPjAwMjEtOTI1OCYjeEQ7MTA4My0zNTFYPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDc0L2piYy5tMDA3NjEwMjAwPC91cmw+PC9yZWxh

dGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDc0L2piYy5tMDA3

NjEwMjAwPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3Rl

Pn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbHZpbTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl

Y051bT45OTI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4y

NzUtMjc3PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+OTkyPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU2NDAiPjk5Mjwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QWx2aW0sIFJhZmFlbCBPLjwvYXV0aG9y

PjxhdXRob3I+Q2hldWhlbiwgTWFyY2VsIFIuPC9hdXRob3I+PGF1dGhvcj5NYWNoYWRvLCBTaWxt

YXJhIFIuPC9hdXRob3I+PGF1dGhvcj5Tb3VzYSwgQW5kcsOJIEd1c3Rhdm8gUC48L2F1dGhvcj48

YXV0aG9yPlNhbnRvcywgUGF1bG8gQy4gSi4gTC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli

dXRvcnM+PHRpdGxlcz48dGl0bGU+R2VuZXJhbCBhc3BlY3RzIG9mIG11c2NsZSBnbHVjb3NlIHVw

dGFrZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbmFpcyBkYSBBY2FkZW1pYSBCcmFzaWxlaXJh

IGRlIENpw6puY2lhczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4zNTEtMzY4PC9w

YWdlcz48dm9sdW1lPjg3PC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIw

MTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDE1LzAzLzA2PC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PHB1Ymxpc2hlcj5GYXBVTklGRVNQIChTY2lFTE8pPC9wdWJsaXNoZXI+PGlzYm4+MTY3

OC0yNjkwJiN4RDswMDAxLTM3NjU8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6

Ly9keC5kb2kub3JnLzEwLjE1OTAvMDAwMS0zNzY1MjAxNTIwMTQwMjI1PC91cmw+PC9yZWxhdGVk

LXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTkwLzAwMDEtMzc2NTIw

MTUyMDE0MDIyNTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRl

PjxBdXRob3I+RW1vdG88L0F1dGhvcj48WWVhcj4yMDAxPC9ZZWFyPjxSZWNOdW0+OTkzPC9SZWNO

dW0+PHJlY29yZD48cmVjLW51bWJlcj45OTM8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5

IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRp

bWVzdGFtcD0iMTUzMjg2NTY0MCI+OTkzPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5FbW90bywgTWFzYWhpcm88L2F1dGhvcj48YXV0aG9yPkxhbmdpbGxlLCBTdGVwaGVu

IEUuPC9hdXRob3I+PGF1dGhvcj5DemVjaCwgTWljaGFlbCBQLjwvYXV0aG9yPjwvYXV0aG9ycz48

L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5BIFJvbGUgZm9yIEtpbmVzaW4gaW4gSW5zdWxp

bi1zdGltdWxhdGVkIEdMVVQ0IEdsdWNvc2UgVHJhbnNwb3J0ZXIgVHJhbnNsb2NhdGlvbiBpbiAz

VDMtTDEgQWRpcG9jeXRlczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Kb3VybmFsIG9mIEJpb2xv

Z2ljYWwgQ2hlbWlzdHJ5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEwNjc3LTEw

NjgyPC9wYWdlcz48dm9sdW1lPjI3Njwvdm9sdW1lPjxudW1iZXI+MTQ8L251bWJlcj48ZGF0ZXM+

PHllYXI+MjAwMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMDEvMDEvMDU8L2RhdGU+PC9wdWIt

ZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkFtZXJpY2FuIFNvY2lldHkgZm9yIEJpb2NoZW1pc3Ry

eSAmYW1wOyBNb2xlY3VsYXIgQmlvbG9neSAoQVNCTUIpPC9wdWJsaXNoZXI+PGlzYm4+MDAyMS05

MjU4JiN4RDsxMDgzLTM1MVg8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9k

eC5kb2kub3JnLzEwLjEwNzQvamJjLm0wMTA3ODUyMDA8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwNzQvamJjLm0wMTA3ODUyMDA8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk9sc29uPC9B

dXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVjTnVtPjk5NDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1u

dW1iZXI+OTk0PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0i

ZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU2

NDAiPjk5NDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj

bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+T2xzb24sIEFu

biBMb3Vpc2U8L2F1dGhvcj48YXV0aG9yPlRydW1ibHksIEFsYW4gUi48L2F1dGhvcj48YXV0aG9y

PkdpYnNvbiwgR2VvcmdlIFYuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRs

ZXM+PHRpdGxlPkluc3VsaW4tbWVkaWF0ZWQgR0xVVDQgVHJhbnNsb2NhdGlvbiBJcyBEZXBlbmRl

bnQgb24gdGhlIE1pY3JvdHVidWxlIE5ldHdvcms8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Sm91

cm5hbCBvZiBCaW9sb2dpY2FsIENoZW1pc3RyeTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxw

YWdlcz4xMDcwNi0xMDcxNDwvcGFnZXM+PHZvbHVtZT4yNzY8L3ZvbHVtZT48bnVtYmVyPjE0PC9u

dW1iZXI+PGRhdGVzPjx5ZWFyPjIwMDE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDAxLzAxLzEy

PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5BbWVyaWNhbiBTb2NpZXR5IGZv

ciBCaW9jaGVtaXN0cnkgJmFtcDsgTW9sZWN1bGFyIEJpb2xvZ3kgKEFTQk1CKTwvcHVibGlzaGVy

Pjxpc2JuPjAwMjEtOTI1OCYjeEQ7MTA4My0zNTFYPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDc0L2piYy5tMDA3NjEwMjAwPC91cmw+PC9yZWxh

dGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDc0L2piYy5tMDA3

NjEwMjAwPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3Rl

Pn==

ADDIN EN.CITE.DATA 275-277.Insulin and its downstream signaling cascades play a crucial role against CNS damage and disease. Besides the known regulation of brain glucose/bioenergetic homeostasis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qb3J0ZTwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJl

Y051bT45OTc8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4y

NzgtMjgwPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+OTk3PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU2NDAiPjk5Nzwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+UG9ydGUsIEQuPC9hdXRob3I+PGF1dGhv

cj5CYXNraW4sIEQuIEcuPC9hdXRob3I+PGF1dGhvcj5TY2h3YXJ0eiwgTS4gVy48L2F1dGhvcj48

L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+SW5zdWxpbiBTaWduYWxpbmcg

aW4gdGhlIENlbnRyYWwgTmVydm91cyBTeXN0ZW06IEEgQ3JpdGljYWwgUm9sZSBpbiBNZXRhYm9s

aWMgSG9tZW9zdGFzaXMgYW5kIERpc2Vhc2UgRnJvbSBDLiBlbGVnYW5zIHRvIEh1bWFuczwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5EaWFiZXRlczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxw

YWdlcz4xMjY0LTEyNzY8L3BhZ2VzPjx2b2x1bWU+NTQ8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJl

cj48ZGF0ZXM+PHllYXI+MjAwNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMDUvMDQvMjY8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkFtZXJpY2FuIERpYWJldGVzIEFzc29j

aWF0aW9uPC9wdWJsaXNoZXI+PGlzYm4+MDAxMi0xNzk3JiN4RDsxOTM5LTMyN1g8L2lzYm4+PHVy

bHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjIzMzcvZGlhYmV0ZXMu

NTQuNS4xMjY0PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNl

LW51bT4xMC4yMzM3L2RpYWJldGVzLjU0LjUuMTI2NDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+WWluPC9BdXRob3I+PFllYXI+MjAxNTwvWWVh

cj48UmVjTnVtPjk5NTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+OTk1PC9yZWMtbnVtYmVy

Pjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBm

d3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU2NDAiPjk5NTwva2V5PjwvZm9yZWln

bi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29u

dHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+WWluLCBGZWk8L2F1dGhvcj48YXV0aG9yPllhbywg

SmlhPC9hdXRob3I+PGF1dGhvcj5TYW5jaGV0aSwgSGFyc2g8L2F1dGhvcj48YXV0aG9yPkZlbmcs

IFRhbzwvYXV0aG9yPjxhdXRob3I+TWVsY2FuZ2ksIFJvYmVydG8gQy48L2F1dGhvcj48YXV0aG9y

Pk1vcmdhbiwgVG9kZCBFLjwvYXV0aG9yPjxhdXRob3I+RmluY2gsIENhbGViIEUuPC9hdXRob3I+

PGF1dGhvcj5QaWtlLCBDaHJpc3RpYW4gSi48L2F1dGhvcj48YXV0aG9yPk1hY2ssIFdlbmR5IEou

PC9hdXRob3I+PGF1dGhvcj5DYWRlbmFzLCBFbnJpcXVlPC9hdXRob3I+PGF1dGhvcj5CcmludG9u

LCBSb2JlcnRhIEQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRp

dGxlPlRoZSBwZXJpbWVub3BhdXNhbCBhZ2luZyB0cmFuc2l0aW9uIGluIHRoZSBmZW1hbGUgcmF0

IGJyYWluOiBkZWNsaW5lIGluIGJpb2VuZXJnZXRpYyBzeXN0ZW1zIGFuZCBzeW5hcHRpYyBwbGFz

dGljaXR5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5ldXJvYmlvbG9neSBvZiBBZ2luZzwvc2Vj

b25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4yMjgyLTIyOTU8L3BhZ2VzPjx2b2x1bWU+MzY8

L3ZvbHVtZT48bnVtYmVyPjc8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNTwveWVhcj48cHViLWRh

dGVzPjxkYXRlPjIwMTUvMDc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVs

c2V2aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MDE5Ny00NTgwPC9pc2JuPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2oubmV1cm9iaW9sYWdpbmcuMjAx

NS4wMy4wMTM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjEwLjEwMTYvai5uZXVyb2Jpb2xhZ2luZy4yMDE1LjAzLjAxMzwvZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TW9yZWlyYTwvQXV0aG9yPjxZ

ZWFyPjIwMDU8L1llYXI+PFJlY051bT4zMjkwPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4z

MjkwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4

NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MDYzODAiPjMy

OTA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x

NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1vcmVpcmEsIFAuIEku

PC9hdXRob3I+PGF1dGhvcj5TYW50b3MsIE0uIFMuPC9hdXRob3I+PGF1dGhvcj5TZW5hLCBDLjwv

YXV0aG9yPjxhdXRob3I+U2VpY2EsIFIuPC9hdXRob3I+PGF1dGhvcj5PbGl2ZWlyYSwgQy4gUi48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DZW50ZXIgZm9y

IE5ldXJvc2NpZW5jZSBvZiBDb2ltYnJhLCBEZXBhcnRtZW50IG9mIFpvb2xvZ3ksIEZhY3VsdHkg

b2YgU2NpZW5jZXMgYW5kIFRlY2hub2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgMzAwNC01

MTcgQ29pbWJyYSwgUG9ydHVnYWwuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+SW5zdWxp

biBwcm90ZWN0cyBhZ2FpbnN0IGFteWxvaWQgYmV0YS1wZXB0aWRlIHRveGljaXR5IGluIGJyYWlu

IG1pdG9jaG9uZHJpYSBvZiBkaWFiZXRpYyByYXRzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5l

dXJvYmlvbCBEaXM8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10

aXRsZT5OZXVyb2Jpb2wgRGlzPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NjI4LTM3

PC9wYWdlcz48dm9sdW1lPjE4PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGtleXdvcmRzPjxr

ZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy8qdG94aWNpdHk8L2tleXdvcmQ+PGtleXdvcmQ+

QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CcmFpbi8qZHJ1ZyBlZmZlY3RzL21ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgTWVsbGl0dXMsIEV4cGVyaW1lbnRhbC8qZHJ1ZyB0

aGVyYXB5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+R2x1dGF0aGlvbmUvbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5JbnN1bGluL3BoYXJtYWNvbG9neS8qdGhlcmFwZXV0aWMgdXNl

PC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2Nob25kcmlhLypk

cnVnIGVmZmVjdHMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5OZXVyb3Byb3RlY3RpdmUg

QWdlbnRzL3BoYXJtYWNvbG9neS90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+UGVw

dGlkZSBGcmFnbWVudHMvKnRveGljaXR5PC9rZXl3b3JkPjxrZXl3b3JkPlJhdHM8L2tleXdvcmQ+

PGtleXdvcmQ+UmF0cywgV2lzdGFyPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MDU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BcHI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4wOTY5LTk5NjEgKFByaW50KSYjeEQ7MDk2OS05OTYxIChMaW5raW5nKTwvaXNibj48YWNj

ZXNzaW9uLW51bT4xNTc1NTY4ODwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1

cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNTc1NTY4ODwvdXJsPjwvcmVs

YXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLm5iZC4y

MDA0LjEwLjAxNzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5k

Tm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qb3J0ZTwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJl

Y051bT45OTc8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4y

NzgtMjgwPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+OTk3PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU2NDAiPjk5Nzwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+UG9ydGUsIEQuPC9hdXRob3I+PGF1dGhv

cj5CYXNraW4sIEQuIEcuPC9hdXRob3I+PGF1dGhvcj5TY2h3YXJ0eiwgTS4gVy48L2F1dGhvcj48

L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+SW5zdWxpbiBTaWduYWxpbmcg

aW4gdGhlIENlbnRyYWwgTmVydm91cyBTeXN0ZW06IEEgQ3JpdGljYWwgUm9sZSBpbiBNZXRhYm9s

aWMgSG9tZW9zdGFzaXMgYW5kIERpc2Vhc2UgRnJvbSBDLiBlbGVnYW5zIHRvIEh1bWFuczwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5EaWFiZXRlczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxw

YWdlcz4xMjY0LTEyNzY8L3BhZ2VzPjx2b2x1bWU+NTQ8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJl

cj48ZGF0ZXM+PHllYXI+MjAwNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMDUvMDQvMjY8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkFtZXJpY2FuIERpYWJldGVzIEFzc29j

aWF0aW9uPC9wdWJsaXNoZXI+PGlzYm4+MDAxMi0xNzk3JiN4RDsxOTM5LTMyN1g8L2lzYm4+PHVy

bHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjIzMzcvZGlhYmV0ZXMu

NTQuNS4xMjY0PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNl

LW51bT4xMC4yMzM3L2RpYWJldGVzLjU0LjUuMTI2NDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+WWluPC9BdXRob3I+PFllYXI+MjAxNTwvWWVh

cj48UmVjTnVtPjk5NTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+OTk1PC9yZWMtbnVtYmVy

Pjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBm

d3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU2NDAiPjk5NTwva2V5PjwvZm9yZWln

bi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29u

dHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+WWluLCBGZWk8L2F1dGhvcj48YXV0aG9yPllhbywg

SmlhPC9hdXRob3I+PGF1dGhvcj5TYW5jaGV0aSwgSGFyc2g8L2F1dGhvcj48YXV0aG9yPkZlbmcs

IFRhbzwvYXV0aG9yPjxhdXRob3I+TWVsY2FuZ2ksIFJvYmVydG8gQy48L2F1dGhvcj48YXV0aG9y

Pk1vcmdhbiwgVG9kZCBFLjwvYXV0aG9yPjxhdXRob3I+RmluY2gsIENhbGViIEUuPC9hdXRob3I+

PGF1dGhvcj5QaWtlLCBDaHJpc3RpYW4gSi48L2F1dGhvcj48YXV0aG9yPk1hY2ssIFdlbmR5IEou

PC9hdXRob3I+PGF1dGhvcj5DYWRlbmFzLCBFbnJpcXVlPC9hdXRob3I+PGF1dGhvcj5CcmludG9u

LCBSb2JlcnRhIEQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRp

dGxlPlRoZSBwZXJpbWVub3BhdXNhbCBhZ2luZyB0cmFuc2l0aW9uIGluIHRoZSBmZW1hbGUgcmF0

IGJyYWluOiBkZWNsaW5lIGluIGJpb2VuZXJnZXRpYyBzeXN0ZW1zIGFuZCBzeW5hcHRpYyBwbGFz

dGljaXR5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5ldXJvYmlvbG9neSBvZiBBZ2luZzwvc2Vj

b25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4yMjgyLTIyOTU8L3BhZ2VzPjx2b2x1bWU+MzY8

L3ZvbHVtZT48bnVtYmVyPjc8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNTwveWVhcj48cHViLWRh

dGVzPjxkYXRlPjIwMTUvMDc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVs

c2V2aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MDE5Ny00NTgwPC9pc2JuPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2oubmV1cm9iaW9sYWdpbmcuMjAx

NS4wMy4wMTM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjEwLjEwMTYvai5uZXVyb2Jpb2xhZ2luZy4yMDE1LjAzLjAxMzwvZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TW9yZWlyYTwvQXV0aG9yPjxZ

ZWFyPjIwMDU8L1llYXI+PFJlY051bT4zMjkwPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4z

MjkwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4

NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MDYzODAiPjMy

OTA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x

NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1vcmVpcmEsIFAuIEku

PC9hdXRob3I+PGF1dGhvcj5TYW50b3MsIE0uIFMuPC9hdXRob3I+PGF1dGhvcj5TZW5hLCBDLjwv

YXV0aG9yPjxhdXRob3I+U2VpY2EsIFIuPC9hdXRob3I+PGF1dGhvcj5PbGl2ZWlyYSwgQy4gUi48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DZW50ZXIgZm9y

IE5ldXJvc2NpZW5jZSBvZiBDb2ltYnJhLCBEZXBhcnRtZW50IG9mIFpvb2xvZ3ksIEZhY3VsdHkg

b2YgU2NpZW5jZXMgYW5kIFRlY2hub2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgMzAwNC01

MTcgQ29pbWJyYSwgUG9ydHVnYWwuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+SW5zdWxp

biBwcm90ZWN0cyBhZ2FpbnN0IGFteWxvaWQgYmV0YS1wZXB0aWRlIHRveGljaXR5IGluIGJyYWlu

IG1pdG9jaG9uZHJpYSBvZiBkaWFiZXRpYyByYXRzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5l

dXJvYmlvbCBEaXM8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10

aXRsZT5OZXVyb2Jpb2wgRGlzPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NjI4LTM3

PC9wYWdlcz48dm9sdW1lPjE4PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGtleXdvcmRzPjxr

ZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy8qdG94aWNpdHk8L2tleXdvcmQ+PGtleXdvcmQ+

QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CcmFpbi8qZHJ1ZyBlZmZlY3RzL21ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgTWVsbGl0dXMsIEV4cGVyaW1lbnRhbC8qZHJ1ZyB0

aGVyYXB5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+R2x1dGF0aGlvbmUvbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5JbnN1bGluL3BoYXJtYWNvbG9neS8qdGhlcmFwZXV0aWMgdXNl

PC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2Nob25kcmlhLypk

cnVnIGVmZmVjdHMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5OZXVyb3Byb3RlY3RpdmUg

QWdlbnRzL3BoYXJtYWNvbG9neS90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+UGVw

dGlkZSBGcmFnbWVudHMvKnRveGljaXR5PC9rZXl3b3JkPjxrZXl3b3JkPlJhdHM8L2tleXdvcmQ+

PGtleXdvcmQ+UmF0cywgV2lzdGFyPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MDU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BcHI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4wOTY5LTk5NjEgKFByaW50KSYjeEQ7MDk2OS05OTYxIChMaW5raW5nKTwvaXNibj48YWNj

ZXNzaW9uLW51bT4xNTc1NTY4ODwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1

cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNTc1NTY4ODwvdXJsPjwvcmVs

YXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLm5iZC4y

MDA0LjEwLjAxNzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5k

Tm90ZT4A

ADDIN EN.CITE.DATA 278-280, insulin signaling protects against oxidative stress, (neuro)inflammation and dysfunctional intracellular quality control mechanisms PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdWFydGU8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS

ZWNOdW0+MTAwMDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI4MS0yODQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMDAwPC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU2NDAiPjEwMDA8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkR1YXJ0ZSwgQS4gSS48L2F1dGhv

cj48YXV0aG9yPlByb2VuY2EsIFQuPC9hdXRob3I+PGF1dGhvcj5PbGl2ZWlyYSwgQy4gUi48L2F1

dGhvcj48YXV0aG9yPlNhbnRvcywgTS4gUy48L2F1dGhvcj48YXV0aG9yPlJlZ28sIEEuIEMuPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkluc3VsaW4gUmVz

dG9yZXMgTWV0YWJvbGljIEZ1bmN0aW9uIGluIEN1bHR1cmVkIENvcnRpY2FsIE5ldXJvbnMgU3Vi

amVjdGVkIHRvIE94aWRhdGl2ZSBTdHJlc3M8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+RGlhYmV0

ZXM8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+Mjg2My0yODcwPC9wYWdlcz48dm9s

dW1lPjU1PC92b2x1bWU+PG51bWJlcj4xMDwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDA2PC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+MjAwNi8wOS8yNjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxw

dWJsaXNoZXI+QW1lcmljYW4gRGlhYmV0ZXMgQXNzb2NpYXRpb248L3B1Ymxpc2hlcj48aXNibj4w

MDEyLTE3OTcmI3hEOzE5MzktMzI3WDwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL2R4LmRvaS5vcmcvMTAuMjMzNy9kYjA2LTAwMzA8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjIzMzcvZGIwNi0wMDMwPC9lbGVjdHJvbmlj

LXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5TYW50b3M8L0F1dGhv

cj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNOdW0+MzI5MTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1i

ZXI+MzI5MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3

YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTA2NTUy

Ij4zMjkxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs

ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TYW50b3MsIFIu

IFguPC9hdXRob3I+PGF1dGhvcj5Db3JyZWlhLCBTLiBDLjwvYXV0aG9yPjxhdXRob3I+QWx2ZXMs

IE0uIEcuPC9hdXRob3I+PGF1dGhvcj5PbGl2ZWlyYSwgUC4gRi48L2F1dGhvcj48YXV0aG9yPkNh

cmRvc28sIFMuPC9hdXRob3I+PGF1dGhvcj5DYXJ2YWxobywgQy48L2F1dGhvcj48YXV0aG9yPkR1

YXJ0ZSwgQS4gSS48L2F1dGhvcj48YXV0aG9yPlNhbnRvcywgTS4gUy48L2F1dGhvcj48YXV0aG9y

Pk1vcmVpcmEsIFAuIEkuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk

ZHJlc3M+RGVwYXJ0bWVudCBvZiBMaWZlIFNjaWVuY2VzLCBGYWN1bHR5IG9mIFNjaWVuY2VzIGFu

ZCBUZWNobm9sb2d5LCBVbml2ZXJzaXR5IG9mIENvaW1icmEsIFBvcnR1Z2FsOyBDTkMgLSBDZW50

ZXIgZm9yIE5ldXJvc2NpZW5jZSBhbmQgQ2VsbCBCaW9sb2d5LCBVbml2ZXJzaXR5IG9mIENvaW1i

cmEsIENvaW1icmEsIFBvcnR1Z2FsLiYjeEQ7Q05DIC0gQ2VudGVyIGZvciBOZXVyb3NjaWVuY2Ug

YW5kIENlbGwgQmlvbG9neSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhLCBDb2ltYnJhLCBQb3J0dWdh

bDsgSW5zdGl0dXRlIGZvciBJbnRlcmRpc2NpcGxpbmFyeSBSZXNlYXJjaCwgVW5pdmVyc2l0eSBv

ZiBDb2ltYnJhLCBDb2ltYnJhLCBQb3J0dWdhbC4mI3hEO0NJQ1MtVUJJLCBIZWFsdGggU2NpZW5j

ZXMgUmVzZWFyY2ggQ2VudHJlLCBVbml2ZXJzaXR5IG9mIEJlaXJhIEludGVyaW9yLCBDb3ZpbGhh

LCBQb3J0dWdhbC4mI3hEO0NOQyAtIENlbnRlciBmb3IgTmV1cm9zY2llbmNlIGFuZCBDZWxsIEJp

b2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgQ29pbWJyYSwgUG9ydHVnYWw7IExhYm9yYXRv

cnkgb2YgUGh5c2lvbG9neSwgRmFjdWx0eSBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBDb2lt

YnJhLCBDb2ltYnJhLCBQb3J0dWdhbC4gRWxlY3Ryb25pYyBhZGRyZXNzOiB2ZW50YUBjaS51Yy5w

dC48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5JbnN1bGluIHRoZXJhcHkgbW9kdWxhdGVz

IG1pdG9jaG9uZHJpYWwgZHluYW1pY3MgYW5kIGJpb2dlbmVzaXMsIGF1dG9waGFneSBhbmQgdGF1

IHByb3RlaW4gcGhvc3Bob3J5bGF0aW9uIGluIHRoZSBicmFpbiBvZiB0eXBlIDEgZGlhYmV0aWMg

cmF0czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5CaW9jaGltIEJpb3BoeXMgQWN0YTwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMTU0LTY2PC9wYWdlcz48dm9sdW1lPjE4NDI8L3Zv

bHVtZT48bnVtYmVyPjc8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5d29y

ZD48a2V5d29yZD5BdXRvcGhhZ3kvKmRydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5DYXNw

YXNlIDMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DYXNwYXNlIDkvbWV0YWJvbGlzbTwv

a2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBDb3J0ZXgvKmRydWcgZWZmZWN0cy9tZXRhYm9saXNt

PC9rZXl3b3JkPjxrZXl3b3JkPkRpYWJldGVzIE1lbGxpdHVzLCBFeHBlcmltZW50YWwvY2hlbWlj

YWxseSBpbmR1Y2VkL2RydWcgdGhlcmFweS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkRp

YWJldGVzIE1lbGxpdHVzLCBUeXBlIDEvY2hlbWljYWxseSBpbmR1Y2VkLypkcnVnIHRoZXJhcHkv

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5EeW5hbWlucy9tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPkdsdWNvc2UvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5HbHljb2dlbiBT

eW50aGFzZSBLaW5hc2UgMy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkdseWNvZ2VuIFN5

bnRoYXNlIEtpbmFzZSAzIGJldGE8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxpbi8qcGhhcm1hY29s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWljcm90dWJ1bGUt

QXNzb2NpYXRlZCBQcm90ZWlucy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pdG9jaG9u

ZHJpYS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5ORi1FMi1SZWxhdGVkIEZhY3RvciAy

L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UGhvc3Bob3J5bGF0aW9uL2RydWcgZWZmZWN0

czwva2V5d29yZD48a2V5d29yZD5QeXJ1dmljIEFjaWQvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5SYXRzPC9rZXl3b3JkPjxrZXl3b3JkPlJhdHMsIFdpc3Rhcjwva2V5d29yZD48a2V5d29y

ZD50YXUgUHJvdGVpbnMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QXV0b3BoYWd5PC9r

ZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIGNvcnRleDwva2V5d29yZD48a2V5d29yZD5JbnN1bGlu

IHRyZWF0bWVudDwva2V5d29yZD48a2V5d29yZD5NaXRvY2hvbmRyaWFsIGZpc3Npb24sIGZ1c2lv

biBhbmQgYmlvZ2VuZXNpczwva2V5d29yZD48a2V5d29yZD5UYXUgcHJvdGVpbiBwaG9zcGhvcnls

YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+VHlwZSAxIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29y

ZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWw8L2RhdGU+PC9w

dWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDA2LTMwMDIgKFByaW50KSYjeEQ7MDAwNi0zMDAyIChM

aW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNDc0Nzc0MDwvYWNjZXNzaW9uLW51bT48dXJs

cz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8y

NDc0Nzc0MDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+MTAuMTAxNi9qLmJiYWRpcy4yMDE0LjA0LjAxMTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+RHVhcnRlPC9BdXRob3I+PFllYXI+MjAwNTwv

WWVhcj48UmVjTnVtPjMyOTk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjMyOTk8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkwNjY1MCI+MzI5OTwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RHVhcnRlLCBBLiBJLjwvYXV0aG9yPjxh

dXRob3I+U2FudG9zLCBNLiBTLjwvYXV0aG9yPjxhdXRob3I+T2xpdmVpcmEsIEMuIFIuPC9hdXRo

b3I+PGF1dGhvcj5SZWdvLCBBLiBDLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48

YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgWm9vbG9neSwgRmFjdWx0eSBvZiBTY2llbmNlcyBh

bmQgVGVjaG5vbG9neSwgQ2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5kIENlbGwgQmlvbG9neSwg

VW5pdmVyc2l0eSBvZiBDb2ltYnJhLCAzMDA0LTUxNyBDb2ltYnJhLCBQb3J0dWdhbC48L2F1dGgt

YWRkcmVzcz48dGl0bGVzPjx0aXRsZT5JbnN1bGluIG5ldXJvcHJvdGVjdGlvbiBhZ2FpbnN0IG94

aWRhdGl2ZSBzdHJlc3MgaW4gY29ydGljYWwgbmV1cm9ucy0taW52b2x2ZW1lbnQgb2YgdXJpYyBh

Y2lkIGFuZCBnbHV0YXRoaW9uZSBhbnRpb3hpZGFudCBkZWZlbnNlczwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5GcmVlIFJhZGljIEJpb2wgTWVkPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBh

Z2VzPjg3Ni04OTwvcGFnZXM+PHZvbHVtZT4zOTwvdm9sdW1lPjxudW1iZXI+NzwvbnVtYmVyPjxr

ZXl3b3Jkcz48a2V5d29yZD5BbGRlaHlkZXMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5B

bmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkFwb3B0b3Npcy9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+

PGtleXdvcmQ+QXNjb3JiaWMgQWNpZC9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2Vs

bCBTdXJ2aXZhbC9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVk

PC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIENvcnRleC9jeXRvbG9neTwva2V5d29yZD48a2V5

d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+RmVycm91cyBDb21wb3VuZHMvcGhhcm1hY29s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkdsdWNvc2UgVHJhbnNwb3J0ZXIgVHlwZSAzL2Jpb3N5bnRo

ZXNpczwva2V5d29yZD48a2V5d29yZD5HbHV0YXRoaW9uZS8qbWV0YWJvbGlzbTwva2V5d29yZD48

a2V5d29yZD5JbnN1bGluLypwaHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkxpcGlkIFBlcm94

aWRhdGlvbi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+TmVjcm9zaXMvcHJldmVudGlv

biAmYW1wOyBjb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbnMvKmRydWcgZWZmZWN0cy9w

aHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk94aWRhdGl2ZSBTdHJlc3MvKmRydWcgZWZmZWN0

czwva2V5d29yZD48a2V5d29yZD5SYXRzPC9rZXl3b3JkPjxrZXl3b3JkPlJhdHMsIFdpc3Rhcjwv

a2V5d29yZD48a2V5d29yZD5TdGltdWxhdGlvbiwgQ2hlbWljYWw8L2tleXdvcmQ+PGtleXdvcmQ+

VXJpYyBBY2lkLyptZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MDU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5PY3QgMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVz

Pjxpc2JuPjA4OTEtNTg0OSAoUHJpbnQpJiN4RDswODkxLTU4NDkgKExpbmtpbmcpPC9pc2JuPjxh

Y2Nlc3Npb24tbnVtPjE2MTQwMjA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE2MTQwMjA4PC91cmw+PC9y

ZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ouZnJl

ZXJhZGJpb21lZC4yMDA1LjA1LjAwMjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+

PC9DaXRlPjxDaXRlPjxBdXRob3I+RHVhcnRlPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48UmVj

TnVtPjMyOTg8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjMyOTg8L3JlYy1udW1iZXI+PGZv

cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6

dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkwNjYxMyI+MzI5ODwva2V5PjwvZm9yZWlnbi1r

ZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJp

YnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RHVhcnRlLCBBLiBJLjwvYXV0aG9yPjxhdXRob3I+U2Fu

dG9zLCBQLjwvYXV0aG9yPjxhdXRob3I+T2xpdmVpcmEsIEMuIFIuPC9hdXRob3I+PGF1dGhvcj5T

YW50b3MsIE0uIFMuPC9hdXRob3I+PGF1dGhvcj5SZWdvLCBBLiBDLjwvYXV0aG9yPjwvYXV0aG9y

cz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkNlbnRlciBmb3IgTmV1cm9zY2llbmNlIGFu

ZCBDZWxsIEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgQ29pbWJyYSwgUG9ydHVnYWwu

PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+SW5zdWxpbiBuZXVyb3Byb3RlY3Rpb24gYWdh

aW5zdCBveGlkYXRpdmUgc3RyZXNzIGlzIG1lZGlhdGVkIGJ5IEFrdCBhbmQgR1NLLTNiZXRhIHNp

Z25hbGluZyBwYXRod2F5cyBhbmQgY2hhbmdlcyBpbiBwcm90ZWluIGV4cHJlc3Npb248L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+QmlvY2hpbSBCaW9waHlzIEFjdGE8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+OTk0LTEwMDI8L3BhZ2VzPjx2b2x1bWU+MTc4Mzwvdm9sdW1lPjxudW1i

ZXI+NjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3Jk

PkJyYWluL2N5dG9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q2FzcGFzZSAzL21l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkdsdXRh

dGhpb25lL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+R2x1dGF0aGlvbmUgUGVyb3hpZGFz

ZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkdseWNvZ2VuIFN5bnRoYXNlIEtpbmFzZSAz

LyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkdseWNvZ2VuIFN5bnRoYXNlIEtpbmFzZSAz

IGJldGE8L2tleXdvcmQ+PGtleXdvcmQ+SGV4b2tpbmFzZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxr

ZXl3b3JkPkh5cG9nbHljZW1pYyBBZ2VudHMvKnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29y

ZD5JbnN1bGluLypwaGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9ucy9jeXRvbG9n

eS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5OZXVyb3Byb3RlY3RpdmUgQWdlbnRzLypw

aGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Kk94aWRhdGl2ZSBTdHJlc3M8L2tleXdvcmQ+

PGtleXdvcmQ+UGhvc3BoYXRpZHlsaW5vc2l0b2wgMy1LaW5hc2VzL21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+UGhvc3Bob3J5bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlByZWduYW5jeTwv

a2V5d29yZD48a2V5d29yZD5Qcm90by1PbmNvZ2VuZSBQcm90ZWlucyBjLWFrdC8qbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5Qcm90by1PbmNvZ2VuZSBQcm90ZWlucyBjLWJjbC0yL21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UmF0czwva2V5d29yZD48a2V5d29yZD5SYXRzLCBXaXN0

YXI8L2tleXdvcmQ+PGtleXdvcmQ+UmVjZXB0b3IsIElHRiBUeXBlIDEvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5TaWduYWwgVHJhbnNkdWN0aW9uLypkcnVnIGVmZmVjdHM8L2tleXdvcmQ+

PGtleXdvcmQ+VHlyb3NpbmUvbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4yMDA4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVuPC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PGlzYm4+MDAwNi0zMDAyIChQcmludCkmI3hEOzAwMDYtMzAwMiAoTGlua2luZyk8L2lz

Ym4+PGFjY2Vzc2lvbi1udW0+MTgzNDg4NzE8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQt

dXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTgzNDg4NzE8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYv

ai5iYmFtY3IuMjAwOC4wMi4wMTY8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdWFydGU8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS

ZWNOdW0+MTAwMDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI4MS0yODQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMDAwPC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU2NDAiPjEwMDA8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkR1YXJ0ZSwgQS4gSS48L2F1dGhv

cj48YXV0aG9yPlByb2VuY2EsIFQuPC9hdXRob3I+PGF1dGhvcj5PbGl2ZWlyYSwgQy4gUi48L2F1

dGhvcj48YXV0aG9yPlNhbnRvcywgTS4gUy48L2F1dGhvcj48YXV0aG9yPlJlZ28sIEEuIEMuPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkluc3VsaW4gUmVz

dG9yZXMgTWV0YWJvbGljIEZ1bmN0aW9uIGluIEN1bHR1cmVkIENvcnRpY2FsIE5ldXJvbnMgU3Vi

amVjdGVkIHRvIE94aWRhdGl2ZSBTdHJlc3M8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+RGlhYmV0

ZXM8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+Mjg2My0yODcwPC9wYWdlcz48dm9s

dW1lPjU1PC92b2x1bWU+PG51bWJlcj4xMDwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDA2PC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+MjAwNi8wOS8yNjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxw

dWJsaXNoZXI+QW1lcmljYW4gRGlhYmV0ZXMgQXNzb2NpYXRpb248L3B1Ymxpc2hlcj48aXNibj4w

MDEyLTE3OTcmI3hEOzE5MzktMzI3WDwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL2R4LmRvaS5vcmcvMTAuMjMzNy9kYjA2LTAwMzA8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjIzMzcvZGIwNi0wMDMwPC9lbGVjdHJvbmlj

LXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5TYW50b3M8L0F1dGhv

cj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNOdW0+MzI5MTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1i

ZXI+MzI5MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3

YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTA2NTUy

Ij4zMjkxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs

ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TYW50b3MsIFIu

IFguPC9hdXRob3I+PGF1dGhvcj5Db3JyZWlhLCBTLiBDLjwvYXV0aG9yPjxhdXRob3I+QWx2ZXMs

IE0uIEcuPC9hdXRob3I+PGF1dGhvcj5PbGl2ZWlyYSwgUC4gRi48L2F1dGhvcj48YXV0aG9yPkNh

cmRvc28sIFMuPC9hdXRob3I+PGF1dGhvcj5DYXJ2YWxobywgQy48L2F1dGhvcj48YXV0aG9yPkR1

YXJ0ZSwgQS4gSS48L2F1dGhvcj48YXV0aG9yPlNhbnRvcywgTS4gUy48L2F1dGhvcj48YXV0aG9y

Pk1vcmVpcmEsIFAuIEkuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk

ZHJlc3M+RGVwYXJ0bWVudCBvZiBMaWZlIFNjaWVuY2VzLCBGYWN1bHR5IG9mIFNjaWVuY2VzIGFu

ZCBUZWNobm9sb2d5LCBVbml2ZXJzaXR5IG9mIENvaW1icmEsIFBvcnR1Z2FsOyBDTkMgLSBDZW50

ZXIgZm9yIE5ldXJvc2NpZW5jZSBhbmQgQ2VsbCBCaW9sb2d5LCBVbml2ZXJzaXR5IG9mIENvaW1i

cmEsIENvaW1icmEsIFBvcnR1Z2FsLiYjeEQ7Q05DIC0gQ2VudGVyIGZvciBOZXVyb3NjaWVuY2Ug

YW5kIENlbGwgQmlvbG9neSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhLCBDb2ltYnJhLCBQb3J0dWdh

bDsgSW5zdGl0dXRlIGZvciBJbnRlcmRpc2NpcGxpbmFyeSBSZXNlYXJjaCwgVW5pdmVyc2l0eSBv

ZiBDb2ltYnJhLCBDb2ltYnJhLCBQb3J0dWdhbC4mI3hEO0NJQ1MtVUJJLCBIZWFsdGggU2NpZW5j

ZXMgUmVzZWFyY2ggQ2VudHJlLCBVbml2ZXJzaXR5IG9mIEJlaXJhIEludGVyaW9yLCBDb3ZpbGhh

LCBQb3J0dWdhbC4mI3hEO0NOQyAtIENlbnRlciBmb3IgTmV1cm9zY2llbmNlIGFuZCBDZWxsIEJp

b2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgQ29pbWJyYSwgUG9ydHVnYWw7IExhYm9yYXRv

cnkgb2YgUGh5c2lvbG9neSwgRmFjdWx0eSBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBDb2lt

YnJhLCBDb2ltYnJhLCBQb3J0dWdhbC4gRWxlY3Ryb25pYyBhZGRyZXNzOiB2ZW50YUBjaS51Yy5w

dC48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5JbnN1bGluIHRoZXJhcHkgbW9kdWxhdGVz

IG1pdG9jaG9uZHJpYWwgZHluYW1pY3MgYW5kIGJpb2dlbmVzaXMsIGF1dG9waGFneSBhbmQgdGF1

IHByb3RlaW4gcGhvc3Bob3J5bGF0aW9uIGluIHRoZSBicmFpbiBvZiB0eXBlIDEgZGlhYmV0aWMg

cmF0czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5CaW9jaGltIEJpb3BoeXMgQWN0YTwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMTU0LTY2PC9wYWdlcz48dm9sdW1lPjE4NDI8L3Zv

bHVtZT48bnVtYmVyPjc8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5d29y

ZD48a2V5d29yZD5BdXRvcGhhZ3kvKmRydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5DYXNw

YXNlIDMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DYXNwYXNlIDkvbWV0YWJvbGlzbTwv

a2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBDb3J0ZXgvKmRydWcgZWZmZWN0cy9tZXRhYm9saXNt

PC9rZXl3b3JkPjxrZXl3b3JkPkRpYWJldGVzIE1lbGxpdHVzLCBFeHBlcmltZW50YWwvY2hlbWlj

YWxseSBpbmR1Y2VkL2RydWcgdGhlcmFweS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkRp

YWJldGVzIE1lbGxpdHVzLCBUeXBlIDEvY2hlbWljYWxseSBpbmR1Y2VkLypkcnVnIHRoZXJhcHkv

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5EeW5hbWlucy9tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPkdsdWNvc2UvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5HbHljb2dlbiBT

eW50aGFzZSBLaW5hc2UgMy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkdseWNvZ2VuIFN5

bnRoYXNlIEtpbmFzZSAzIGJldGE8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxpbi8qcGhhcm1hY29s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWljcm90dWJ1bGUt

QXNzb2NpYXRlZCBQcm90ZWlucy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pdG9jaG9u

ZHJpYS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5ORi1FMi1SZWxhdGVkIEZhY3RvciAy

L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UGhvc3Bob3J5bGF0aW9uL2RydWcgZWZmZWN0

czwva2V5d29yZD48a2V5d29yZD5QeXJ1dmljIEFjaWQvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5SYXRzPC9rZXl3b3JkPjxrZXl3b3JkPlJhdHMsIFdpc3Rhcjwva2V5d29yZD48a2V5d29y

ZD50YXUgUHJvdGVpbnMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QXV0b3BoYWd5PC9r

ZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIGNvcnRleDwva2V5d29yZD48a2V5d29yZD5JbnN1bGlu

IHRyZWF0bWVudDwva2V5d29yZD48a2V5d29yZD5NaXRvY2hvbmRyaWFsIGZpc3Npb24sIGZ1c2lv

biBhbmQgYmlvZ2VuZXNpczwva2V5d29yZD48a2V5d29yZD5UYXUgcHJvdGVpbiBwaG9zcGhvcnls

YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+VHlwZSAxIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29y

ZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWw8L2RhdGU+PC9w

dWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDA2LTMwMDIgKFByaW50KSYjeEQ7MDAwNi0zMDAyIChM

aW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNDc0Nzc0MDwvYWNjZXNzaW9uLW51bT48dXJs

cz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8y

NDc0Nzc0MDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+MTAuMTAxNi9qLmJiYWRpcy4yMDE0LjA0LjAxMTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+RHVhcnRlPC9BdXRob3I+PFllYXI+MjAwNTwv

WWVhcj48UmVjTnVtPjMyOTk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjMyOTk8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkwNjY1MCI+MzI5OTwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RHVhcnRlLCBBLiBJLjwvYXV0aG9yPjxh

dXRob3I+U2FudG9zLCBNLiBTLjwvYXV0aG9yPjxhdXRob3I+T2xpdmVpcmEsIEMuIFIuPC9hdXRo

b3I+PGF1dGhvcj5SZWdvLCBBLiBDLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48

YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgWm9vbG9neSwgRmFjdWx0eSBvZiBTY2llbmNlcyBh

bmQgVGVjaG5vbG9neSwgQ2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5kIENlbGwgQmlvbG9neSwg

VW5pdmVyc2l0eSBvZiBDb2ltYnJhLCAzMDA0LTUxNyBDb2ltYnJhLCBQb3J0dWdhbC48L2F1dGgt

YWRkcmVzcz48dGl0bGVzPjx0aXRsZT5JbnN1bGluIG5ldXJvcHJvdGVjdGlvbiBhZ2FpbnN0IG94

aWRhdGl2ZSBzdHJlc3MgaW4gY29ydGljYWwgbmV1cm9ucy0taW52b2x2ZW1lbnQgb2YgdXJpYyBh

Y2lkIGFuZCBnbHV0YXRoaW9uZSBhbnRpb3hpZGFudCBkZWZlbnNlczwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5GcmVlIFJhZGljIEJpb2wgTWVkPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBh

Z2VzPjg3Ni04OTwvcGFnZXM+PHZvbHVtZT4zOTwvdm9sdW1lPjxudW1iZXI+NzwvbnVtYmVyPjxr

ZXl3b3Jkcz48a2V5d29yZD5BbGRlaHlkZXMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5B

bmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkFwb3B0b3Npcy9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+

PGtleXdvcmQ+QXNjb3JiaWMgQWNpZC9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2Vs

bCBTdXJ2aXZhbC9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVk

PC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIENvcnRleC9jeXRvbG9neTwva2V5d29yZD48a2V5

d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+RmVycm91cyBDb21wb3VuZHMvcGhhcm1hY29s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkdsdWNvc2UgVHJhbnNwb3J0ZXIgVHlwZSAzL2Jpb3N5bnRo

ZXNpczwva2V5d29yZD48a2V5d29yZD5HbHV0YXRoaW9uZS8qbWV0YWJvbGlzbTwva2V5d29yZD48

a2V5d29yZD5JbnN1bGluLypwaHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkxpcGlkIFBlcm94

aWRhdGlvbi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+TmVjcm9zaXMvcHJldmVudGlv

biAmYW1wOyBjb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbnMvKmRydWcgZWZmZWN0cy9w

aHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk94aWRhdGl2ZSBTdHJlc3MvKmRydWcgZWZmZWN0

czwva2V5d29yZD48a2V5d29yZD5SYXRzPC9rZXl3b3JkPjxrZXl3b3JkPlJhdHMsIFdpc3Rhcjwv

a2V5d29yZD48a2V5d29yZD5TdGltdWxhdGlvbiwgQ2hlbWljYWw8L2tleXdvcmQ+PGtleXdvcmQ+

VXJpYyBBY2lkLyptZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MDU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5PY3QgMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVz

Pjxpc2JuPjA4OTEtNTg0OSAoUHJpbnQpJiN4RDswODkxLTU4NDkgKExpbmtpbmcpPC9pc2JuPjxh

Y2Nlc3Npb24tbnVtPjE2MTQwMjA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE2MTQwMjA4PC91cmw+PC9y

ZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ouZnJl

ZXJhZGJpb21lZC4yMDA1LjA1LjAwMjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+

PC9DaXRlPjxDaXRlPjxBdXRob3I+RHVhcnRlPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48UmVj

TnVtPjMyOTg8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjMyOTg8L3JlYy1udW1iZXI+PGZv

cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6

dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkwNjYxMyI+MzI5ODwva2V5PjwvZm9yZWlnbi1r

ZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJp

YnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RHVhcnRlLCBBLiBJLjwvYXV0aG9yPjxhdXRob3I+U2Fu

dG9zLCBQLjwvYXV0aG9yPjxhdXRob3I+T2xpdmVpcmEsIEMuIFIuPC9hdXRob3I+PGF1dGhvcj5T

YW50b3MsIE0uIFMuPC9hdXRob3I+PGF1dGhvcj5SZWdvLCBBLiBDLjwvYXV0aG9yPjwvYXV0aG9y

cz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkNlbnRlciBmb3IgTmV1cm9zY2llbmNlIGFu

ZCBDZWxsIEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgQ29pbWJyYSwgUG9ydHVnYWwu

PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+SW5zdWxpbiBuZXVyb3Byb3RlY3Rpb24gYWdh

aW5zdCBveGlkYXRpdmUgc3RyZXNzIGlzIG1lZGlhdGVkIGJ5IEFrdCBhbmQgR1NLLTNiZXRhIHNp

Z25hbGluZyBwYXRod2F5cyBhbmQgY2hhbmdlcyBpbiBwcm90ZWluIGV4cHJlc3Npb248L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+QmlvY2hpbSBCaW9waHlzIEFjdGE8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+OTk0LTEwMDI8L3BhZ2VzPjx2b2x1bWU+MTc4Mzwvdm9sdW1lPjxudW1i

ZXI+NjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3Jk

PkJyYWluL2N5dG9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q2FzcGFzZSAzL21l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkdsdXRh

dGhpb25lL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+R2x1dGF0aGlvbmUgUGVyb3hpZGFz

ZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkdseWNvZ2VuIFN5bnRoYXNlIEtpbmFzZSAz

LyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkdseWNvZ2VuIFN5bnRoYXNlIEtpbmFzZSAz

IGJldGE8L2tleXdvcmQ+PGtleXdvcmQ+SGV4b2tpbmFzZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxr

ZXl3b3JkPkh5cG9nbHljZW1pYyBBZ2VudHMvKnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29y

ZD5JbnN1bGluLypwaGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9ucy9jeXRvbG9n

eS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5OZXVyb3Byb3RlY3RpdmUgQWdlbnRzLypw

aGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Kk94aWRhdGl2ZSBTdHJlc3M8L2tleXdvcmQ+

PGtleXdvcmQ+UGhvc3BoYXRpZHlsaW5vc2l0b2wgMy1LaW5hc2VzL21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+UGhvc3Bob3J5bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlByZWduYW5jeTwv

a2V5d29yZD48a2V5d29yZD5Qcm90by1PbmNvZ2VuZSBQcm90ZWlucyBjLWFrdC8qbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5Qcm90by1PbmNvZ2VuZSBQcm90ZWlucyBjLWJjbC0yL21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UmF0czwva2V5d29yZD48a2V5d29yZD5SYXRzLCBXaXN0

YXI8L2tleXdvcmQ+PGtleXdvcmQ+UmVjZXB0b3IsIElHRiBUeXBlIDEvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5TaWduYWwgVHJhbnNkdWN0aW9uLypkcnVnIGVmZmVjdHM8L2tleXdvcmQ+

PGtleXdvcmQ+VHlyb3NpbmUvbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4yMDA4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVuPC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PGlzYm4+MDAwNi0zMDAyIChQcmludCkmI3hEOzAwMDYtMzAwMiAoTGlua2luZyk8L2lz

Ym4+PGFjY2Vzc2lvbi1udW0+MTgzNDg4NzE8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQt

dXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTgzNDg4NzE8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYv

ai5iYmFtY3IuMjAwOC4wMi4wMTY8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 281-284, rescuing synaptic/neuronal function PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdWFydGU8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS

ZWNOdW0+MTAwMjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI4NSwyODY8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMDAyPC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU2NDAiPjEwMDI8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkR1YXJ0ZSwgQS4gSS48L2F1dGhv

cj48YXV0aG9yPlNhbnRvcywgTS4gUy48L2F1dGhvcj48YXV0aG9yPlNlaWNhLCBSLjwvYXV0aG9y

PjxhdXRob3I+T2xpdmVpcmEsIEMuIFIuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

Pjx0aXRsZXM+PHRpdGxlPk94aWRhdGl2ZSBTdHJlc3MgQWZmZWN0cyBTeW5hcHRvc29tYWwgwqAt

QW1pbm9idXR5cmljIEFjaWQgYW5kIEdsdXRhbWF0ZSBUcmFuc3BvcnQgaW4gRGlhYmV0aWMgUmF0

czogVGhlIFJvbGUgb2YgSW5zdWxpbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5EaWFiZXRlczwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4yMTEwLTIxMTY8L3BhZ2VzPjx2b2x1bWU+

NTM8L3ZvbHVtZT48bnVtYmVyPjg8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAwNDwveWVhcj48cHVi

LWRhdGVzPjxkYXRlPjIwMDQvMDcvMjY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlz

aGVyPkFtZXJpY2FuIERpYWJldGVzIEFzc29jaWF0aW9uPC9wdWJsaXNoZXI+PGlzYm4+MDAxMi0x

Nzk3JiN4RDsxOTM5LTMyN1g8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9k

eC5kb2kub3JnLzEwLjIzMzcvZGlhYmV0ZXMuNTMuOC4yMTEwPC91cmw+PC9yZWxhdGVkLXVybHM+

PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4yMzM3L2RpYWJldGVzLjUzLjguMjEx

MDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+

RHVhcnRlPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVjTnVtPjEwMDM8L1JlY051bT48cmVj

b3JkPjxyZWMtbnVtYmVyPjEwMDM8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFt

cD0iMTUzMjg2NTY0MCI+MTAwMzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+RHVhcnRlLCBBbmEgSXNhYmVsPC9hdXRob3I+PGF1dGhvcj5TYW50b3MsIE1hcmlhIFNhbmNo

YTwvYXV0aG9yPjxhdXRob3I+U2Vpw6dhLCBSYXF1ZWw8L2F1dGhvcj48YXV0aG9yPk9saXZlaXJh

LCBDYXRhcmluYSBSZXNlbmRlIGRlPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0

aXRsZXM+PHRpdGxlPkluc3VsaW4gYWZmZWN0cyBzeW5hcHRvc29tYWwgR0FCQSBhbmQgZ2x1dGFt

YXRlIHRyYW5zcG9ydCB1bmRlciBveGlkYXRpdmUgc3RyZXNzIGNvbmRpdGlvbnM8L3RpdGxlPjxz

ZWNvbmRhcnktdGl0bGU+QnJhaW4gUmVzZWFyY2g8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48

cGFnZXM+MjMtMzA8L3BhZ2VzPjx2b2x1bWU+OTc3PC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+

PGRhdGVzPjx5ZWFyPjIwMDM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDAzLzA3PC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5FbHNldmllciBCVjwvcHVibGlzaGVyPjxpc2Ju

PjAwMDYtODk5MzwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5v

cmcvMTAuMTAxNi9zMDAwNi04OTkzKDAzKTAyNjc5LTk8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvczAwMDYtODk5MygwMykwMjY3OS05

PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdWFydGU8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS

ZWNOdW0+MTAwMjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI4NSwyODY8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMDAyPC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU2NDAiPjEwMDI8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkR1YXJ0ZSwgQS4gSS48L2F1dGhv

cj48YXV0aG9yPlNhbnRvcywgTS4gUy48L2F1dGhvcj48YXV0aG9yPlNlaWNhLCBSLjwvYXV0aG9y

PjxhdXRob3I+T2xpdmVpcmEsIEMuIFIuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

Pjx0aXRsZXM+PHRpdGxlPk94aWRhdGl2ZSBTdHJlc3MgQWZmZWN0cyBTeW5hcHRvc29tYWwgwqAt

QW1pbm9idXR5cmljIEFjaWQgYW5kIEdsdXRhbWF0ZSBUcmFuc3BvcnQgaW4gRGlhYmV0aWMgUmF0

czogVGhlIFJvbGUgb2YgSW5zdWxpbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5EaWFiZXRlczwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4yMTEwLTIxMTY8L3BhZ2VzPjx2b2x1bWU+

NTM8L3ZvbHVtZT48bnVtYmVyPjg8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAwNDwveWVhcj48cHVi

LWRhdGVzPjxkYXRlPjIwMDQvMDcvMjY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlz

aGVyPkFtZXJpY2FuIERpYWJldGVzIEFzc29jaWF0aW9uPC9wdWJsaXNoZXI+PGlzYm4+MDAxMi0x

Nzk3JiN4RDsxOTM5LTMyN1g8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9k

eC5kb2kub3JnLzEwLjIzMzcvZGlhYmV0ZXMuNTMuOC4yMTEwPC91cmw+PC9yZWxhdGVkLXVybHM+

PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4yMzM3L2RpYWJldGVzLjUzLjguMjEx

MDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+

RHVhcnRlPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVjTnVtPjEwMDM8L1JlY051bT48cmVj

b3JkPjxyZWMtbnVtYmVyPjEwMDM8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFt

cD0iMTUzMjg2NTY0MCI+MTAwMzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+RHVhcnRlLCBBbmEgSXNhYmVsPC9hdXRob3I+PGF1dGhvcj5TYW50b3MsIE1hcmlhIFNhbmNo

YTwvYXV0aG9yPjxhdXRob3I+U2Vpw6dhLCBSYXF1ZWw8L2F1dGhvcj48YXV0aG9yPk9saXZlaXJh

LCBDYXRhcmluYSBSZXNlbmRlIGRlPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0

aXRsZXM+PHRpdGxlPkluc3VsaW4gYWZmZWN0cyBzeW5hcHRvc29tYWwgR0FCQSBhbmQgZ2x1dGFt

YXRlIHRyYW5zcG9ydCB1bmRlciBveGlkYXRpdmUgc3RyZXNzIGNvbmRpdGlvbnM8L3RpdGxlPjxz

ZWNvbmRhcnktdGl0bGU+QnJhaW4gUmVzZWFyY2g8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48

cGFnZXM+MjMtMzA8L3BhZ2VzPjx2b2x1bWU+OTc3PC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+

PGRhdGVzPjx5ZWFyPjIwMDM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDAzLzA3PC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5FbHNldmllciBCVjwvcHVibGlzaGVyPjxpc2Ju

PjAwMDYtODk5MzwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5v

cmcvMTAuMTAxNi9zMDAwNi04OTkzKDAzKTAyNjc5LTk8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvczAwMDYtODk5MygwMykwMjY3OS05

PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 285,286 and cognition ADDIN EN.CITE <EndNote><Cite><Author>De Felice</Author><Year>2015</Year><RecNum>1004</RecNum><DisplayText><style face="superscript">287</style></DisplayText><record><rec-number>1004</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865640">1004</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>De Felice, Fernanda G.</author><author>Benedict, Christian</author></authors></contributors><titles><title>A Key Role of Insulin Receptors in Memory: Figure 1</title><secondary-title>Diabetes</secondary-title></titles><pages>3653-3655</pages><volume>64</volume><number>11</number><dates><year>2015</year><pub-dates><date>2015/10/22</date></pub-dates></dates><publisher>American Diabetes Association</publisher><isbn>0012-1797&#xD;1939-327X</isbn><urls><related-urls><url>. This downregulation of bioenergetic metabolism in insulin-resistant brain may arise years before the onset of clinical symptoms (possibly during midlife), affecting Aβ or Tau homeostasis and rendering people (especially women) more prone to dementia and AD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb2RyaWd1ZXotUm9kcmlndWV6PC9BdXRob3I+PFllYXI+

MjAxNzwvWWVhcj48UmVjTnVtPjI2MTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0i

c3VwZXJzY3JpcHQiPjI4OC0yOTI8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51

bWJlcj4yNjE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJm

d2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMTc3NTI3

MSI+MjYxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs

ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Sb2RyaWd1ZXot

Um9kcmlndWV6LCBQLjwvYXV0aG9yPjxhdXRob3I+U2FuZGVicmluZy1NYXR0b24sIEEuPC9hdXRo

b3I+PGF1dGhvcj5NZXJpbm8tU2VycmFpcywgUC48L2F1dGhvcj48YXV0aG9yPlBhcnJhZG8tRmVy

bmFuZGV6LCBDLjwvYXV0aG9yPjxhdXRob3I+UmFiYW5vLCBBLjwvYXV0aG9yPjxhdXRob3I+V2lu

YmxhZCwgQi48L2F1dGhvcj48YXV0aG9yPkF2aWxhLCBKLjwvYXV0aG9yPjxhdXRob3I+RmVycmVy

LCBJLjwvYXV0aG9yPjxhdXRob3I+Q2VkYXpvLU1pbmd1ZXosIEEuPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+S2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBDZW50

ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3kgQ2Fy

ZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgRGl2aXNpb24gb2YgTmV1cm9nZXJpYXRyaWNzLCBTdG9j

a2hvbG0sIFN3ZWRlbi4mI3hEO05ldHdvcmtpbmcgUmVzZWFyY2ggQ2VudGVyIG9uIE5ldXJvZGVn

ZW5lcmF0aXZlIERpc2Vhc2VzIChDSUJFUk5FRCksIEluc3RpdHV0byBkZSBTYWx1ZCBDYXJsb3Mg

SUlJLCBTcGFpbi4mI3hEO0Z1bmRhY2lvbiBDSUVOLCBNYWRyaWQsIFNwYWluLiYjeEQ7Q2VudHJv

IGRlIEJpb2xvZ2lhIE1vbGVjdWxhciBTZXZlcm8gT2Nob2EgKENTSUMtVUFNKSwgTWFkcmlkLCBT

cGFpbi4mI3hEO0luc3RpdHV0IGRlIE5ldXJvcGF0b2xvZ2lhLCBTZXJ2ZWkgQW5hdG9taWEgUGF0

b2xvZ2ljYSwgSURJQkVMTC1Ib3NwaXRhbCBVbml2ZXJzaXRhcmkgZGUgQmVsbHZpdGdlLCBVbml2

ZXJzaXRhdCBkZSBCYXJjZWxvbmEsIEhvc3BpdGFsZXQgZGUgTGxvYnJlZ2F0LCBCYXJjZWxvbmEs

IFNwYWluLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRhdSBoeXBlcnBob3NwaG9yeWxh

dGlvbiBpbmR1Y2VzIG9saWdvbWVyaWMgaW5zdWxpbiBhY2N1bXVsYXRpb24gYW5kIGluc3VsaW4g

cmVzaXN0YW5jZSBpbiBuZXVyb25zPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkJyYWluPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QnJhaW48L2Z1bGwt

dGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4zMjY5LTMyODU8L3BhZ2VzPjx2b2x1bWU+MTQwPC92

b2x1bWU+PG51bWJlcj4xMjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3Jk

PjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBE

aXNlYXNlLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluLyptZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+

PGtleXdvcmQ+SW5zdWxpbi8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD4qSW5zdWxpbiBS

ZXNpc3RhbmNlPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxl

IEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9ucy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5QaG9zcGhvcnlsYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+U3VwcmFudWNsZWFyIFBhbHN5

LCBQcm9ncmVzc2l2ZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPnRhdSBQcm90ZWlucy8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+aW5zdWxpbjwva2V5d29yZD48a2V5d29yZD5uZXVyb2ZpYnJpbGxhcnkg

dGFuZ2xlczwva2V5d29yZD48a2V5d29yZD5vbGlnb21lcnM8L2tleXdvcmQ+PGtleXdvcmQ+dGF1

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5EZWMgMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0NjAtMjE1NiAoRWxl

Y3Ryb25pYykmI3hEOzAwMDYtODk1MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjkw

NTM3ODY8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjkwNTM3ODY8L3VybD48dXJsPmh0dHBzOi8vd2F0ZXJt

YXJrLnNpbHZlcmNoYWlyLmNvbS9hd3gyNTYucGRmP3Rva2VuPUFRRUNBSGkyMDhCRTQ5T29hbjlr

a2hXX0VyY3k3RG0zWkxfOUNmM3FmS0FjNDg1eXNnQUFBY2N3Z2dIREJna3Foa2lHOXcwQkJ3YWdn

Z0cwTUlJQnNBSUJBRENDQWFrR0NTcUdTSWIzRFFFSEFUQWVCZ2xnaGtnQlpRTUVBUzR3RVFRTUxx

SlV1TjhucE9kQkpnQ0RBZ0VRZ0lJQmVtS3BDOXBKaWxkbm45TW5qVTNqWU9tQi1EVmJ5TnhwN09y

ZXBoUFliVDJLR0RuQXBuYzhsR3dETlNZaDVId05lbDZ1Vmh4UjNzZ3lCUHhZZzVUdVRPQzh2S2c3

d054MDk5aWJqZlpfRVd5M3N0ZXp3dFc0Y0lqSWtjdWRPczVxN1NxOXlpUGt2WkV4c1E2cTB5MXNO

RlZZMW5IdVgxUnROSWxueUJFUjA5RWRuOC1LR1pyZTdhN1o3ZHh2UXBCNWtGbDZsd0xmWnFEQTcy

U3F4VXBRdjdJWDRVWVUxUi1qOWRaVHRsRjAxaUNJcm95VEZZVFZ1a0kzeHljQjhtbWFLalVqdkFk

Z1MyX0duTWFiU3FVWlFkeTQzZ0pOSXNlWUJaSVFlbkxIb0swRmxWYXNYbHA2U1RPQXB5TjhJR3lF

MDdBYjh2ckp1WDlNQ2JwN0FNUGN3TVM0aWNseThfbjZiaVAyVEtIeHJ2R2JxN1BqQ0JhWHFCSjE3

ZktyTkJTdkVrWDNTTERZWVc4WTdaaFRYclR0RmRVMXVJME9jX0RkN08wTHE1bTZwWXd1SnpJS2E5

YS1hZzNvTzUzbE9vNm5vRy0ydTU1Vlo0LURBUFc4bTZITDNidVQ4OXJ6eTNEZ09CUDBVOFp2NnVj

MG5fanMtZ0t6R25IbndRPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4xMDkzL2JyYWluL2F3eDI1NjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+S3VsbG1hbm48L0F1dGhvcj48WWVhcj4yMDE2

PC9ZZWFyPjxSZWNOdW0+MTAwNjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTAwNjwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyODY1NjQwIj4xMDA2PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LdWxsbWFubiwgU3RlcGhhbmllPC9h

dXRob3I+PGF1dGhvcj5IZW5pLCBNYXJ0aW48L2F1dGhvcj48YXV0aG9yPkhhbGxzY2htaWQsIE1h

bmZyZWQ8L2F1dGhvcj48YXV0aG9yPkZyaXRzY2hlLCBBbmRyZWFzPC9hdXRob3I+PGF1dGhvcj5Q

cmVpc3NsLCBIdWJlcnQ8L2F1dGhvcj48YXV0aG9yPkjDpHJpbmcsIEhhbnMtVWxyaWNoPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkJyYWluIEluc3VsaW4g

UmVzaXN0YW5jZSBhdCB0aGUgQ3Jvc3Nyb2FkcyBvZiBNZXRhYm9saWMgYW5kIENvZ25pdGl2ZSBE

aXNvcmRlcnMgaW4gSHVtYW5zPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlBoeXNpb2xvZ2ljYWwg

UmV2aWV3czwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMTY5LTEyMDk8L3BhZ2Vz

Pjx2b2x1bWU+OTY8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMTA8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

cHVibGlzaGVyPkFtZXJpY2FuIFBoeXNpb2xvZ2ljYWwgU29jaWV0eTwvcHVibGlzaGVyPjxpc2Ju

PjAwMzEtOTMzMyYjeEQ7MTUyMi0xMjEwPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwOi8vZHguZG9pLm9yZy8xMC4xMTUyL3BoeXNyZXYuMDAwMzIuMjAxNTwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTE1Mi9waHlzcmV2LjAw

MDMyLjIwMTU8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48

QXV0aG9yPlpoYW88L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNOdW0+MTAwNzwvUmVjTnVt

PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTAwNzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg

YXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGlt

ZXN0YW1wPSIxNTMyODY1NjQwIj4xMDA3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5aaGFvLCBMaXFpbjwvYXV0aG9yPjxhdXRob3I+TWFvLCBaaXN1PC9hdXRob3I+PGF1

dGhvcj5Xb29keSwgU2FyYWggSy48L2F1dGhvcj48YXV0aG9yPkJyaW50b24sIFJvYmVydGEgRC48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+U2V4IGRpZmZl

cmVuY2VzIGluIG1ldGFib2xpYyBhZ2luZyBvZiB0aGUgYnJhaW46IGluc2lnaHRzIGludG8gZmVt

YWxlIHN1c2NlcHRpYmlsaXR5IHRvIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5OZXVyb2Jpb2xvZ3kgb2YgQWdpbmc8L3NlY29uZGFyeS10aXRsZT48L3Rp

dGxlcz48cGFnZXM+NjktNzk8L3BhZ2VzPjx2b2x1bWU+NDI8L3ZvbHVtZT48ZGF0ZXM+PHllYXI+

MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MDE5Ny00NTgwPC9p

c2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2ou

bmV1cm9iaW9sYWdpbmcuMjAxNi4wMi4wMTE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb2Jpb2xhZ2luZy4yMDE2LjAyLjAx

MTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+

QnJpbnRvbjwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJlY051bT4xMDA4PC9SZWNOdW0+PHJl

Y29yZD48cmVjLW51bWJlcj4xMDA4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3Rh

bXA9IjE1MzI4NjU2NDAiPjEwMDg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkJyaW50b24sIFJvYmVydGEgRC48L2F1dGhvcj48YXV0aG9yPllhbywgSmlhPC9hdXRob3I+

PGF1dGhvcj5ZaW4sIEZlaTwvYXV0aG9yPjxhdXRob3I+TWFjaywgV2VuZHkgSi48L2F1dGhvcj48

YXV0aG9yPkNhZGVuYXMsIEVucmlxdWU8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+

PHRpdGxlcz48dGl0bGU+UGVyaW1lbm9wYXVzZSBhcyBhIG5ldXJvbG9naWNhbCB0cmFuc2l0aW9u

IHN0YXRlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5hdHVyZSBSZXZpZXdzIEVuZG9jcmlub2xv

Z3k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MzkzLTQwNTwvcGFnZXM+PHZvbHVt

ZT4xMTwvdm9sdW1lPjxudW1iZXI+NzwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDE1PC95ZWFyPjxw

dWItZGF0ZXM+PGRhdGU+MjAxNS8wNS8yNjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxwdWJs

aXNoZXI+U3ByaW5nZXIgTmF0dXJlPC9wdWJsaXNoZXI+PGlzYm4+MTc1OS01MDI5JiN4RDsxNzU5

LTUwMzc8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEw

LjEwMzgvbnJlbmRvLjIwMTUuODI8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjEwLjEwMzgvbnJlbmRvLjIwMTUuODI8L2VsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlN3ZXJkbG93PC9BdXRob3I+PFll

YXI+MjAxNDwvWWVhcj48UmVjTnVtPjEwMDk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEw

MDk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1

MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY0MCI+MTAw

OTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3

PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U3dlcmRsb3csIFJ1c3Nl

bGwgSC48L2F1dGhvcj48YXV0aG9yPkJ1cm5zLCBKZWZmcmV5IE0uPC9hdXRob3I+PGF1dGhvcj5L

aGFuLCBTaGFoYXJ5YXIgTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxl

cz48dGl0bGU+VGhlIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZSBtaXRvY2hvbmRyaWFsIGNhc2Nh

ZGUgaHlwb3RoZXNpczogUHJvZ3Jlc3MgYW5kIHBlcnNwZWN0aXZlczwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5CaW9jaGltaWNhIGV0IEJpb3BoeXNpY2EgQWN0YSAoQkJBKSAtIE1vbGVjdWxhciBC

YXNpcyBvZiBEaXNlYXNlPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEyMTktMTIz

MTwvcGFnZXM+PHZvbHVtZT4xODQyPC92b2x1bWU+PG51bWJlcj44PC9udW1iZXI+PGRhdGVzPjx5

ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDE0LzA4PC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PHB1Ymxpc2hlcj5FbHNldmllciBCVjwvcHVibGlzaGVyPjxpc2JuPjA5MjUtNDQz

OTwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAx

Ni9qLmJiYWRpcy4yMDEzLjA5LjAxMDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmJiYWRpcy4yMDEzLjA5LjAxMDwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb2RyaWd1ZXotUm9kcmlndWV6PC9BdXRob3I+PFllYXI+

MjAxNzwvWWVhcj48UmVjTnVtPjI2MTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0i

c3VwZXJzY3JpcHQiPjI4OC0yOTI8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51

bWJlcj4yNjE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJm

d2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMTc3NTI3

MSI+MjYxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs

ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Sb2RyaWd1ZXot

Um9kcmlndWV6LCBQLjwvYXV0aG9yPjxhdXRob3I+U2FuZGVicmluZy1NYXR0b24sIEEuPC9hdXRo

b3I+PGF1dGhvcj5NZXJpbm8tU2VycmFpcywgUC48L2F1dGhvcj48YXV0aG9yPlBhcnJhZG8tRmVy

bmFuZGV6LCBDLjwvYXV0aG9yPjxhdXRob3I+UmFiYW5vLCBBLjwvYXV0aG9yPjxhdXRob3I+V2lu

YmxhZCwgQi48L2F1dGhvcj48YXV0aG9yPkF2aWxhLCBKLjwvYXV0aG9yPjxhdXRob3I+RmVycmVy

LCBJLjwvYXV0aG9yPjxhdXRob3I+Q2VkYXpvLU1pbmd1ZXosIEEuPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+S2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBDZW50

ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3kgQ2Fy

ZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgRGl2aXNpb24gb2YgTmV1cm9nZXJpYXRyaWNzLCBTdG9j

a2hvbG0sIFN3ZWRlbi4mI3hEO05ldHdvcmtpbmcgUmVzZWFyY2ggQ2VudGVyIG9uIE5ldXJvZGVn

ZW5lcmF0aXZlIERpc2Vhc2VzIChDSUJFUk5FRCksIEluc3RpdHV0byBkZSBTYWx1ZCBDYXJsb3Mg

SUlJLCBTcGFpbi4mI3hEO0Z1bmRhY2lvbiBDSUVOLCBNYWRyaWQsIFNwYWluLiYjeEQ7Q2VudHJv

IGRlIEJpb2xvZ2lhIE1vbGVjdWxhciBTZXZlcm8gT2Nob2EgKENTSUMtVUFNKSwgTWFkcmlkLCBT

cGFpbi4mI3hEO0luc3RpdHV0IGRlIE5ldXJvcGF0b2xvZ2lhLCBTZXJ2ZWkgQW5hdG9taWEgUGF0

b2xvZ2ljYSwgSURJQkVMTC1Ib3NwaXRhbCBVbml2ZXJzaXRhcmkgZGUgQmVsbHZpdGdlLCBVbml2

ZXJzaXRhdCBkZSBCYXJjZWxvbmEsIEhvc3BpdGFsZXQgZGUgTGxvYnJlZ2F0LCBCYXJjZWxvbmEs

IFNwYWluLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRhdSBoeXBlcnBob3NwaG9yeWxh

dGlvbiBpbmR1Y2VzIG9saWdvbWVyaWMgaW5zdWxpbiBhY2N1bXVsYXRpb24gYW5kIGluc3VsaW4g

cmVzaXN0YW5jZSBpbiBuZXVyb25zPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkJyYWluPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QnJhaW48L2Z1bGwt

dGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4zMjY5LTMyODU8L3BhZ2VzPjx2b2x1bWU+MTQwPC92

b2x1bWU+PG51bWJlcj4xMjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3Jk

PjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBE

aXNlYXNlLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluLyptZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+

PGtleXdvcmQ+SW5zdWxpbi8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD4qSW5zdWxpbiBS

ZXNpc3RhbmNlPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxl

IEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9ucy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5QaG9zcGhvcnlsYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+U3VwcmFudWNsZWFyIFBhbHN5

LCBQcm9ncmVzc2l2ZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPnRhdSBQcm90ZWlucy8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+aW5zdWxpbjwva2V5d29yZD48a2V5d29yZD5uZXVyb2ZpYnJpbGxhcnkg

dGFuZ2xlczwva2V5d29yZD48a2V5d29yZD5vbGlnb21lcnM8L2tleXdvcmQ+PGtleXdvcmQ+dGF1

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5EZWMgMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0NjAtMjE1NiAoRWxl

Y3Ryb25pYykmI3hEOzAwMDYtODk1MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjkw

NTM3ODY8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjkwNTM3ODY8L3VybD48dXJsPmh0dHBzOi8vd2F0ZXJt

YXJrLnNpbHZlcmNoYWlyLmNvbS9hd3gyNTYucGRmP3Rva2VuPUFRRUNBSGkyMDhCRTQ5T29hbjlr

a2hXX0VyY3k3RG0zWkxfOUNmM3FmS0FjNDg1eXNnQUFBY2N3Z2dIREJna3Foa2lHOXcwQkJ3YWdn

Z0cwTUlJQnNBSUJBRENDQWFrR0NTcUdTSWIzRFFFSEFUQWVCZ2xnaGtnQlpRTUVBUzR3RVFRTUxx

SlV1TjhucE9kQkpnQ0RBZ0VRZ0lJQmVtS3BDOXBKaWxkbm45TW5qVTNqWU9tQi1EVmJ5TnhwN09y

ZXBoUFliVDJLR0RuQXBuYzhsR3dETlNZaDVId05lbDZ1Vmh4UjNzZ3lCUHhZZzVUdVRPQzh2S2c3

d054MDk5aWJqZlpfRVd5M3N0ZXp3dFc0Y0lqSWtjdWRPczVxN1NxOXlpUGt2WkV4c1E2cTB5MXNO

RlZZMW5IdVgxUnROSWxueUJFUjA5RWRuOC1LR1pyZTdhN1o3ZHh2UXBCNWtGbDZsd0xmWnFEQTcy

U3F4VXBRdjdJWDRVWVUxUi1qOWRaVHRsRjAxaUNJcm95VEZZVFZ1a0kzeHljQjhtbWFLalVqdkFk

Z1MyX0duTWFiU3FVWlFkeTQzZ0pOSXNlWUJaSVFlbkxIb0swRmxWYXNYbHA2U1RPQXB5TjhJR3lF

MDdBYjh2ckp1WDlNQ2JwN0FNUGN3TVM0aWNseThfbjZiaVAyVEtIeHJ2R2JxN1BqQ0JhWHFCSjE3

ZktyTkJTdkVrWDNTTERZWVc4WTdaaFRYclR0RmRVMXVJME9jX0RkN08wTHE1bTZwWXd1SnpJS2E5

YS1hZzNvTzUzbE9vNm5vRy0ydTU1Vlo0LURBUFc4bTZITDNidVQ4OXJ6eTNEZ09CUDBVOFp2NnVj

MG5fanMtZ0t6R25IbndRPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4xMDkzL2JyYWluL2F3eDI1NjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+S3VsbG1hbm48L0F1dGhvcj48WWVhcj4yMDE2

PC9ZZWFyPjxSZWNOdW0+MTAwNjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTAwNjwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyODY1NjQwIj4xMDA2PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LdWxsbWFubiwgU3RlcGhhbmllPC9h

dXRob3I+PGF1dGhvcj5IZW5pLCBNYXJ0aW48L2F1dGhvcj48YXV0aG9yPkhhbGxzY2htaWQsIE1h

bmZyZWQ8L2F1dGhvcj48YXV0aG9yPkZyaXRzY2hlLCBBbmRyZWFzPC9hdXRob3I+PGF1dGhvcj5Q

cmVpc3NsLCBIdWJlcnQ8L2F1dGhvcj48YXV0aG9yPkjDpHJpbmcsIEhhbnMtVWxyaWNoPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkJyYWluIEluc3VsaW4g

UmVzaXN0YW5jZSBhdCB0aGUgQ3Jvc3Nyb2FkcyBvZiBNZXRhYm9saWMgYW5kIENvZ25pdGl2ZSBE

aXNvcmRlcnMgaW4gSHVtYW5zPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlBoeXNpb2xvZ2ljYWwg

UmV2aWV3czwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMTY5LTEyMDk8L3BhZ2Vz

Pjx2b2x1bWU+OTY8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMTA8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

cHVibGlzaGVyPkFtZXJpY2FuIFBoeXNpb2xvZ2ljYWwgU29jaWV0eTwvcHVibGlzaGVyPjxpc2Ju

PjAwMzEtOTMzMyYjeEQ7MTUyMi0xMjEwPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwOi8vZHguZG9pLm9yZy8xMC4xMTUyL3BoeXNyZXYuMDAwMzIuMjAxNTwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTE1Mi9waHlzcmV2LjAw

MDMyLjIwMTU8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48

QXV0aG9yPlpoYW88L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNOdW0+MTAwNzwvUmVjTnVt

PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTAwNzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg

YXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGlt

ZXN0YW1wPSIxNTMyODY1NjQwIj4xMDA3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5aaGFvLCBMaXFpbjwvYXV0aG9yPjxhdXRob3I+TWFvLCBaaXN1PC9hdXRob3I+PGF1

dGhvcj5Xb29keSwgU2FyYWggSy48L2F1dGhvcj48YXV0aG9yPkJyaW50b24sIFJvYmVydGEgRC48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+U2V4IGRpZmZl

cmVuY2VzIGluIG1ldGFib2xpYyBhZ2luZyBvZiB0aGUgYnJhaW46IGluc2lnaHRzIGludG8gZmVt

YWxlIHN1c2NlcHRpYmlsaXR5IHRvIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5OZXVyb2Jpb2xvZ3kgb2YgQWdpbmc8L3NlY29uZGFyeS10aXRsZT48L3Rp

dGxlcz48cGFnZXM+NjktNzk8L3BhZ2VzPjx2b2x1bWU+NDI8L3ZvbHVtZT48ZGF0ZXM+PHllYXI+

MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MDE5Ny00NTgwPC9p

c2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2ou

bmV1cm9iaW9sYWdpbmcuMjAxNi4wMi4wMTE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb2Jpb2xhZ2luZy4yMDE2LjAyLjAx

MTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+

QnJpbnRvbjwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJlY051bT4xMDA4PC9SZWNOdW0+PHJl

Y29yZD48cmVjLW51bWJlcj4xMDA4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3Rh

bXA9IjE1MzI4NjU2NDAiPjEwMDg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkJyaW50b24sIFJvYmVydGEgRC48L2F1dGhvcj48YXV0aG9yPllhbywgSmlhPC9hdXRob3I+

PGF1dGhvcj5ZaW4sIEZlaTwvYXV0aG9yPjxhdXRob3I+TWFjaywgV2VuZHkgSi48L2F1dGhvcj48

YXV0aG9yPkNhZGVuYXMsIEVucmlxdWU8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+

PHRpdGxlcz48dGl0bGU+UGVyaW1lbm9wYXVzZSBhcyBhIG5ldXJvbG9naWNhbCB0cmFuc2l0aW9u

IHN0YXRlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5hdHVyZSBSZXZpZXdzIEVuZG9jcmlub2xv

Z3k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MzkzLTQwNTwvcGFnZXM+PHZvbHVt

ZT4xMTwvdm9sdW1lPjxudW1iZXI+NzwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDE1PC95ZWFyPjxw

dWItZGF0ZXM+PGRhdGU+MjAxNS8wNS8yNjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxwdWJs

aXNoZXI+U3ByaW5nZXIgTmF0dXJlPC9wdWJsaXNoZXI+PGlzYm4+MTc1OS01MDI5JiN4RDsxNzU5

LTUwMzc8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEw

LjEwMzgvbnJlbmRvLjIwMTUuODI8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjEwLjEwMzgvbnJlbmRvLjIwMTUuODI8L2VsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlN3ZXJkbG93PC9BdXRob3I+PFll

YXI+MjAxNDwvWWVhcj48UmVjTnVtPjEwMDk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEw

MDk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1

MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY0MCI+MTAw

OTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3

PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U3dlcmRsb3csIFJ1c3Nl

bGwgSC48L2F1dGhvcj48YXV0aG9yPkJ1cm5zLCBKZWZmcmV5IE0uPC9hdXRob3I+PGF1dGhvcj5L

aGFuLCBTaGFoYXJ5YXIgTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxl

cz48dGl0bGU+VGhlIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZSBtaXRvY2hvbmRyaWFsIGNhc2Nh

ZGUgaHlwb3RoZXNpczogUHJvZ3Jlc3MgYW5kIHBlcnNwZWN0aXZlczwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5CaW9jaGltaWNhIGV0IEJpb3BoeXNpY2EgQWN0YSAoQkJBKSAtIE1vbGVjdWxhciBC

YXNpcyBvZiBEaXNlYXNlPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEyMTktMTIz

MTwvcGFnZXM+PHZvbHVtZT4xODQyPC92b2x1bWU+PG51bWJlcj44PC9udW1iZXI+PGRhdGVzPjx5

ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDE0LzA4PC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PHB1Ymxpc2hlcj5FbHNldmllciBCVjwvcHVibGlzaGVyPjxpc2JuPjA5MjUtNDQz

OTwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAx

Ni9qLmJiYWRpcy4yMDEzLjA5LjAxMDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmJiYWRpcy4yMDEzLjA5LjAxMDwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 288-292. Thus, AD has been increasingly considered a metabolic disorder, also termed “type 3 diabetes” ADDIN EN.CITE <EndNote><Cite><Author>Kandimalla</Author><Year>2017</Year><RecNum>1010</RecNum><DisplayText><style face="superscript">293</style></DisplayText><record><rec-number>1010</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865640">1010</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kandimalla, Ramesh</author><author>Thirumala, Vani</author><author>Reddy, P. Hemachandra</author></authors></contributors><titles><title>Is Alzheimer&apos;s disease a Type 3 Diabetes? A critical appraisal</title><secondary-title>Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease</secondary-title></titles><pages>1078-1089</pages><volume>1863</volume><number>5</number><dates><year>2017</year><pub-dates><date>2017/05</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>0925-4439</isbn><urls><related-urls><url> for AD-related brain glucose hypometabolism includes the slowdown in cerebral blood flow due, e.g., to brain vascular atrophy ADDIN EN.CITE <EndNote><Cite><Author>Winblad</Author><Year>2016</Year><RecNum>983</RecNum><DisplayText><style face="superscript">294</style></DisplayText><record><rec-number>983</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865640">983</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Winblad, Bengt</author><author>Qiu, Chengxuan</author><author>Ballard, Clive</author><author>Johansson, Gunilla</author></authors></contributors><titles><title>Evidence-based prevention and treatment of dementia – Authors&apos; reply</title><secondary-title>The Lancet Neurology</secondary-title></titles><pages>1007-1008</pages><volume>15</volume><number>10</number><dates><year>2016</year><pub-dates><date>2016/09</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>1474-4422</isbn><urls><related-urls><url>(16)30128-4</url></related-urls></urls><electronic-resource-num>10.1016/s1474-4422(16)30128-4</electronic-resource-num></record></Cite></EndNote>294. This, together with the lower levels of GLUT-3 and -4 in AD brain, may attenuate the glucose uptake across the blood-brain barrier (BBB) and its use by CNS PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZWFyc29uLUxlYXJ5PC9BdXRob3I+PFllYXI+MjAxODwv

WWVhcj48UmVjTnVtPjEwMTE8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVy

c2NyaXB0Ij4yOTUsMjk2PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+

MTAxMTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTBy

eDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyODY1NjQwIj4x

MDExPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+

MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5QZWFyc29uLUxlYXJ5

LCBKLjwvYXV0aG9yPjxhdXRob3I+SmFoYWdpcmRhciwgVi48L2F1dGhvcj48YXV0aG9yPlNhZ2Us

IEouPC9hdXRob3I+PGF1dGhvcj5NY05heSwgRS4gQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+SW5zdWxpbiBtb2R1bGF0ZXMgaGlwcG9jYW1wYWxseS1t

ZWRpYXRlZCBzcGF0aWFsIHdvcmtpbmcgbWVtb3J5IHZpYSBnbHVjb3NlIHRyYW5zcG9ydGVyLTQ8

L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QmVoYXZpb3VyYWwgQnJhaW4gUmVzZWFyY2g8L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MzItMzk8L3BhZ2VzPjx2b2x1bWU+MzM4PC92b2x1

bWU+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDE4LzAyPC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5FbHNldmllciBCVjwvcHVibGlzaGVyPjxp

c2JuPjAxNjYtNDMyODwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRv

aS5vcmcvMTAuMTAxNi9qLmJici4yMDE3LjA5LjAzMzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmJici4yMDE3LjA5LjAzMzwvZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+V2lua2xl

cjwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJlY051bT4xMDEyPC9SZWNOdW0+PHJlY29yZD48

cmVjLW51bWJlcj4xMDEyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk

Yi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1

MzI4NjU2NDAiPjEwMTI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h

bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPldp

bmtsZXIsIEV0aGFuIEEuPC9hdXRob3I+PGF1dGhvcj5OaXNoaWRhLCBZb2ljaGlybzwvYXV0aG9y

PjxhdXRob3I+U2FnYXJlLCBBYmhheSBQLjwvYXV0aG9yPjxhdXRob3I+UmVnZSwgU2Fua2V0IFYu

PC9hdXRob3I+PGF1dGhvcj5CZWxsLCBSb2JlcnQgRC48L2F1dGhvcj48YXV0aG9yPlBlcmxtdXR0

ZXIsIERhdmlkPC9hdXRob3I+PGF1dGhvcj5TZW5naWxsbywgSmVzc2UgRC48L2F1dGhvcj48YXV0

aG9yPkhpbGxtYW4sIFNhcmE8L2F1dGhvcj48YXV0aG9yPktvbmcsIFBhbjwvYXV0aG9yPjxhdXRo

b3I+TmVsc29uLCBBbXkgUi48L2F1dGhvcj48YXV0aG9yPlN1bGxpdmFuLCBKb2huIFMuPC9hdXRo

b3I+PGF1dGhvcj5aaGFvLCBaaGVuPC9hdXRob3I+PGF1dGhvcj5NZWlzZWxtYW4sIEhlcmJlcnQg

Si48L2F1dGhvcj48YXV0aG9yPldlbmJ5LCBSb3NhbGluZGEgQi48L2F1dGhvcj48YXV0aG9yPlNv

dG8sIEphbWllPC9hdXRob3I+PGF1dGhvcj5BYmVsLCBFLiBEYWxlPC9hdXRob3I+PGF1dGhvcj5N

YWtzaGFub2ZmLCBKYWNvYjwvYXV0aG9yPjxhdXRob3I+WnVuaWdhLCBFZHdhcmQ8L2F1dGhvcj48

YXV0aG9yPkRlIFZpdm8sIERhcnJ5bCBDLjwvYXV0aG9yPjxhdXRob3I+Wmxva292aWMsIEJlcmlz

bGF2IFYuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkdM

VVQxIHJlZHVjdGlvbnMgZXhhY2VyYmF0ZSBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgdmFzY3Vs

by1uZXVyb25hbCBkeXNmdW5jdGlvbiBhbmQgZGVnZW5lcmF0aW9uPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPk5hdHVyZSBOZXVyb3NjaWVuY2U8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFn

ZXM+NTIxLTUzMDwvcGFnZXM+PHZvbHVtZT4xODwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxk

YXRlcz48eWVhcj4yMDE1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxNS8wMy8wMjwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxwdWJsaXNoZXI+U3ByaW5nZXIgTmF0dXJlPC9wdWJsaXNoZXI+

PGlzYm4+MTA5Ny02MjU2JiN4RDsxNTQ2LTE3MjY8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48

dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjEwMzgvbm4uMzk2NjwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9ubi4zOTY2PC9lbGVjdHJv

bmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZWFyc29uLUxlYXJ5PC9BdXRob3I+PFllYXI+MjAxODwv

WWVhcj48UmVjTnVtPjEwMTE8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVy

c2NyaXB0Ij4yOTUsMjk2PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+

MTAxMTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTBy

eDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyODY1NjQwIj4x

MDExPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+

MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5QZWFyc29uLUxlYXJ5

LCBKLjwvYXV0aG9yPjxhdXRob3I+SmFoYWdpcmRhciwgVi48L2F1dGhvcj48YXV0aG9yPlNhZ2Us

IEouPC9hdXRob3I+PGF1dGhvcj5NY05heSwgRS4gQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+SW5zdWxpbiBtb2R1bGF0ZXMgaGlwcG9jYW1wYWxseS1t

ZWRpYXRlZCBzcGF0aWFsIHdvcmtpbmcgbWVtb3J5IHZpYSBnbHVjb3NlIHRyYW5zcG9ydGVyLTQ8

L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QmVoYXZpb3VyYWwgQnJhaW4gUmVzZWFyY2g8L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MzItMzk8L3BhZ2VzPjx2b2x1bWU+MzM4PC92b2x1

bWU+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDE4LzAyPC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5FbHNldmllciBCVjwvcHVibGlzaGVyPjxp

c2JuPjAxNjYtNDMyODwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRv

aS5vcmcvMTAuMTAxNi9qLmJici4yMDE3LjA5LjAzMzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmJici4yMDE3LjA5LjAzMzwvZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+V2lua2xl

cjwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJlY051bT4xMDEyPC9SZWNOdW0+PHJlY29yZD48

cmVjLW51bWJlcj4xMDEyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk

Yi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1

MzI4NjU2NDAiPjEwMTI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h

bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPldp

bmtsZXIsIEV0aGFuIEEuPC9hdXRob3I+PGF1dGhvcj5OaXNoaWRhLCBZb2ljaGlybzwvYXV0aG9y

PjxhdXRob3I+U2FnYXJlLCBBYmhheSBQLjwvYXV0aG9yPjxhdXRob3I+UmVnZSwgU2Fua2V0IFYu

PC9hdXRob3I+PGF1dGhvcj5CZWxsLCBSb2JlcnQgRC48L2F1dGhvcj48YXV0aG9yPlBlcmxtdXR0

ZXIsIERhdmlkPC9hdXRob3I+PGF1dGhvcj5TZW5naWxsbywgSmVzc2UgRC48L2F1dGhvcj48YXV0

aG9yPkhpbGxtYW4sIFNhcmE8L2F1dGhvcj48YXV0aG9yPktvbmcsIFBhbjwvYXV0aG9yPjxhdXRo

b3I+TmVsc29uLCBBbXkgUi48L2F1dGhvcj48YXV0aG9yPlN1bGxpdmFuLCBKb2huIFMuPC9hdXRo

b3I+PGF1dGhvcj5aaGFvLCBaaGVuPC9hdXRob3I+PGF1dGhvcj5NZWlzZWxtYW4sIEhlcmJlcnQg

Si48L2F1dGhvcj48YXV0aG9yPldlbmJ5LCBSb3NhbGluZGEgQi48L2F1dGhvcj48YXV0aG9yPlNv

dG8sIEphbWllPC9hdXRob3I+PGF1dGhvcj5BYmVsLCBFLiBEYWxlPC9hdXRob3I+PGF1dGhvcj5N

YWtzaGFub2ZmLCBKYWNvYjwvYXV0aG9yPjxhdXRob3I+WnVuaWdhLCBFZHdhcmQ8L2F1dGhvcj48

YXV0aG9yPkRlIFZpdm8sIERhcnJ5bCBDLjwvYXV0aG9yPjxhdXRob3I+Wmxva292aWMsIEJlcmlz

bGF2IFYuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkdM

VVQxIHJlZHVjdGlvbnMgZXhhY2VyYmF0ZSBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgdmFzY3Vs

by1uZXVyb25hbCBkeXNmdW5jdGlvbiBhbmQgZGVnZW5lcmF0aW9uPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPk5hdHVyZSBOZXVyb3NjaWVuY2U8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFn

ZXM+NTIxLTUzMDwvcGFnZXM+PHZvbHVtZT4xODwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxk

YXRlcz48eWVhcj4yMDE1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxNS8wMy8wMjwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxwdWJsaXNoZXI+U3ByaW5nZXIgTmF0dXJlPC9wdWJsaXNoZXI+

PGlzYm4+MTA5Ny02MjU2JiN4RDsxNTQ2LTE3MjY8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48

dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjEwMzgvbm4uMzk2NjwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9ubi4zOTY2PC9lbGVjdHJv

bmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 295,296. AD also inhibits brain enzymes from glycolysis and Krebs cycle (e.g. lactate dehydrogenase (LDH), aconitase, glutamine synthetase, creatine kinase, pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (α-KGDH) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYXBvZ2lhbm5pczwvQXV0aG9yPjxZZWFyPjIwMTE8L1ll

YXI+PFJlY051bT4xMDE0PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNj

cmlwdCI+Mjk3LDI5ODwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEw

MTQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1

MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY0MCI+MTAx

NDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3

PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+S2Fwb2dpYW5uaXMsIERp

bWl0cmlvczwvYXV0aG9yPjxhdXRob3I+TWF0dHNvbiwgTWFyayBQLjwvYXV0aG9yPjwvYXV0aG9y

cz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5EaXNydXB0ZWQgZW5lcmd5IG1ldGFib2xp

c20gYW5kIG5ldXJvbmFsIGNpcmN1aXQgZHlzZnVuY3Rpb24gaW4gY29nbml0aXZlIGltcGFpcm1l

bnQgYW5kIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5U

aGUgTGFuY2V0IE5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xODct

MTk4PC9wYWdlcz48dm9sdW1lPjEwPC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGRhdGVzPjx5

ZWFyPjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDExLzAyPC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PHB1Ymxpc2hlcj5FbHNldmllciBCVjwvcHVibGlzaGVyPjxpc2JuPjE0NzQtNDQy

MjwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAx

Ni9zMTQ3NC00NDIyKDEwKTcwMjc3LTU8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvczE0NzQtNDQyMigxMCk3MDI3Ny01PC9lbGVjdHJv

bmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5DdW5uYW5lPC9B

dXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVjTnVtPjMzMTY8L1JlY051bT48cmVjb3JkPjxyZWMt

bnVtYmVyPjMzMTY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk

PSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkw

OTA4NCI+MzMxNjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFy

dGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Q3VubmFu

ZSwgUy48L2F1dGhvcj48YXV0aG9yPk51Z2VudCwgUy48L2F1dGhvcj48YXV0aG9yPlJveSwgTS48

L2F1dGhvcj48YXV0aG9yPkNvdXJjaGVzbmUtTG95ZXIsIEEuPC9hdXRob3I+PGF1dGhvcj5Dcm90

ZWF1LCBFLjwvYXV0aG9yPjxhdXRob3I+VHJlbWJsYXksIFMuPC9hdXRob3I+PGF1dGhvcj5DYXN0

ZWxsYW5vLCBBLjwvYXV0aG9yPjxhdXRob3I+UGlmZmVyaSwgRi48L2F1dGhvcj48YXV0aG9yPkJv

Y3RpLCBDLjwvYXV0aG9yPjxhdXRob3I+UGFxdWV0LCBOLjwvYXV0aG9yPjxhdXRob3I+QmVnZG91

cmksIEguPC9hdXRob3I+PGF1dGhvcj5CZW50b3Vya2lhLCBNLjwvYXV0aG9yPjxhdXRob3I+VHVy

Y290dGUsIEUuPC9hdXRob3I+PGF1dGhvcj5BbGxhcmQsIE0uPC9hdXRob3I+PGF1dGhvcj5CYXJi

ZXJnZXItR2F0ZWF1LCBQLjwvYXV0aG9yPjxhdXRob3I+RnVsb3AsIFQuPC9hdXRob3I+PGF1dGhv

cj5SYXBvcG9ydCwgUy4gSS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgt

YWRkcmVzcz5SZXNlYXJjaCBDZW50ZXIgb24gQWdpbmcsIEhlYWx0aCBhbmQgU29jaWFsIFNlcnZp

Y2VzIENlbnRlci1TaGVyYnJvb2tlIFVuaXZlcnNpdHkgR2VyaWF0cmljcyBJbnN0aXR1dGUsIFVu

aXZlcnNpdGUgZGUgU2hlcmJyb29rZSwgU2hlcmJyb29rZSwgUUMsIENhbmFkYTsgRGVwYXJ0bWVu

dCBvZiBNZWRpY2luZSwgVW5pdmVyc2l0ZSBkZSBTaGVyYnJvb2tlLCBTaGVyYnJvb2tlLCBRQywg

Q2FuYWRhOyBEZXBhcnRtZW50IG9mIFBoeXNpb2xvZ3kgYW5kIEJpb3BoeXNpY3MsIFVuaXZlcnNp

dGUgZGUgU2hlcmJyb29rZSwgU2hlcmJyb29rZSwgUUMsIENhbmFkYS4gRWxlY3Ryb25pYyBhZGRy

ZXNzOiBzdGVwaGVuLmN1bm5hbmVAdXNoZXJicm9va2UuY2EuJiN4RDtSZXNlYXJjaCBDZW50ZXIg

b24gQWdpbmcsIEhlYWx0aCBhbmQgU29jaWFsIFNlcnZpY2VzIENlbnRlci1TaGVyYnJvb2tlIFVu

aXZlcnNpdHkgR2VyaWF0cmljcyBJbnN0aXR1dGUsIFVuaXZlcnNpdGUgZGUgU2hlcmJyb29rZSwg

U2hlcmJyb29rZSwgUUMsIENhbmFkYTsgRGVwYXJ0bWVudCBvZiBQaHlzaW9sb2d5IGFuZCBCaW9w

aHlzaWNzLCBVbml2ZXJzaXRlIGRlIFNoZXJicm9va2UsIFNoZXJicm9va2UsIFFDLCBDYW5hZGEu

JiN4RDtEZXBhcnRtZW50IG9mIFJhZGlvYmlvbG9neSBhbmQgTnVjbGVhciBNZWRpY2luZSwgVW5p

dmVyc2l0ZSBkZSBTaGVyYnJvb2tlLCBTaGVyYnJvb2tlLCBRQywgQ2FuYWRhLiYjeEQ7UmVzZWFy

Y2ggQ2VudGVyIG9uIEFnaW5nLCBIZWFsdGggYW5kIFNvY2lhbCBTZXJ2aWNlcyBDZW50ZXItU2hl

cmJyb29rZSBVbml2ZXJzaXR5IEdlcmlhdHJpY3MgSW5zdGl0dXRlLCBVbml2ZXJzaXRlIGRlIFNo

ZXJicm9va2UsIFNoZXJicm9va2UsIFFDLCBDYW5hZGE7IERlcGFydG1lbnQgb2YgUmFkaW9iaW9s

b2d5IGFuZCBOdWNsZWFyIE1lZGljaW5lLCBVbml2ZXJzaXRlIGRlIFNoZXJicm9va2UsIFNoZXJi

cm9va2UsIFFDLCBDYW5hZGEuJiN4RDtSZXNlYXJjaCBDZW50ZXIgb24gQWdpbmcsIEhlYWx0aCBh

bmQgU29jaWFsIFNlcnZpY2VzIENlbnRlci1TaGVyYnJvb2tlIFVuaXZlcnNpdHkgR2VyaWF0cmlj

cyBJbnN0aXR1dGUsIFVuaXZlcnNpdGUgZGUgU2hlcmJyb29rZSwgU2hlcmJyb29rZSwgUUMsIENh

bmFkYS4mI3hEO1VNUiBDTlJTLU1OSE4gNzE3OSwgQnJ1bm95LCBGcmFuY2UuJiN4RDtSZXNlYXJj

aCBDZW50ZXIgb24gQWdpbmcsIEhlYWx0aCBhbmQgU29jaWFsIFNlcnZpY2VzIENlbnRlci1TaGVy

YnJvb2tlIFVuaXZlcnNpdHkgR2VyaWF0cmljcyBJbnN0aXR1dGUsIFVuaXZlcnNpdGUgZGUgU2hl

cmJyb29rZSwgU2hlcmJyb29rZSwgUUMsIENhbmFkYTsgRGVwYXJ0bWVudCBvZiBNZWRpY2luZSwg

VW5pdmVyc2l0ZSBkZSBTaGVyYnJvb2tlLCBTaGVyYnJvb2tlLCBRQywgQ2FuYWRhLiYjeEQ7VU1S

IENOUlMgNTIzMSBhbmQgRWNvbGUgUHJhdGlxdWUgZGVzIEhhdXRlcyBFdHVkZXMsIEZyYW5jZS4m

I3hEO0lOU0VSTSBVODk3LCBCb3JkZWF1eCBGLTMzMDc2LCBGcmFuY2U7IFVuaXZlcnNpdGUgVmlj

dG9yIFNlZ2FsZW4gQm9yZGVhdXggMiwgQm9yZGVhdXggRi0zMzA3NiwgRnJhbmNlLiYjeEQ7QnJh

aW4gUGh5c2lvbG9neSBhbmQgTWV0YWJvbGlzbSBTZWN0aW9uLCBOYXRpb25hbCBJbnN0aXR1dGUg

b2YgQWdpbmcsIEJldGhlc2RhLCBNRCwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxl

PkJyYWluIGZ1ZWwgbWV0YWJvbGlzbSwgYWdpbmcsIGFuZCBBbHpoZWltZXImYXBvcztzIGRpc2Vh

c2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TnV0cml0aW9uPC9zZWNvbmRhcnktdGl0bGU+PC90

aXRsZXM+PHBhZ2VzPjMtMjA8L3BhZ2VzPjx2b2x1bWU+Mjc8L3ZvbHVtZT48bnVtYmVyPjE8L251

bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWdpbmcvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+QWx6aGVpbWVyIERpc2Vhc2UvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4v

Km1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y29zZS8qbWV0YWJvbGlzbTwva2V5d29y

ZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMTwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju

PjE4NzMtMTI0NCAoRWxlY3Ryb25pYykmI3hEOzA4OTktOTAwNyAoTGlua2luZyk8L2lzYm4+PGFj

Y2Vzc2lvbi1udW0+MjEwMzUzMDg8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48

dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjEwMzUzMDg8L3VybD48L3Jl

bGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMzQ3ODA2NzwvY3VzdG9tMj48ZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLm51dC4yMDEwLjA3LjAyMTwvZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYXBvZ2lhbm5pczwvQXV0aG9yPjxZZWFyPjIwMTE8L1ll

YXI+PFJlY051bT4xMDE0PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNj

cmlwdCI+Mjk3LDI5ODwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEw

MTQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1

MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY0MCI+MTAx

NDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3

PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+S2Fwb2dpYW5uaXMsIERp

bWl0cmlvczwvYXV0aG9yPjxhdXRob3I+TWF0dHNvbiwgTWFyayBQLjwvYXV0aG9yPjwvYXV0aG9y

cz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5EaXNydXB0ZWQgZW5lcmd5IG1ldGFib2xp

c20gYW5kIG5ldXJvbmFsIGNpcmN1aXQgZHlzZnVuY3Rpb24gaW4gY29nbml0aXZlIGltcGFpcm1l

bnQgYW5kIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5U

aGUgTGFuY2V0IE5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xODct

MTk4PC9wYWdlcz48dm9sdW1lPjEwPC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGRhdGVzPjx5

ZWFyPjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDExLzAyPC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PHB1Ymxpc2hlcj5FbHNldmllciBCVjwvcHVibGlzaGVyPjxpc2JuPjE0NzQtNDQy

MjwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAx

Ni9zMTQ3NC00NDIyKDEwKTcwMjc3LTU8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvczE0NzQtNDQyMigxMCk3MDI3Ny01PC9lbGVjdHJv

bmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5DdW5uYW5lPC9B

dXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVjTnVtPjMzMTY8L1JlY051bT48cmVjb3JkPjxyZWMt

bnVtYmVyPjMzMTY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk

PSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkw

OTA4NCI+MzMxNjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFy

dGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Q3VubmFu

ZSwgUy48L2F1dGhvcj48YXV0aG9yPk51Z2VudCwgUy48L2F1dGhvcj48YXV0aG9yPlJveSwgTS48

L2F1dGhvcj48YXV0aG9yPkNvdXJjaGVzbmUtTG95ZXIsIEEuPC9hdXRob3I+PGF1dGhvcj5Dcm90

ZWF1LCBFLjwvYXV0aG9yPjxhdXRob3I+VHJlbWJsYXksIFMuPC9hdXRob3I+PGF1dGhvcj5DYXN0

ZWxsYW5vLCBBLjwvYXV0aG9yPjxhdXRob3I+UGlmZmVyaSwgRi48L2F1dGhvcj48YXV0aG9yPkJv

Y3RpLCBDLjwvYXV0aG9yPjxhdXRob3I+UGFxdWV0LCBOLjwvYXV0aG9yPjxhdXRob3I+QmVnZG91

cmksIEguPC9hdXRob3I+PGF1dGhvcj5CZW50b3Vya2lhLCBNLjwvYXV0aG9yPjxhdXRob3I+VHVy

Y290dGUsIEUuPC9hdXRob3I+PGF1dGhvcj5BbGxhcmQsIE0uPC9hdXRob3I+PGF1dGhvcj5CYXJi

ZXJnZXItR2F0ZWF1LCBQLjwvYXV0aG9yPjxhdXRob3I+RnVsb3AsIFQuPC9hdXRob3I+PGF1dGhv

cj5SYXBvcG9ydCwgUy4gSS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgt

YWRkcmVzcz5SZXNlYXJjaCBDZW50ZXIgb24gQWdpbmcsIEhlYWx0aCBhbmQgU29jaWFsIFNlcnZp

Y2VzIENlbnRlci1TaGVyYnJvb2tlIFVuaXZlcnNpdHkgR2VyaWF0cmljcyBJbnN0aXR1dGUsIFVu

aXZlcnNpdGUgZGUgU2hlcmJyb29rZSwgU2hlcmJyb29rZSwgUUMsIENhbmFkYTsgRGVwYXJ0bWVu

dCBvZiBNZWRpY2luZSwgVW5pdmVyc2l0ZSBkZSBTaGVyYnJvb2tlLCBTaGVyYnJvb2tlLCBRQywg

Q2FuYWRhOyBEZXBhcnRtZW50IG9mIFBoeXNpb2xvZ3kgYW5kIEJpb3BoeXNpY3MsIFVuaXZlcnNp

dGUgZGUgU2hlcmJyb29rZSwgU2hlcmJyb29rZSwgUUMsIENhbmFkYS4gRWxlY3Ryb25pYyBhZGRy

ZXNzOiBzdGVwaGVuLmN1bm5hbmVAdXNoZXJicm9va2UuY2EuJiN4RDtSZXNlYXJjaCBDZW50ZXIg

b24gQWdpbmcsIEhlYWx0aCBhbmQgU29jaWFsIFNlcnZpY2VzIENlbnRlci1TaGVyYnJvb2tlIFVu

aXZlcnNpdHkgR2VyaWF0cmljcyBJbnN0aXR1dGUsIFVuaXZlcnNpdGUgZGUgU2hlcmJyb29rZSwg

U2hlcmJyb29rZSwgUUMsIENhbmFkYTsgRGVwYXJ0bWVudCBvZiBQaHlzaW9sb2d5IGFuZCBCaW9w

aHlzaWNzLCBVbml2ZXJzaXRlIGRlIFNoZXJicm9va2UsIFNoZXJicm9va2UsIFFDLCBDYW5hZGEu

JiN4RDtEZXBhcnRtZW50IG9mIFJhZGlvYmlvbG9neSBhbmQgTnVjbGVhciBNZWRpY2luZSwgVW5p

dmVyc2l0ZSBkZSBTaGVyYnJvb2tlLCBTaGVyYnJvb2tlLCBRQywgQ2FuYWRhLiYjeEQ7UmVzZWFy

Y2ggQ2VudGVyIG9uIEFnaW5nLCBIZWFsdGggYW5kIFNvY2lhbCBTZXJ2aWNlcyBDZW50ZXItU2hl

cmJyb29rZSBVbml2ZXJzaXR5IEdlcmlhdHJpY3MgSW5zdGl0dXRlLCBVbml2ZXJzaXRlIGRlIFNo

ZXJicm9va2UsIFNoZXJicm9va2UsIFFDLCBDYW5hZGE7IERlcGFydG1lbnQgb2YgUmFkaW9iaW9s

b2d5IGFuZCBOdWNsZWFyIE1lZGljaW5lLCBVbml2ZXJzaXRlIGRlIFNoZXJicm9va2UsIFNoZXJi

cm9va2UsIFFDLCBDYW5hZGEuJiN4RDtSZXNlYXJjaCBDZW50ZXIgb24gQWdpbmcsIEhlYWx0aCBh

bmQgU29jaWFsIFNlcnZpY2VzIENlbnRlci1TaGVyYnJvb2tlIFVuaXZlcnNpdHkgR2VyaWF0cmlj

cyBJbnN0aXR1dGUsIFVuaXZlcnNpdGUgZGUgU2hlcmJyb29rZSwgU2hlcmJyb29rZSwgUUMsIENh

bmFkYS4mI3hEO1VNUiBDTlJTLU1OSE4gNzE3OSwgQnJ1bm95LCBGcmFuY2UuJiN4RDtSZXNlYXJj

aCBDZW50ZXIgb24gQWdpbmcsIEhlYWx0aCBhbmQgU29jaWFsIFNlcnZpY2VzIENlbnRlci1TaGVy

YnJvb2tlIFVuaXZlcnNpdHkgR2VyaWF0cmljcyBJbnN0aXR1dGUsIFVuaXZlcnNpdGUgZGUgU2hl

cmJyb29rZSwgU2hlcmJyb29rZSwgUUMsIENhbmFkYTsgRGVwYXJ0bWVudCBvZiBNZWRpY2luZSwg

VW5pdmVyc2l0ZSBkZSBTaGVyYnJvb2tlLCBTaGVyYnJvb2tlLCBRQywgQ2FuYWRhLiYjeEQ7VU1S

IENOUlMgNTIzMSBhbmQgRWNvbGUgUHJhdGlxdWUgZGVzIEhhdXRlcyBFdHVkZXMsIEZyYW5jZS4m

I3hEO0lOU0VSTSBVODk3LCBCb3JkZWF1eCBGLTMzMDc2LCBGcmFuY2U7IFVuaXZlcnNpdGUgVmlj

dG9yIFNlZ2FsZW4gQm9yZGVhdXggMiwgQm9yZGVhdXggRi0zMzA3NiwgRnJhbmNlLiYjeEQ7QnJh

aW4gUGh5c2lvbG9neSBhbmQgTWV0YWJvbGlzbSBTZWN0aW9uLCBOYXRpb25hbCBJbnN0aXR1dGUg

b2YgQWdpbmcsIEJldGhlc2RhLCBNRCwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxl

PkJyYWluIGZ1ZWwgbWV0YWJvbGlzbSwgYWdpbmcsIGFuZCBBbHpoZWltZXImYXBvcztzIGRpc2Vh

c2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TnV0cml0aW9uPC9zZWNvbmRhcnktdGl0bGU+PC90

aXRsZXM+PHBhZ2VzPjMtMjA8L3BhZ2VzPjx2b2x1bWU+Mjc8L3ZvbHVtZT48bnVtYmVyPjE8L251

bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWdpbmcvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+QWx6aGVpbWVyIERpc2Vhc2UvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4v

Km1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y29zZS8qbWV0YWJvbGlzbTwva2V5d29y

ZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMTwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju

PjE4NzMtMTI0NCAoRWxlY3Ryb25pYykmI3hEOzA4OTktOTAwNyAoTGlua2luZyk8L2lzYm4+PGFj

Y2Vzc2lvbi1udW0+MjEwMzUzMDg8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48

dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjEwMzUzMDg8L3VybD48L3Jl

bGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMzQ3ODA2NzwvY3VzdG9tMj48ZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLm51dC4yMDEwLjA3LjAyMTwvZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 297,298, depending on disease progressionPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYWxraW5zPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48

UmVjTnVtPjMzNDY8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4yOTk8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zMzQ2PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MDkxNzUiPjMzNDY8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkNhbGtpbnMsIE0uIEouPC9hdXRob3I+

PGF1dGhvcj5NYW5jemFrLCBNLjwvYXV0aG9yPjxhdXRob3I+TWFvLCBQLjwvYXV0aG9yPjxhdXRo

b3I+U2hpcmVuZGViLCBVLjwvYXV0aG9yPjxhdXRob3I+UmVkZHksIFAuIEguPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+TmV1cm9nZW5ldGljcyBMYWJvcmF0

b3J5LCBEaXZpc2lvbiBvZiBOZXVyb3NjaWVuY2UsIE9yZWdvbiBOYXRpb25hbCBQcmltYXRlIFJl

c2VhcmNoIENlbnRlciwgT3JlZ29uIEhlYWx0aCAmYW1wOyBTY2llbmNlIFVuaXZlcnNpdHksIEJl

YXZlcnRvbiwgT1IgOTcwMDYsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5JbXBh

aXJlZCBtaXRvY2hvbmRyaWFsIGJpb2dlbmVzaXMsIGRlZmVjdGl2ZSBheG9uYWwgdHJhbnNwb3J0

IG9mIG1pdG9jaG9uZHJpYSwgYWJub3JtYWwgbWl0b2Nob25kcmlhbCBkeW5hbWljcyBhbmQgc3lu

YXB0aWMgZGVnZW5lcmF0aW9uIGluIGEgbW91c2UgbW9kZWwgb2YgQWx6aGVpbWVyJmFwb3M7cyBk

aXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkh1bSBNb2wgR2VuZXQ8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5IdW0gTW9sIEdlbmV0PC9mdWxs

LXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NDUxNS0yOTwvcGFnZXM+PHZvbHVtZT4yMDwvdm9s

dW1lPjxudW1iZXI+MjM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWRlbm9zaW5lIFRyaXBo

b3NwaGF0ZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypt

ZXRhYm9saXNtLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3Rl

aW4gUHJlY3Vyc29yL2NoZW1pc3RyeS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1h

bHM8L2tleXdvcmQ+PGtleXdvcmQ+QXBvcHRvc2lzL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5

d29yZD4qQXhvbmFsIFRyYW5zcG9ydC9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+Qmxv

dHRpbmcsIFdlc3Rlcm48L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVkPC9rZXl3b3Jk

PjxrZXl3b3JkPkN5Y2xvcGhpbGlucy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkRpc2Vh

c2UgTW9kZWxzLCBBbmltYWw8L2tleXdvcmQ+PGtleXdvcmQ+RWxlY3Ryb24gVHJhbnNwb3J0IENv

bXBsZXggSVYvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5HZW5lIEV4cHJlc3Npb24gUmVn

dWxhdGlvbi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+SHlkcm9nZW4gUGVyb3hpZGUv

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pdG9j

aG9uZHJpYS9kcnVnIGVmZmVjdHMvKm1ldGFib2xpc20vKnBhdGhvbG9neS91bHRyYXN0cnVjdHVy

ZTwva2V5d29yZD48a2V5d29yZD5Nb2xlY3VsYXIgV2VpZ2h0PC9rZXl3b3JkPjxrZXl3b3JkPk5l

dXJpdGVzL2RydWcgZWZmZWN0cy9tZXRhYm9saXNtL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5PbGlnb3BlcHRpZGVzL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5QZXJveGlyZWRv

eGlucy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlByb3RlaW4gU3RydWN0dXJlLCBRdWF0

ZXJuYXJ5PC9rZXl3b3JkPjxrZXl3b3JkPlJOQSwgTWVzc2VuZ2VyL2dlbmV0aWNzL21ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+U3luYXBzZXMvZHJ1ZyBlZmZlY3RzL21ldGFib2xpc20vKnBh

dGhvbG9neTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWIt

ZGF0ZXM+PGRhdGU+RGVjIDE8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDYwLTIw

ODMgKEVsZWN0cm9uaWMpJiN4RDswOTY0LTY5MDYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24t

bnVtPjIxODczMjYwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRw

Oi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIxODczMjYwPC91cmw+PC9yZWxhdGVkLXVy

bHM+PC91cmxzPjxjdXN0b20yPlBNQzMyMDk4MjQ8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjEwOTMvaG1nL2RkcjM4MTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNv

cmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYWxraW5zPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48

UmVjTnVtPjMzNDY8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4yOTk8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zMzQ2PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MDkxNzUiPjMzNDY8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkNhbGtpbnMsIE0uIEouPC9hdXRob3I+

PGF1dGhvcj5NYW5jemFrLCBNLjwvYXV0aG9yPjxhdXRob3I+TWFvLCBQLjwvYXV0aG9yPjxhdXRo

b3I+U2hpcmVuZGViLCBVLjwvYXV0aG9yPjxhdXRob3I+UmVkZHksIFAuIEguPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+TmV1cm9nZW5ldGljcyBMYWJvcmF0

b3J5LCBEaXZpc2lvbiBvZiBOZXVyb3NjaWVuY2UsIE9yZWdvbiBOYXRpb25hbCBQcmltYXRlIFJl

c2VhcmNoIENlbnRlciwgT3JlZ29uIEhlYWx0aCAmYW1wOyBTY2llbmNlIFVuaXZlcnNpdHksIEJl

YXZlcnRvbiwgT1IgOTcwMDYsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5JbXBh

aXJlZCBtaXRvY2hvbmRyaWFsIGJpb2dlbmVzaXMsIGRlZmVjdGl2ZSBheG9uYWwgdHJhbnNwb3J0

IG9mIG1pdG9jaG9uZHJpYSwgYWJub3JtYWwgbWl0b2Nob25kcmlhbCBkeW5hbWljcyBhbmQgc3lu

YXB0aWMgZGVnZW5lcmF0aW9uIGluIGEgbW91c2UgbW9kZWwgb2YgQWx6aGVpbWVyJmFwb3M7cyBk

aXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkh1bSBNb2wgR2VuZXQ8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5IdW0gTW9sIEdlbmV0PC9mdWxs

LXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NDUxNS0yOTwvcGFnZXM+PHZvbHVtZT4yMDwvdm9s

dW1lPjxudW1iZXI+MjM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWRlbm9zaW5lIFRyaXBo

b3NwaGF0ZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypt

ZXRhYm9saXNtLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3Rl

aW4gUHJlY3Vyc29yL2NoZW1pc3RyeS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1h

bHM8L2tleXdvcmQ+PGtleXdvcmQ+QXBvcHRvc2lzL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5

d29yZD4qQXhvbmFsIFRyYW5zcG9ydC9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+Qmxv

dHRpbmcsIFdlc3Rlcm48L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVkPC9rZXl3b3Jk

PjxrZXl3b3JkPkN5Y2xvcGhpbGlucy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkRpc2Vh

c2UgTW9kZWxzLCBBbmltYWw8L2tleXdvcmQ+PGtleXdvcmQ+RWxlY3Ryb24gVHJhbnNwb3J0IENv

bXBsZXggSVYvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5HZW5lIEV4cHJlc3Npb24gUmVn

dWxhdGlvbi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+SHlkcm9nZW4gUGVyb3hpZGUv

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pdG9j

aG9uZHJpYS9kcnVnIGVmZmVjdHMvKm1ldGFib2xpc20vKnBhdGhvbG9neS91bHRyYXN0cnVjdHVy

ZTwva2V5d29yZD48a2V5d29yZD5Nb2xlY3VsYXIgV2VpZ2h0PC9rZXl3b3JkPjxrZXl3b3JkPk5l

dXJpdGVzL2RydWcgZWZmZWN0cy9tZXRhYm9saXNtL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5PbGlnb3BlcHRpZGVzL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5QZXJveGlyZWRv

eGlucy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlByb3RlaW4gU3RydWN0dXJlLCBRdWF0

ZXJuYXJ5PC9rZXl3b3JkPjxrZXl3b3JkPlJOQSwgTWVzc2VuZ2VyL2dlbmV0aWNzL21ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+U3luYXBzZXMvZHJ1ZyBlZmZlY3RzL21ldGFib2xpc20vKnBh

dGhvbG9neTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWIt

ZGF0ZXM+PGRhdGU+RGVjIDE8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDYwLTIw

ODMgKEVsZWN0cm9uaWMpJiN4RDswOTY0LTY5MDYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24t

bnVtPjIxODczMjYwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRw

Oi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIxODczMjYwPC91cmw+PC9yZWxhdGVkLXVy

bHM+PC91cmxzPjxjdXN0b20yPlBNQzMyMDk4MjQ8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjEwOTMvaG1nL2RkcjM4MTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNv

cmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 299. Besides the possible direct impact of PDH inhibition in lowering the levels of acetyl-coenzyme A, acetylcholine, cholesterol and neurosteroidal hormones (e.g. estrogen) upon AD ADDIN EN.CITE <EndNote><Cite><Author>Bubber</Author><Year>2005</Year><RecNum>3409</RecNum><DisplayText><style face="superscript">300</style></DisplayText><record><rec-number>3409</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535909274">3409</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bubber, P.</author><author>Haroutunian, V.</author><author>Fisch, G.</author><author>Blass, J. P.</author><author>Gibson, G. E.</author></authors></contributors><auth-address>Weill Medical College of Cornell University at Burke Medical Research Institute, White Plains, NY 10605, USA.</auth-address><titles><title>Mitochondrial abnormalities in Alzheimer brain: mechanistic implications</title><secondary-title>Ann Neurol</secondary-title></titles><pages>695-703</pages><volume>57</volume><number>5</number><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Aging/pathology</keyword><keyword>Alzheimer Disease/enzymology/*pathology/physiopathology</keyword><keyword>Animals</keyword><keyword>Brain/enzymology/*pathology/physiopathology</keyword><keyword>Choline O-Acetyltransferase/metabolism</keyword><keyword>Citric Acid Cycle/physiology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Middle Aged</keyword><keyword>Mitochondria/enzymology/*pathology</keyword><keyword>Plaque, Amyloid/pathology</keyword><keyword>Postmortem Changes</keyword><keyword>Prefrontal Cortex/enzymology/pathology</keyword><keyword>Psychiatric Status Rating Scales</keyword><keyword>Pyruvate Dehydrogenase Complex/metabolism</keyword></keywords><dates><year>2005</year><pub-dates><date>May</date></pub-dates></dates><isbn>0364-5134 (Print)&#xD;0364-5134 (Linking)</isbn><accession-num>15852400</accession-num><urls><related-urls><url>, these metabolic changes further associate with mitochondrial alterations along disease progression ADDIN EN.CITE <EndNote><Cite><Author>Melo</Author><Year>2002</Year><RecNum>3410</RecNum><DisplayText><style face="superscript">301</style></DisplayText><record><rec-number>3410</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535909329">3410</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Melo, J. B.</author><author>Agostinho, P.</author><author>Oliveira, C. R.</author></authors></contributors><auth-address>Center for Neurosciences of Coimbra, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal.</auth-address><titles><title>Amyloid beta-peptide 25-35 reduces [3H]acetylcholine release in retinal neurons. Involvement of metabolic dysfunction</title><secondary-title>Amyloid</secondary-title></titles><pages>221-8</pages><volume>9</volume><number>4</number><keywords><keyword>Acetylcholine/*metabolism</keyword><keyword>Amyloid beta-Peptides/*physiology</keyword><keyword>Animals</keyword><keyword>Chick Embryo</keyword><keyword>Neurons/*metabolism</keyword><keyword>Peptide Fragments/*physiology</keyword><keyword>Retina/cytology/*metabolism</keyword><keyword>Tritium</keyword></keywords><dates><year>2002</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1350-6129 (Print)&#xD;1350-6129 (Linking)</isbn><accession-num>12557749</accession-num><urls><related-urls><url>. In this perspective, Aβ is widely known to deregulate mitochondrial proteins, blunting mitochondrial cytochrome c oxidase (or complex IV) activity and oxygen respiration rate, either centrally and/or peripherally (e.g. in platelets) ADDIN EN.CITE <EndNote><Cite><Author>Onyango</Author><Year>2016</Year><RecNum>3439</RecNum><DisplayText><style face="superscript">302</style></DisplayText><record><rec-number>3439</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535909454">3439</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Onyango, I. G.</author><author>Dennis, J.</author><author>Khan, S. M.</author></authors></contributors><auth-address>Gencia Biotechnology, 706 B Forest St, Charlottesville, VA 22903, USA.</auth-address><titles><title>Mitochondrial Dysfunction in Alzheimer&apos;s Disease and the Rationale for Bioenergetics Based Therapies</title><secondary-title>Aging Dis</secondary-title></titles><pages>201-14</pages><volume>7</volume><number>2</number><keywords><keyword>Alzheimer&apos;s disease</keyword><keyword>mitochondria</keyword><keyword>mitochondrial biogenesis</keyword><keyword>mitophagy</keyword><keyword>neuroinflammation</keyword><keyword>oxidative stress</keyword></keywords><dates><year>2016</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>2152-5250 (Print)&#xD;2152-5250 (Linking)</isbn><accession-num>27114851</accession-num><urls><related-urls><url> PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZYW88L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO

dW0+MzQ2NjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjMw

My0zMDU8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zNDY2PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MDk2ODciPjM0NjY8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPllhbywgSi48L2F1dGhvcj48YXV0aG9y

PlpoYW8sIEwuPC9hdXRob3I+PGF1dGhvcj5NYW8sIFouPC9hdXRob3I+PGF1dGhvcj5DaGVuLCBT

LjwvYXV0aG9yPjxhdXRob3I+V29uZywgSy4gQy48L2F1dGhvcj48YXV0aG9yPlRvLCBKLjwvYXV0

aG9yPjxhdXRob3I+QnJpbnRvbiwgUi4gRC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5Vbml2ZXJzaXR5IG9mIFNvdXRoZXJuIENhbGlmb3JuaWEsIFBoYXJt

YWNvbG9neSBhbmQgUGhhcm1hY2V1dGljYWwgU2NpZW5jZXMsIFNjaG9vbCBvZiBQaGFybWFjeSwg

MTk4NSBab25hbCBBdmVudWUsIFBTQy01MDIsIExvcyBBbmdlbGVzLCBDQSA5MDAzMywgVW5pdGVk

IFN0YXRlcy48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Qb3RlbnRpYXRpb24gb2YgYnJh

aW4gbWl0b2Nob25kcmlhbCBmdW5jdGlvbiBieSBTLWVxdW9sIGFuZCBSL1MtZXF1b2wgZXN0cm9n

ZW4gcmVjZXB0b3IgYmV0YS1zZWxlY3RpdmUgcGh5dG9TRVJNIHRyZWF0bWVudHM8L3RpdGxlPjxz

ZWNvbmRhcnktdGl0bGU+QnJhaW4gUmVzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlv

ZGljYWw+PGZ1bGwtdGl0bGU+QnJhaW4gUmVzPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFn

ZXM+MTI4LTQxPC9wYWdlcz48dm9sdW1lPjE1MTQ8L3ZvbHVtZT48a2V5d29yZHM+PGtleXdvcmQ+

QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CcmFpbi8qY3l0b2xvZ3kvZHJ1ZyBlZmZlY3RzPC9r

ZXl3b3JkPjxrZXl3b3JkPkNlbGxzLCBDdWx0dXJlZDwva2V5d29yZD48a2V5d29yZD5FbGVjdHJv

biBUcmFuc3BvcnQgQ2hhaW4gQ29tcGxleCBQcm90ZWlucy9tZXRhYm9saXNtPC9rZXl3b3JkPjxr

ZXl3b3JkPkVtYnJ5bywgTWFtbWFsaWFuPC9rZXl3b3JkPjxrZXl3b3JkPkVuZXJneSBNZXRhYm9s

aXNtL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5FcXVvbC8qcGhhcm1hY29sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPkVzdHJvZ2VuIFJlY2VwdG9yIGJldGEvKm1ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmUgRXhwcmVzc2lvbiBSZWd1

bGF0aW9uL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtl

eXdvcmQ+TGlwaWQgUGVyb3hpZGF0aW9uL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5N

aWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIEluYnJlZCBDNTdCTDwva2V5d29yZD48a2V5d29y

ZD5NaXRvY2hvbmRyaWEvKmRydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5OZXVyb25zL2Ry

dWcgZWZmZWN0cy8qdWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+PGtleXdvcmQ+T3ZhcmllY3RvbXk8

L2tleXdvcmQ+PGtleXdvcmQ+UGh5dG9lc3Ryb2dlbnMvKnBoYXJtYWNvbG9neTwva2V5d29yZD48

a2V5d29yZD5QcmVnbmFuY3k8L2tleXdvcmQ+PGtleXdvcmQ+UHlydXZhdGUgRGVoeWRyb2dlbmFz

ZSBDb21wbGV4L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UmF0czwva2V5d29yZD48a2V5

d29yZD5SYXRzLCBTcHJhZ3VlLURhd2xleTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVh

cj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVuIDEzPC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PGlzYm4+MTg3Mi02MjQwIChFbGVjdHJvbmljKSYjeEQ7MDAwNi04OTkzIChMaW5raW5n

KTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzQyODU0MjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVs

YXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMzQyODU0

MjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUMzNjcyMzk0PC9jdXN0b20y

PjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ouYnJhaW5yZXMuMjAxMy4wMi4wMjE8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkZh

bmc8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNOdW0+MzQ1MTwvUmVjTnVtPjxyZWNvcmQ+

PHJlYy1udW1iZXI+MzQ1MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIg

ZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIx

NTM1OTA5NjMwIj4zNDUxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5G

YW5nLCBELjwvYXV0aG9yPjxhdXRob3I+V2FuZywgWS48L2F1dGhvcj48YXV0aG9yPlpoYW5nLCBa

LjwvYXV0aG9yPjxhdXRob3I+RHUsIEguPC9hdXRob3I+PGF1dGhvcj5ZYW4sIFMuPC9hdXRob3I+

PGF1dGhvcj5TdW4sIFEuPC9hdXRob3I+PGF1dGhvcj5aaG9uZywgQy48L2F1dGhvcj48YXV0aG9y

Pld1LCBMLjwvYXV0aG9yPjxhdXRob3I+VmFuZ2F2YXJhZ3UsIEouIFIuPC9hdXRob3I+PGF1dGhv

cj5ZYW4sIFMuPC9hdXRob3I+PGF1dGhvcj5IdSwgRy48L2F1dGhvcj48YXV0aG9yPkd1bywgTC48

L2F1dGhvcj48YXV0aG9yPlJhYmlub3dpdHosIE0uPC9hdXRob3I+PGF1dGhvcj5HbGFzZXIsIEUu

PC9hdXRob3I+PGF1dGhvcj5BcmFuY2lvLCBPLjwvYXV0aG9yPjxhdXRob3I+U29zdW5vdiwgQS4g

QS48L2F1dGhvcj48YXV0aG9yPk1jS2hhbm4sIEcuIE0uPC9hdXRob3I+PGF1dGhvcj5DaGVuLCBK

LiBYLjwvYXV0aG9yPjxhdXRob3I+WWFuLCBTLiBTLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy

aWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgUGhhcm1hY29sb2d5IGFuZCBUb3hp

Y29sb2d5LCBIaWd1Y2hpIEJpb3NjaWVuY2UgQ2VudGVyLCBTY2hvb2wgb2YgUGhhcm1hY3ksIFVu

aXZlcnNpdHkgb2YgS2Fuc2FzLCBMYXdyZW5jZSwgS1MgNjYwNDcsIFVTQS4mI3hEO0RlcGFydG1l

bnQgb2YgUGhhcm1hY29sb2d5IGFuZCBUb3hpY29sb2d5LCBIaWd1Y2hpIEJpb3NjaWVuY2UgQ2Vu

dGVyLCBTY2hvb2wgb2YgUGhhcm1hY3ksIFVuaXZlcnNpdHkgb2YgS2Fuc2FzLCBMYXdyZW5jZSwg

S1MgNjYwNDcsIFVTQSwgU2Nob29sIG9mIExpZmUgU2NpZW5jZXMsIEJlaWppbmcgTm9ybWFsIFVu

aXZlcnNpdHksIEJlaWppbmcgMTAwODcxLCBDaGluYS4mI3hEO1RhdWIgSW5zdGl0dXRlIGZvciBS

ZXNlYXJjaCBvbiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgYW5kIHRoZSBBZ2luZyBCcmFpbiwg

TmV3IFlvcmssIE5ZIDEwMDMyLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIEJpb2NoZW1pc3RyeSBh

bmQgQmlvcGh5c2ljcywgU3RvY2tob2xtIFVuaXZlcnNpdHksIFN0b2NraG9sbSwgU3dlZGVuLiYj

eEQ7RGVwYXJ0bWVudCBvZiBOZXVyb3N1cmdlcnksIFBoeXNpY2lhbnMgJmFtcDsgU3VyZ2VvbnMg

Q29sbGVnZSBvZiBDb2x1bWJpYSBVbml2ZXJzaXR5LCBOZXcgWW9yaywgTlkgMTAwMzIsIFVTQSBh

bmQuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgTWVtb3JpYWwgU2xvYW4tS2V0dGVyaW5n

IENhbmNlciBDZW50ZXIsIDEyNzUgWW9yayBBdmVudWUsIE5ldyBZb3JrLCBOWSAxMDA2NSwgVVNB

LiYjeEQ7RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xvZ3kgYW5kIFRveGljb2xvZ3ksIEhpZ3VjaGkg

Qmlvc2NpZW5jZSBDZW50ZXIsIFNjaG9vbCBvZiBQaGFybWFjeSwgVW5pdmVyc2l0eSBvZiBLYW5z

YXMsIExhd3JlbmNlLCBLUyA2NjA0NywgVVNBLCBzaGlkdUBrdS5lZHUuPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+SW5jcmVhc2VkIG5ldXJvbmFsIFByZVAgYWN0aXZpdHkgcmVkdWNlcyBB

YmV0YSBhY2N1bXVsYXRpb24sIGF0dGVudWF0ZXMgbmV1cm9pbmZsYW1tYXRpb24gYW5kIGltcHJv

dmVzIG1pdG9jaG9uZHJpYWwgYW5kIHN5bmFwdGljIGZ1bmN0aW9uIGluIEFsemhlaW1lciBkaXNl

YXNlJmFwb3M7cyBtb3VzZSBtb2RlbDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5IdW0gTW9sIEdl

bmV0PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SHVt

IE1vbCBHZW5ldDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjUxOTgtMjEwPC9wYWdl

cz48dm9sdW1lPjI0PC92b2x1bWU+PG51bWJlcj4xODwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29y

ZD5BbHpoZWltZXIgRGlzZWFzZS8qbWV0YWJvbGlzbS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3

b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QmVoYXZpb3IsIEFuaW1hbDwva2V5d29yZD48

a2V5d29yZD5DZWxscywgQ3VsdHVyZWQ8L2tleXdvcmQ+PGtleXdvcmQ+Q29nbml0aW9uPC9rZXl3

b3JkPjxrZXl3b3JkPkRpc2Vhc2UgTW9kZWxzLCBBbmltYWw8L2tleXdvcmQ+PGtleXdvcmQ+R2Vu

ZSBFeHByZXNzaW9uPC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1hdGlvbiBNZWRpYXRvcnMvbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIFRy

YW5zZ2VuaWM8L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2Nob25kcmlhLyptZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPk5ldXJvbnMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+T3hpZGF0

aXZlIFN0cmVzczwva2V5d29yZD48a2V5d29yZD5Qcm90ZWluIEFnZ3JlZ2F0aW9uLCBQYXRob2xv

Z2ljYWwvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVvbHlzaXM8L2tleXdvcmQ+

PGtleXdvcmQ+U2VyaW5lIEVuZG9wZXB0aWRhc2VzL2dlbmV0aWNzLyptZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPlN5bmFwc2VzLyptZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRh

dGVzPjx5ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMTU8L2RhdGU+PC9wdWIt

ZGF0ZXM+PC9kYXRlcz48aXNibj4xNDYwLTIwODMgKEVsZWN0cm9uaWMpJiN4RDswOTY0LTY5MDYg

KExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2MTIzNDg4PC9hY2Nlc3Npb24tbnVtPjx1

cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVk

LzI2MTIzNDg4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQ1NTA4MjE8

L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwOTMvaG1nL2RkdjI0MTwvZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+WWFvPC9B

dXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVjTnVtPjM0NzQ8L1JlY051bT48cmVjb3JkPjxyZWMt

bnVtYmVyPjM0NzQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk

PSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkw

OTczMCI+MzQ3NDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFy

dGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+WWFvLCBK

LjwvYXV0aG9yPjxhdXRob3I+SXJ3aW4sIFIuPC9hdXRob3I+PGF1dGhvcj5DaGVuLCBTLjwvYXV0

aG9yPjxhdXRob3I+SGFtaWx0b24sIFIuPC9hdXRob3I+PGF1dGhvcj5DYWRlbmFzLCBFLjwvYXV0

aG9yPjxhdXRob3I+QnJpbnRvbiwgUi4gRC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIFBoYXJtYWNvbG9neSBhbmQgUGhhcm1hY2V1

dGljYWwgU2NpZW5jZXMsIFNjaG9vbCBvZiBQaGFybWFjeSwgVW5pdmVyc2l0eSBvZiBTb3V0aGVy

biBDYWxpZm9ybmlhLCBMb3MgQW5nZWxlcywgQ0EgOTAwMzMsIFVTQS48L2F1dGgtYWRkcmVzcz48

dGl0bGVzPjx0aXRsZT5PdmFyaWFuIGhvcm1vbmUgbG9zcyBpbmR1Y2VzIGJpb2VuZXJnZXRpYyBk

ZWZpY2l0cyBhbmQgbWl0b2Nob25kcmlhbCBiZXRhLWFteWxvaWQ8L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+TmV1cm9iaW9sIEFnaW5nPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+TmV1cm9iaW9sIEFnaW5nPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48

cGFnZXM+MTUwNy0yMTwvcGFnZXM+PHZvbHVtZT4zMzwvdm9sdW1lPjxudW1iZXI+ODwvbnVtYmVy

PjxrZXl3b3Jkcz48a2V5d29yZD4zLUh5ZHJveHlhY3lsIENvQSBEZWh5ZHJvZ2VuYXNlcy8qbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BZ2luZy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BbXls

b2lkIGJldGEtUGVwdGlkZXMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwv

a2V5d29yZD48a2V5d29yZD5CcmFpbi8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5Fc3Ry

YWRpb2wvKmRlZmljaWVuY3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3

b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgS25vY2tvdXQ8L2tleXdvcmQ+PGtleXdv

cmQ+TWl0b2Nob25kcmlhLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk94aWRhdGl2ZSBT

dHJlc3M8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMjwveWVhcj48cHViLWRh

dGVzPjxkYXRlPkF1ZzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTgtMTQ5NyAo

RWxlY3Ryb25pYykmI3hEOzAxOTctNDU4MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+

MjE1MTQ2OTM8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93

d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjE1MTQ2OTM8L3VybD48L3JlbGF0ZWQtdXJscz48

L3VybHM+PGN1c3RvbTI+UE1DMzE4MTI3MzwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+MTAuMTAxNi9qLm5ldXJvYmlvbGFnaW5nLjIwMTEuMDMuMDAxPC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZYW88L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO

dW0+MzQ2NjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjMw

My0zMDU8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zNDY2PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MDk2ODciPjM0NjY8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPllhbywgSi48L2F1dGhvcj48YXV0aG9y

PlpoYW8sIEwuPC9hdXRob3I+PGF1dGhvcj5NYW8sIFouPC9hdXRob3I+PGF1dGhvcj5DaGVuLCBT

LjwvYXV0aG9yPjxhdXRob3I+V29uZywgSy4gQy48L2F1dGhvcj48YXV0aG9yPlRvLCBKLjwvYXV0

aG9yPjxhdXRob3I+QnJpbnRvbiwgUi4gRC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5Vbml2ZXJzaXR5IG9mIFNvdXRoZXJuIENhbGlmb3JuaWEsIFBoYXJt

YWNvbG9neSBhbmQgUGhhcm1hY2V1dGljYWwgU2NpZW5jZXMsIFNjaG9vbCBvZiBQaGFybWFjeSwg

MTk4NSBab25hbCBBdmVudWUsIFBTQy01MDIsIExvcyBBbmdlbGVzLCBDQSA5MDAzMywgVW5pdGVk

IFN0YXRlcy48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Qb3RlbnRpYXRpb24gb2YgYnJh

aW4gbWl0b2Nob25kcmlhbCBmdW5jdGlvbiBieSBTLWVxdW9sIGFuZCBSL1MtZXF1b2wgZXN0cm9n

ZW4gcmVjZXB0b3IgYmV0YS1zZWxlY3RpdmUgcGh5dG9TRVJNIHRyZWF0bWVudHM8L3RpdGxlPjxz

ZWNvbmRhcnktdGl0bGU+QnJhaW4gUmVzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlv

ZGljYWw+PGZ1bGwtdGl0bGU+QnJhaW4gUmVzPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFn

ZXM+MTI4LTQxPC9wYWdlcz48dm9sdW1lPjE1MTQ8L3ZvbHVtZT48a2V5d29yZHM+PGtleXdvcmQ+

QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CcmFpbi8qY3l0b2xvZ3kvZHJ1ZyBlZmZlY3RzPC9r

ZXl3b3JkPjxrZXl3b3JkPkNlbGxzLCBDdWx0dXJlZDwva2V5d29yZD48a2V5d29yZD5FbGVjdHJv

biBUcmFuc3BvcnQgQ2hhaW4gQ29tcGxleCBQcm90ZWlucy9tZXRhYm9saXNtPC9rZXl3b3JkPjxr

ZXl3b3JkPkVtYnJ5bywgTWFtbWFsaWFuPC9rZXl3b3JkPjxrZXl3b3JkPkVuZXJneSBNZXRhYm9s

aXNtL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5FcXVvbC8qcGhhcm1hY29sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPkVzdHJvZ2VuIFJlY2VwdG9yIGJldGEvKm1ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmUgRXhwcmVzc2lvbiBSZWd1

bGF0aW9uL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtl

eXdvcmQ+TGlwaWQgUGVyb3hpZGF0aW9uL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5N

aWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIEluYnJlZCBDNTdCTDwva2V5d29yZD48a2V5d29y

ZD5NaXRvY2hvbmRyaWEvKmRydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5OZXVyb25zL2Ry

dWcgZWZmZWN0cy8qdWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+PGtleXdvcmQ+T3ZhcmllY3RvbXk8

L2tleXdvcmQ+PGtleXdvcmQ+UGh5dG9lc3Ryb2dlbnMvKnBoYXJtYWNvbG9neTwva2V5d29yZD48

a2V5d29yZD5QcmVnbmFuY3k8L2tleXdvcmQ+PGtleXdvcmQ+UHlydXZhdGUgRGVoeWRyb2dlbmFz

ZSBDb21wbGV4L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UmF0czwva2V5d29yZD48a2V5

d29yZD5SYXRzLCBTcHJhZ3VlLURhd2xleTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVh

cj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVuIDEzPC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PGlzYm4+MTg3Mi02MjQwIChFbGVjdHJvbmljKSYjeEQ7MDAwNi04OTkzIChMaW5raW5n

KTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzQyODU0MjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVs

YXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMzQyODU0

MjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUMzNjcyMzk0PC9jdXN0b20y

PjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ouYnJhaW5yZXMuMjAxMy4wMi4wMjE8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkZh

bmc8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNOdW0+MzQ1MTwvUmVjTnVtPjxyZWNvcmQ+

PHJlYy1udW1iZXI+MzQ1MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIg

ZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIx

NTM1OTA5NjMwIj4zNDUxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5G

YW5nLCBELjwvYXV0aG9yPjxhdXRob3I+V2FuZywgWS48L2F1dGhvcj48YXV0aG9yPlpoYW5nLCBa

LjwvYXV0aG9yPjxhdXRob3I+RHUsIEguPC9hdXRob3I+PGF1dGhvcj5ZYW4sIFMuPC9hdXRob3I+

PGF1dGhvcj5TdW4sIFEuPC9hdXRob3I+PGF1dGhvcj5aaG9uZywgQy48L2F1dGhvcj48YXV0aG9y

Pld1LCBMLjwvYXV0aG9yPjxhdXRob3I+VmFuZ2F2YXJhZ3UsIEouIFIuPC9hdXRob3I+PGF1dGhv

cj5ZYW4sIFMuPC9hdXRob3I+PGF1dGhvcj5IdSwgRy48L2F1dGhvcj48YXV0aG9yPkd1bywgTC48

L2F1dGhvcj48YXV0aG9yPlJhYmlub3dpdHosIE0uPC9hdXRob3I+PGF1dGhvcj5HbGFzZXIsIEUu

PC9hdXRob3I+PGF1dGhvcj5BcmFuY2lvLCBPLjwvYXV0aG9yPjxhdXRob3I+U29zdW5vdiwgQS4g

QS48L2F1dGhvcj48YXV0aG9yPk1jS2hhbm4sIEcuIE0uPC9hdXRob3I+PGF1dGhvcj5DaGVuLCBK

LiBYLjwvYXV0aG9yPjxhdXRob3I+WWFuLCBTLiBTLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy

aWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgUGhhcm1hY29sb2d5IGFuZCBUb3hp

Y29sb2d5LCBIaWd1Y2hpIEJpb3NjaWVuY2UgQ2VudGVyLCBTY2hvb2wgb2YgUGhhcm1hY3ksIFVu

aXZlcnNpdHkgb2YgS2Fuc2FzLCBMYXdyZW5jZSwgS1MgNjYwNDcsIFVTQS4mI3hEO0RlcGFydG1l

bnQgb2YgUGhhcm1hY29sb2d5IGFuZCBUb3hpY29sb2d5LCBIaWd1Y2hpIEJpb3NjaWVuY2UgQ2Vu

dGVyLCBTY2hvb2wgb2YgUGhhcm1hY3ksIFVuaXZlcnNpdHkgb2YgS2Fuc2FzLCBMYXdyZW5jZSwg

S1MgNjYwNDcsIFVTQSwgU2Nob29sIG9mIExpZmUgU2NpZW5jZXMsIEJlaWppbmcgTm9ybWFsIFVu

aXZlcnNpdHksIEJlaWppbmcgMTAwODcxLCBDaGluYS4mI3hEO1RhdWIgSW5zdGl0dXRlIGZvciBS

ZXNlYXJjaCBvbiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgYW5kIHRoZSBBZ2luZyBCcmFpbiwg

TmV3IFlvcmssIE5ZIDEwMDMyLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIEJpb2NoZW1pc3RyeSBh

bmQgQmlvcGh5c2ljcywgU3RvY2tob2xtIFVuaXZlcnNpdHksIFN0b2NraG9sbSwgU3dlZGVuLiYj

eEQ7RGVwYXJ0bWVudCBvZiBOZXVyb3N1cmdlcnksIFBoeXNpY2lhbnMgJmFtcDsgU3VyZ2VvbnMg

Q29sbGVnZSBvZiBDb2x1bWJpYSBVbml2ZXJzaXR5LCBOZXcgWW9yaywgTlkgMTAwMzIsIFVTQSBh

bmQuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgTWVtb3JpYWwgU2xvYW4tS2V0dGVyaW5n

IENhbmNlciBDZW50ZXIsIDEyNzUgWW9yayBBdmVudWUsIE5ldyBZb3JrLCBOWSAxMDA2NSwgVVNB

LiYjeEQ7RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xvZ3kgYW5kIFRveGljb2xvZ3ksIEhpZ3VjaGkg

Qmlvc2NpZW5jZSBDZW50ZXIsIFNjaG9vbCBvZiBQaGFybWFjeSwgVW5pdmVyc2l0eSBvZiBLYW5z

YXMsIExhd3JlbmNlLCBLUyA2NjA0NywgVVNBLCBzaGlkdUBrdS5lZHUuPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+SW5jcmVhc2VkIG5ldXJvbmFsIFByZVAgYWN0aXZpdHkgcmVkdWNlcyBB

YmV0YSBhY2N1bXVsYXRpb24sIGF0dGVudWF0ZXMgbmV1cm9pbmZsYW1tYXRpb24gYW5kIGltcHJv

dmVzIG1pdG9jaG9uZHJpYWwgYW5kIHN5bmFwdGljIGZ1bmN0aW9uIGluIEFsemhlaW1lciBkaXNl

YXNlJmFwb3M7cyBtb3VzZSBtb2RlbDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5IdW0gTW9sIEdl

bmV0PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SHVt

IE1vbCBHZW5ldDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjUxOTgtMjEwPC9wYWdl

cz48dm9sdW1lPjI0PC92b2x1bWU+PG51bWJlcj4xODwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29y

ZD5BbHpoZWltZXIgRGlzZWFzZS8qbWV0YWJvbGlzbS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3

b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QmVoYXZpb3IsIEFuaW1hbDwva2V5d29yZD48

a2V5d29yZD5DZWxscywgQ3VsdHVyZWQ8L2tleXdvcmQ+PGtleXdvcmQ+Q29nbml0aW9uPC9rZXl3

b3JkPjxrZXl3b3JkPkRpc2Vhc2UgTW9kZWxzLCBBbmltYWw8L2tleXdvcmQ+PGtleXdvcmQ+R2Vu

ZSBFeHByZXNzaW9uPC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1hdGlvbiBNZWRpYXRvcnMvbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIFRy

YW5zZ2VuaWM8L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2Nob25kcmlhLyptZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPk5ldXJvbnMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+T3hpZGF0

aXZlIFN0cmVzczwva2V5d29yZD48a2V5d29yZD5Qcm90ZWluIEFnZ3JlZ2F0aW9uLCBQYXRob2xv

Z2ljYWwvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVvbHlzaXM8L2tleXdvcmQ+

PGtleXdvcmQ+U2VyaW5lIEVuZG9wZXB0aWRhc2VzL2dlbmV0aWNzLyptZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPlN5bmFwc2VzLyptZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRh

dGVzPjx5ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMTU8L2RhdGU+PC9wdWIt

ZGF0ZXM+PC9kYXRlcz48aXNibj4xNDYwLTIwODMgKEVsZWN0cm9uaWMpJiN4RDswOTY0LTY5MDYg

KExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2MTIzNDg4PC9hY2Nlc3Npb24tbnVtPjx1

cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVk

LzI2MTIzNDg4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQ1NTA4MjE8

L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwOTMvaG1nL2RkdjI0MTwvZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+WWFvPC9B

dXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVjTnVtPjM0NzQ8L1JlY051bT48cmVjb3JkPjxyZWMt

bnVtYmVyPjM0NzQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk

PSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkw

OTczMCI+MzQ3NDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFy

dGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+WWFvLCBK

LjwvYXV0aG9yPjxhdXRob3I+SXJ3aW4sIFIuPC9hdXRob3I+PGF1dGhvcj5DaGVuLCBTLjwvYXV0

aG9yPjxhdXRob3I+SGFtaWx0b24sIFIuPC9hdXRob3I+PGF1dGhvcj5DYWRlbmFzLCBFLjwvYXV0

aG9yPjxhdXRob3I+QnJpbnRvbiwgUi4gRC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIFBoYXJtYWNvbG9neSBhbmQgUGhhcm1hY2V1

dGljYWwgU2NpZW5jZXMsIFNjaG9vbCBvZiBQaGFybWFjeSwgVW5pdmVyc2l0eSBvZiBTb3V0aGVy

biBDYWxpZm9ybmlhLCBMb3MgQW5nZWxlcywgQ0EgOTAwMzMsIFVTQS48L2F1dGgtYWRkcmVzcz48

dGl0bGVzPjx0aXRsZT5PdmFyaWFuIGhvcm1vbmUgbG9zcyBpbmR1Y2VzIGJpb2VuZXJnZXRpYyBk

ZWZpY2l0cyBhbmQgbWl0b2Nob25kcmlhbCBiZXRhLWFteWxvaWQ8L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+TmV1cm9iaW9sIEFnaW5nPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+TmV1cm9iaW9sIEFnaW5nPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48

cGFnZXM+MTUwNy0yMTwvcGFnZXM+PHZvbHVtZT4zMzwvdm9sdW1lPjxudW1iZXI+ODwvbnVtYmVy

PjxrZXl3b3Jkcz48a2V5d29yZD4zLUh5ZHJveHlhY3lsIENvQSBEZWh5ZHJvZ2VuYXNlcy8qbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BZ2luZy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BbXls

b2lkIGJldGEtUGVwdGlkZXMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwv

a2V5d29yZD48a2V5d29yZD5CcmFpbi8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5Fc3Ry

YWRpb2wvKmRlZmljaWVuY3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3

b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgS25vY2tvdXQ8L2tleXdvcmQ+PGtleXdv

cmQ+TWl0b2Nob25kcmlhLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk94aWRhdGl2ZSBT

dHJlc3M8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMjwveWVhcj48cHViLWRh

dGVzPjxkYXRlPkF1ZzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTgtMTQ5NyAo

RWxlY3Ryb25pYykmI3hEOzAxOTctNDU4MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+

MjE1MTQ2OTM8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93

d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjE1MTQ2OTM8L3VybD48L3JlbGF0ZWQtdXJscz48

L3VybHM+PGN1c3RvbTI+UE1DMzE4MTI3MzwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+MTAuMTAxNi9qLm5ldXJvYmlvbGFnaW5nLjIwMTEuMDMuMDAxPC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 303-305. This may be also due to a reduction in the neuronal expression of nuclear genes that code for mitochondrial electron transport chain subunits PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3Njb25pPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48

UmVjTnVtPjM0NzU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMDY8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zNDc1PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MDk4MjAiPjM0NzU8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1vc2NvbmksIEwuPC9hdXRob3I+PGF1

dGhvcj5kZSBMZW9uLCBNLjwvYXV0aG9yPjxhdXRob3I+TXVycmF5LCBKLjwvYXV0aG9yPjxhdXRo

b3I+RSwgTC48L2F1dGhvcj48YXV0aG9yPkx1LCBKLjwvYXV0aG9yPjxhdXRob3I+SmF2aWVyLCBF

LjwvYXV0aG9yPjxhdXRob3I+TWNIdWdoLCBQLjwvYXV0aG9yPjxhdXRob3I+U3dlcmRsb3csIFIu

IEguPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+Q2VudGVy

IGZvciBCcmFpbiBIZWFsdGgsIERlcGFydG1lbnQgb2YgUHN5Y2hpYXRyeSwgTmV3IFlvcmsgVW5p

dmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUsIE5ldyBZb3JrLCBOWSAxMDAxNiwgVVNBLiBsaXNh

Lm1vc2NvbmlAbnl1bWMub3JnPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UmVkdWNlZCBt

aXRvY2hvbmRyaWEgY3l0b2Nocm9tZSBveGlkYXNlIGFjdGl2aXR5IGluIGFkdWx0IGNoaWxkcmVu

IG9mIG1vdGhlcnMgd2l0aCBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+SiBBbHpoZWltZXJzIERpczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJp

b2RpY2FsPjxmdWxsLXRpdGxlPkogQWx6aGVpbWVycyBEaXM8L2Z1bGwtdGl0bGU+PC9wZXJpb2Rp

Y2FsPjxwYWdlcz40ODMtOTA8L3BhZ2VzPjx2b2x1bWU+Mjc8L3ZvbHVtZT48bnVtYmVyPjM8L251

bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlIG9mIE9u

c2V0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERp

c2Vhc2UvKmVuenltb2xvZ3kvZ2VuZXRpY3MvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJp

b21hcmtlcnMvYmxvb2Q8L2tleXdvcmQ+PGtleXdvcmQ+Qmxvb2QgUGxhdGVsZXRzL2Vuenltb2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+Q29ob3J0IFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+RG93

bi1SZWd1bGF0aW9uLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5FbGVjdHJvbiBUcmFuc3Bv

cnQgQ29tcGxleCBJVi8qYW50YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9ycy9nZW5ldGljcy9tZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkVuenltZSBBY3RpdmF0aW9uL2dlbmV0aWNzPC9rZXl3

b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5HZW5ldGljIFByZWRpc3Bvc2l0

aW9uIHRvIERpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TWl0

b2Nob25kcmlhLyplbnp5bW9sb2d5L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD4qTW90aGVy

czwva2V5d29yZD48a2V5d29yZD5TZXggRmFjdG9yczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRl

cz48eWVhcj4yMDExPC95ZWFyPjwvZGF0ZXM+PGlzYm4+MTg3NS04OTA4IChFbGVjdHJvbmljKSYj

eEQ7MTM4Ny0yODc3IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMTg0MTI0NjwvYWNj

ZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5u

aWguZ292L3B1Ym1lZC8yMTg0MTI0NjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9t

Mj5QTUMzMjkxOTU0PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4zMjMzL0pB

RC0yMDExLTExMDg2NjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwv

RW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3Njb25pPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48

UmVjTnVtPjM0NzU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMDY8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zNDc1PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MDk4MjAiPjM0NzU8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1vc2NvbmksIEwuPC9hdXRob3I+PGF1

dGhvcj5kZSBMZW9uLCBNLjwvYXV0aG9yPjxhdXRob3I+TXVycmF5LCBKLjwvYXV0aG9yPjxhdXRo

b3I+RSwgTC48L2F1dGhvcj48YXV0aG9yPkx1LCBKLjwvYXV0aG9yPjxhdXRob3I+SmF2aWVyLCBF

LjwvYXV0aG9yPjxhdXRob3I+TWNIdWdoLCBQLjwvYXV0aG9yPjxhdXRob3I+U3dlcmRsb3csIFIu

IEguPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+Q2VudGVy

IGZvciBCcmFpbiBIZWFsdGgsIERlcGFydG1lbnQgb2YgUHN5Y2hpYXRyeSwgTmV3IFlvcmsgVW5p

dmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUsIE5ldyBZb3JrLCBOWSAxMDAxNiwgVVNBLiBsaXNh

Lm1vc2NvbmlAbnl1bWMub3JnPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UmVkdWNlZCBt

aXRvY2hvbmRyaWEgY3l0b2Nocm9tZSBveGlkYXNlIGFjdGl2aXR5IGluIGFkdWx0IGNoaWxkcmVu

IG9mIG1vdGhlcnMgd2l0aCBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+SiBBbHpoZWltZXJzIERpczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJp

b2RpY2FsPjxmdWxsLXRpdGxlPkogQWx6aGVpbWVycyBEaXM8L2Z1bGwtdGl0bGU+PC9wZXJpb2Rp

Y2FsPjxwYWdlcz40ODMtOTA8L3BhZ2VzPjx2b2x1bWU+Mjc8L3ZvbHVtZT48bnVtYmVyPjM8L251

bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlIG9mIE9u

c2V0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERp

c2Vhc2UvKmVuenltb2xvZ3kvZ2VuZXRpY3MvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJp

b21hcmtlcnMvYmxvb2Q8L2tleXdvcmQ+PGtleXdvcmQ+Qmxvb2QgUGxhdGVsZXRzL2Vuenltb2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+Q29ob3J0IFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+RG93

bi1SZWd1bGF0aW9uLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5FbGVjdHJvbiBUcmFuc3Bv

cnQgQ29tcGxleCBJVi8qYW50YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9ycy9nZW5ldGljcy9tZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkVuenltZSBBY3RpdmF0aW9uL2dlbmV0aWNzPC9rZXl3

b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5HZW5ldGljIFByZWRpc3Bvc2l0

aW9uIHRvIERpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TWl0

b2Nob25kcmlhLyplbnp5bW9sb2d5L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD4qTW90aGVy

czwva2V5d29yZD48a2V5d29yZD5TZXggRmFjdG9yczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRl

cz48eWVhcj4yMDExPC95ZWFyPjwvZGF0ZXM+PGlzYm4+MTg3NS04OTA4IChFbGVjdHJvbmljKSYj

eEQ7MTM4Ny0yODc3IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMTg0MTI0NjwvYWNj

ZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5u

aWguZ292L3B1Ym1lZC8yMTg0MTI0NjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9t

Mj5QTUMzMjkxOTU0PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4zMjMzL0pB

RC0yMDExLTExMDg2NjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwv

RW5kTm90ZT5=

ADDIN EN.CITE.DATA 306, or to a decrease in the number of neuronal mitochondria ADDIN EN.CITE <EndNote><Cite><Author>Swerdlow</Author><Year>2014</Year><RecNum>1009</RecNum><DisplayText><style face="superscript">292</style></DisplayText><record><rec-number>1009</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865640">1009</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Swerdlow, Russell H.</author><author>Burns, Jeffrey M.</author><author>Khan, Shaharyar M.</author></authors></contributors><titles><title>The Alzheimer&apos;s disease mitochondrial cascade hypothesis: Progress and perspectives</title><secondary-title>Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease</secondary-title></titles><pages>1219-1231</pages><volume>1842</volume><number>8</number><dates><year>2014</year><pub-dates><date>2014/08</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>0925-4439</isbn><urls><related-urls><url>. Importantly, the disruption between mitochondrial respiration and energy metabolism in AD was also associated with oxidative stress PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Td2VyZGxvdzwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+

PFJlY051bT4zNDc2PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjkzLDMwNzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM0NzY8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkwOTkzMyI+MzQ3Njwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U3dlcmRsb3csIFIuIEguPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBv

ZiBOZXVyb2xvZ3ksIFVuaXZlcnNpdHkgb2YgS2Fuc2FzIE1lZGljYWwgQ2VudGVyLCBLYW5zYXMg

Q2l0eSwgS2Fuc2FzLCBVU0EuIHJzd2VyZGxvd0BrdW1jLmVkdTwvYXV0aC1hZGRyZXNzPjx0aXRs

ZXM+PHRpdGxlPk1pdG9jaG9uZHJpYSBhbmQgY2VsbCBiaW9lbmVyZ2V0aWNzOiBpbmNyZWFzaW5n

bHkgcmVjb2duaXplZCBjb21wb25lbnRzIGFuZCBhIHBvc3NpYmxlIGV0aW9sb2dpYyBjYXVzZSBv

ZiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW50aW94

aWQgUmVkb3ggU2lnbmFsPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1

bGwtdGl0bGU+QW50aW94aWQgUmVkb3ggU2lnbmFsPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48

cGFnZXM+MTQzNC01NTwvcGFnZXM+PHZvbHVtZT4xNjwvdm9sdW1lPjxudW1iZXI+MTI8L251bWJl

cj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmV0aW9sb2d5L21ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5FbmVyZ3kgTWV0

YWJvbGlzbS9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5

d29yZD5NaXRvY2hvbmRyaWEvKm1ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1biAxNTwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxpc2JuPjE1NTctNzcxNiAoRWxlY3Ryb25pYykmI3hEOzE1MjMtMDg2NCAoTGlu

a2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjE5MDI1OTc8L2FjY2Vzc2lvbi1udW0+PHVybHM+

PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjE5

MDI1OTc8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMzMyOTk0OTwvY3Vz

dG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA4OS9hcnMuMjAxMS40MTQ5PC9lbGVj

dHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5LYW5kaW1h

bGxhPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48UmVjTnVtPjEwMTA8L1JlY051bT48cmVjb3Jk

PjxyZWMtbnVtYmVyPjEwMTA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0i

MTUzMjg2NTY0MCI+MTAxMDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy

bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+

S2FuZGltYWxsYSwgUmFtZXNoPC9hdXRob3I+PGF1dGhvcj5UaGlydW1hbGEsIFZhbmk8L2F1dGhv

cj48YXV0aG9yPlJlZGR5LCBQLiBIZW1hY2hhbmRyYTwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy

aWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5JcyBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgYSBUeXBl

IDMgRGlhYmV0ZXM/IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PkJpb2NoaW1pY2EgZXQgQmlvcGh5c2ljYSBBY3RhIChCQkEpIC0gTW9sZWN1bGFyIEJhc2lzIG9m

IERpc2Vhc2U8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTA3OC0xMDg5PC9wYWdl

cz48dm9sdW1lPjE4NjM8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAx

NzwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTcvMDU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MDkyNS00NDM5PC9pc2Ju

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2ouYmJh

ZGlzLjIwMTYuMDguMDE4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4xMDE2L2ouYmJhZGlzLjIwMTYuMDguMDE4PC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Td2VyZGxvdzwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+

PFJlY051bT4zNDc2PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjkzLDMwNzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM0NzY8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkwOTkzMyI+MzQ3Njwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U3dlcmRsb3csIFIuIEguPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBv

ZiBOZXVyb2xvZ3ksIFVuaXZlcnNpdHkgb2YgS2Fuc2FzIE1lZGljYWwgQ2VudGVyLCBLYW5zYXMg

Q2l0eSwgS2Fuc2FzLCBVU0EuIHJzd2VyZGxvd0BrdW1jLmVkdTwvYXV0aC1hZGRyZXNzPjx0aXRs

ZXM+PHRpdGxlPk1pdG9jaG9uZHJpYSBhbmQgY2VsbCBiaW9lbmVyZ2V0aWNzOiBpbmNyZWFzaW5n

bHkgcmVjb2duaXplZCBjb21wb25lbnRzIGFuZCBhIHBvc3NpYmxlIGV0aW9sb2dpYyBjYXVzZSBv

ZiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW50aW94

aWQgUmVkb3ggU2lnbmFsPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1

bGwtdGl0bGU+QW50aW94aWQgUmVkb3ggU2lnbmFsPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48

cGFnZXM+MTQzNC01NTwvcGFnZXM+PHZvbHVtZT4xNjwvdm9sdW1lPjxudW1iZXI+MTI8L251bWJl

cj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmV0aW9sb2d5L21ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5FbmVyZ3kgTWV0

YWJvbGlzbS9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5

d29yZD5NaXRvY2hvbmRyaWEvKm1ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1biAxNTwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxpc2JuPjE1NTctNzcxNiAoRWxlY3Ryb25pYykmI3hEOzE1MjMtMDg2NCAoTGlu

a2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjE5MDI1OTc8L2FjY2Vzc2lvbi1udW0+PHVybHM+

PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjE5

MDI1OTc8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMzMyOTk0OTwvY3Vz

dG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA4OS9hcnMuMjAxMS40MTQ5PC9lbGVj

dHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5LYW5kaW1h

bGxhPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48UmVjTnVtPjEwMTA8L1JlY051bT48cmVjb3Jk

PjxyZWMtbnVtYmVyPjEwMTA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0i

MTUzMjg2NTY0MCI+MTAxMDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy

bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+

S2FuZGltYWxsYSwgUmFtZXNoPC9hdXRob3I+PGF1dGhvcj5UaGlydW1hbGEsIFZhbmk8L2F1dGhv

cj48YXV0aG9yPlJlZGR5LCBQLiBIZW1hY2hhbmRyYTwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy

aWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5JcyBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgYSBUeXBl

IDMgRGlhYmV0ZXM/IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PkJpb2NoaW1pY2EgZXQgQmlvcGh5c2ljYSBBY3RhIChCQkEpIC0gTW9sZWN1bGFyIEJhc2lzIG9m

IERpc2Vhc2U8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTA3OC0xMDg5PC9wYWdl

cz48dm9sdW1lPjE4NjM8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAx

NzwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTcvMDU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MDkyNS00NDM5PC9pc2Ju

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2ouYmJh

ZGlzLjIwMTYuMDguMDE4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4xMDE2L2ouYmJhZGlzLjIwMTYuMDguMDE4PC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 293,307, possibly due to activation of p38MAPK signaling and subsequent hippocampal glutamatergic synaptotoxicity/death, culminating in the AD cognitive deficits PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Td2VyZGxvdzwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+

PFJlY051bT4zNDc2PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MzA3LDMwODwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM0NzY8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkwOTkzMyI+MzQ3Njwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U3dlcmRsb3csIFIuIEguPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBv

ZiBOZXVyb2xvZ3ksIFVuaXZlcnNpdHkgb2YgS2Fuc2FzIE1lZGljYWwgQ2VudGVyLCBLYW5zYXMg

Q2l0eSwgS2Fuc2FzLCBVU0EuIHJzd2VyZGxvd0BrdW1jLmVkdTwvYXV0aC1hZGRyZXNzPjx0aXRs

ZXM+PHRpdGxlPk1pdG9jaG9uZHJpYSBhbmQgY2VsbCBiaW9lbmVyZ2V0aWNzOiBpbmNyZWFzaW5n

bHkgcmVjb2duaXplZCBjb21wb25lbnRzIGFuZCBhIHBvc3NpYmxlIGV0aW9sb2dpYyBjYXVzZSBv

ZiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW50aW94

aWQgUmVkb3ggU2lnbmFsPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1

bGwtdGl0bGU+QW50aW94aWQgUmVkb3ggU2lnbmFsPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48

cGFnZXM+MTQzNC01NTwvcGFnZXM+PHZvbHVtZT4xNjwvdm9sdW1lPjxudW1iZXI+MTI8L251bWJl

cj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmV0aW9sb2d5L21ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5FbmVyZ3kgTWV0

YWJvbGlzbS9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5

d29yZD5NaXRvY2hvbmRyaWEvKm1ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1biAxNTwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxpc2JuPjE1NTctNzcxNiAoRWxlY3Ryb25pYykmI3hEOzE1MjMtMDg2NCAoTGlu

a2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjE5MDI1OTc8L2FjY2Vzc2lvbi1udW0+PHVybHM+

PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjE5

MDI1OTc8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMzMyOTk0OTwvY3Vz

dG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA4OS9hcnMuMjAxMS40MTQ5PC9lbGVj

dHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5ZdTwvQXV0

aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJlY051bT4zNDc3PC9SZWNOdW0+PHJlY29yZD48cmVjLW51

bWJlcj4zNDc3PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0i

ZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTAx

MDgiPjM0Nzc8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRp

Y2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPll1LCBRLjwv

YXV0aG9yPjxhdXRob3I+RHUsIEYuPC9hdXRob3I+PGF1dGhvcj5Eb3VnbGFzLCBKLiBULjwvYXV0

aG9yPjxhdXRob3I+WXUsIEguPC9hdXRob3I+PGF1dGhvcj5ZYW4sIFMuIFMuPC9hdXRob3I+PGF1

dGhvcj5ZYW4sIFMuIEYuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk

ZHJlc3M+U3RhdGUgS2V5IExhYm9yYXRvcnkgb2YgT3JhbCBEaXNlYXNlcywgTmF0aW9uYWwgQ2xp

bmljYWwgUmVzZWFyY2ggQ2VudGVyIGZvciBPcmFsIERpc2Vhc2VzLCBXZXN0IENoaW5hIEhvc3Bp

dGFsIG9mIFN0b21hdG9sb2d5LCBTaWNodWFuIFVuaXZlcnNpdHksIENoZW5nIER1LCBDaGluYS4m

I3hEO0RlcGFydG1lbnRzIG9mIFBoYXJtYWNvbG9neSBhbmQgVG94aWNvbG9neSwgYW5kIEhpZ3Vj

aGkgQmlvc2NpZW5jZSBDZW50ZXIsIFNjaG9vbCBvZiBQaGFybWFjeSwgVW5pdmVyc2l0eSBvZiBL

YW5zYXMsIExhd3JlbmNlLCBLUywgVVNBLiYjeEQ7TnVjbGVhciBNYWduZXRpYyBSZXNvbmFuY2Ug

TGFib3JhdG9yeSwgTW9sZWN1bGFyIFN0cnVjdHVyZXMgZ3JvdXAsIFNjaG9vbCBvZiBQaGFybWFj

eSwgVW5pdmVyc2l0eSBvZiBLYW5zYXMsIExhd3JlbmNlLCBLUywgVVNBLjwvYXV0aC1hZGRyZXNz

Pjx0aXRsZXM+PHRpdGxlPk1pdG9jaG9uZHJpYWwgRHlzZnVuY3Rpb24gVHJpZ2dlcnMgU3luYXB0

aWMgRGVmaWNpdHMgdmlhIEFjdGl2YXRpb24gb2YgcDM4IE1BUCBLaW5hc2UgU2lnbmFsaW5nIGlu

IERpZmZlcmVudGlhdGVkIEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZSBUcmFucy1NaXRvY2hvbmRy

aWFsIEN5YnJpZCBDZWxsczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEFsemhlaW1lcnMgRGlz

PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBBbHpo

ZWltZXJzIERpczwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIyMy0yMzk8L3BhZ2Vz

Pjx2b2x1bWU+NTk8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+

QWRlbm9zaW5lIFRyaXBob3NwaGF0ZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8

L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QWx6

aGVpbWVyIERpc2Vhc2UvKmNvbXBsaWNhdGlvbnMvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5DYXNlLUNvbnRyb2wgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5DZWxsIERpZmZlcmVudGlh

dGlvbjwva2V5d29yZD48a2V5d29yZD5EaXNrcyBMYXJnZSBIb21vbG9nIDQgUHJvdGVpbjwva2V5

d29yZD48a2V5d29yZD5FbGVjdHJvbiBUcmFuc3BvcnQgQ29tcGxleCBJVi9tZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+

PGtleXdvcmQ+SHlicmlkIENlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtl

eXdvcmQ+TWVtYnJhbmUgUG90ZW50aWFsLCBNaXRvY2hvbmRyaWFsPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1pdG9jaG9uZHJpYS8qcGF0aG9sb2d5L3VsdHJhc3RydWN0dXJlPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1pdG9jaG9uZHJpYWwgRGlzZWFzZXMvKmV0aW9sb2d5L3BhdGhvbG9neTwva2V5d29yZD48a2V5

d29yZD5OZXVyb2JsYXN0b21hL3BhdGhvbG9neS91bHRyYXN0cnVjdHVyZTwva2V5d29yZD48a2V5

d29yZD5PeGlkYXRpdmUgU3RyZXNzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UmVhY3Rp

dmUgT3h5Z2VuIFNwZWNpZXMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5SaG9kYW1pbmVz

L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+U2lnbmFsIFRyYW5zZHVjdGlvbi8qcGh5c2lv

bG9neTwva2V5d29yZD48a2V5d29yZD5TeW5hcHNlcy9tZXRhYm9saXNtL3BhdGhvbG9neTwva2V5

d29yZD48a2V5d29yZD5TeW5hcHRvcGh5c2luL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+

cDM4IE1pdG9nZW4tQWN0aXZhdGVkIFByb3RlaW4gS2luYXNlcy8qbWV0YWJvbGlzbTwva2V5d29y

ZD48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Y3li

cmlkIGNlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPm1pdG9jaG9uZHJpYWwgZHlzZnVuY3Rpb248L2tl

eXdvcmQ+PGtleXdvcmQ+c3luYXB0aWMgZGVmaWNpdHM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0

ZXM+PHllYXI+MjAxNzwveWVhcj48L2RhdGVzPjxpc2JuPjE4NzUtODkwOCAoRWxlY3Ryb25pYykm

I3hEOzEzODctMjg3NyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjg1OTg4NTE8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMjg1OTg4NTE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3Rv

bTI+UE1DNTkzNTQ4OTwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMzIzMy9K

QUQtMTcwMjgzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmRO

b3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Td2VyZGxvdzwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+

PFJlY051bT4zNDc2PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MzA3LDMwODwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM0NzY8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkwOTkzMyI+MzQ3Njwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U3dlcmRsb3csIFIuIEguPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBv

ZiBOZXVyb2xvZ3ksIFVuaXZlcnNpdHkgb2YgS2Fuc2FzIE1lZGljYWwgQ2VudGVyLCBLYW5zYXMg

Q2l0eSwgS2Fuc2FzLCBVU0EuIHJzd2VyZGxvd0BrdW1jLmVkdTwvYXV0aC1hZGRyZXNzPjx0aXRs

ZXM+PHRpdGxlPk1pdG9jaG9uZHJpYSBhbmQgY2VsbCBiaW9lbmVyZ2V0aWNzOiBpbmNyZWFzaW5n

bHkgcmVjb2duaXplZCBjb21wb25lbnRzIGFuZCBhIHBvc3NpYmxlIGV0aW9sb2dpYyBjYXVzZSBv

ZiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW50aW94

aWQgUmVkb3ggU2lnbmFsPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1

bGwtdGl0bGU+QW50aW94aWQgUmVkb3ggU2lnbmFsPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48

cGFnZXM+MTQzNC01NTwvcGFnZXM+PHZvbHVtZT4xNjwvdm9sdW1lPjxudW1iZXI+MTI8L251bWJl

cj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmV0aW9sb2d5L21ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5FbmVyZ3kgTWV0

YWJvbGlzbS9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5

d29yZD5NaXRvY2hvbmRyaWEvKm1ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1biAxNTwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxpc2JuPjE1NTctNzcxNiAoRWxlY3Ryb25pYykmI3hEOzE1MjMtMDg2NCAoTGlu

a2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjE5MDI1OTc8L2FjY2Vzc2lvbi1udW0+PHVybHM+

PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjE5

MDI1OTc8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMzMyOTk0OTwvY3Vz

dG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA4OS9hcnMuMjAxMS40MTQ5PC9lbGVj

dHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5ZdTwvQXV0

aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJlY051bT4zNDc3PC9SZWNOdW0+PHJlY29yZD48cmVjLW51

bWJlcj4zNDc3PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0i

ZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTAx

MDgiPjM0Nzc8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRp

Y2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPll1LCBRLjwv

YXV0aG9yPjxhdXRob3I+RHUsIEYuPC9hdXRob3I+PGF1dGhvcj5Eb3VnbGFzLCBKLiBULjwvYXV0

aG9yPjxhdXRob3I+WXUsIEguPC9hdXRob3I+PGF1dGhvcj5ZYW4sIFMuIFMuPC9hdXRob3I+PGF1

dGhvcj5ZYW4sIFMuIEYuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk

ZHJlc3M+U3RhdGUgS2V5IExhYm9yYXRvcnkgb2YgT3JhbCBEaXNlYXNlcywgTmF0aW9uYWwgQ2xp

bmljYWwgUmVzZWFyY2ggQ2VudGVyIGZvciBPcmFsIERpc2Vhc2VzLCBXZXN0IENoaW5hIEhvc3Bp

dGFsIG9mIFN0b21hdG9sb2d5LCBTaWNodWFuIFVuaXZlcnNpdHksIENoZW5nIER1LCBDaGluYS4m

I3hEO0RlcGFydG1lbnRzIG9mIFBoYXJtYWNvbG9neSBhbmQgVG94aWNvbG9neSwgYW5kIEhpZ3Vj

aGkgQmlvc2NpZW5jZSBDZW50ZXIsIFNjaG9vbCBvZiBQaGFybWFjeSwgVW5pdmVyc2l0eSBvZiBL

YW5zYXMsIExhd3JlbmNlLCBLUywgVVNBLiYjeEQ7TnVjbGVhciBNYWduZXRpYyBSZXNvbmFuY2Ug

TGFib3JhdG9yeSwgTW9sZWN1bGFyIFN0cnVjdHVyZXMgZ3JvdXAsIFNjaG9vbCBvZiBQaGFybWFj

eSwgVW5pdmVyc2l0eSBvZiBLYW5zYXMsIExhd3JlbmNlLCBLUywgVVNBLjwvYXV0aC1hZGRyZXNz

Pjx0aXRsZXM+PHRpdGxlPk1pdG9jaG9uZHJpYWwgRHlzZnVuY3Rpb24gVHJpZ2dlcnMgU3luYXB0

aWMgRGVmaWNpdHMgdmlhIEFjdGl2YXRpb24gb2YgcDM4IE1BUCBLaW5hc2UgU2lnbmFsaW5nIGlu

IERpZmZlcmVudGlhdGVkIEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZSBUcmFucy1NaXRvY2hvbmRy

aWFsIEN5YnJpZCBDZWxsczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEFsemhlaW1lcnMgRGlz

PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBBbHpo

ZWltZXJzIERpczwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIyMy0yMzk8L3BhZ2Vz

Pjx2b2x1bWU+NTk8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+

QWRlbm9zaW5lIFRyaXBob3NwaGF0ZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8

L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QWx6

aGVpbWVyIERpc2Vhc2UvKmNvbXBsaWNhdGlvbnMvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5DYXNlLUNvbnRyb2wgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5DZWxsIERpZmZlcmVudGlh

dGlvbjwva2V5d29yZD48a2V5d29yZD5EaXNrcyBMYXJnZSBIb21vbG9nIDQgUHJvdGVpbjwva2V5

d29yZD48a2V5d29yZD5FbGVjdHJvbiBUcmFuc3BvcnQgQ29tcGxleCBJVi9tZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+

PGtleXdvcmQ+SHlicmlkIENlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtl

eXdvcmQ+TWVtYnJhbmUgUG90ZW50aWFsLCBNaXRvY2hvbmRyaWFsPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1pdG9jaG9uZHJpYS8qcGF0aG9sb2d5L3VsdHJhc3RydWN0dXJlPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1pdG9jaG9uZHJpYWwgRGlzZWFzZXMvKmV0aW9sb2d5L3BhdGhvbG9neTwva2V5d29yZD48a2V5

d29yZD5OZXVyb2JsYXN0b21hL3BhdGhvbG9neS91bHRyYXN0cnVjdHVyZTwva2V5d29yZD48a2V5

d29yZD5PeGlkYXRpdmUgU3RyZXNzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UmVhY3Rp

dmUgT3h5Z2VuIFNwZWNpZXMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5SaG9kYW1pbmVz

L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+U2lnbmFsIFRyYW5zZHVjdGlvbi8qcGh5c2lv

bG9neTwva2V5d29yZD48a2V5d29yZD5TeW5hcHNlcy9tZXRhYm9saXNtL3BhdGhvbG9neTwva2V5

d29yZD48a2V5d29yZD5TeW5hcHRvcGh5c2luL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+

cDM4IE1pdG9nZW4tQWN0aXZhdGVkIFByb3RlaW4gS2luYXNlcy8qbWV0YWJvbGlzbTwva2V5d29y

ZD48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Y3li

cmlkIGNlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPm1pdG9jaG9uZHJpYWwgZHlzZnVuY3Rpb248L2tl

eXdvcmQ+PGtleXdvcmQ+c3luYXB0aWMgZGVmaWNpdHM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0

ZXM+PHllYXI+MjAxNzwveWVhcj48L2RhdGVzPjxpc2JuPjE4NzUtODkwOCAoRWxlY3Ryb25pYykm

I3hEOzEzODctMjg3NyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjg1OTg4NTE8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMjg1OTg4NTE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3Rv

bTI+UE1DNTkzNTQ4OTwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMzIzMy9K

QUQtMTcwMjgzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmRO

b3RlPgB=

ADDIN EN.CITE.DATA 307,308. Alternatively, disrupted mitochondrial dynamics (fission and fusion) and trafficking upon AD may hamper the development and maturation of synapses PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZWxvPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48UmVj

TnVtPjM0MTA8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4z

MDEsMzA5LDMxMDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM0MTA8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkwOTMyOSI+MzQxMDwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWVsbywgSi4gQi48L2F1dGhv

cj48YXV0aG9yPkFnb3N0aW5obywgUC48L2F1dGhvcj48YXV0aG9yPk9saXZlaXJhLCBDLiBSLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkNlbnRlciBmb3Ig

TmV1cm9zY2llbmNlcyBvZiBDb2ltYnJhLCBGYWN1bHR5IG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5

IG9mIENvaW1icmEsIDMwMDQtNTA0IENvaW1icmEsIFBvcnR1Z2FsLjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPkFteWxvaWQgYmV0YS1wZXB0aWRlIDI1LTM1IHJlZHVjZXMgWzNIXWFjZXR5

bGNob2xpbmUgcmVsZWFzZSBpbiByZXRpbmFsIG5ldXJvbnMuIEludm9sdmVtZW50IG9mIG1ldGFi

b2xpYyBkeXNmdW5jdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbXlsb2lkPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjIyMS04PC9wYWdlcz48dm9sdW1lPjk8L3ZvbHVtZT48

bnVtYmVyPjQ8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWNldHlsY2hvbGluZS8qbWV0YWJv

bGlzbTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvKnBoeXNpb2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5DaGljayBFbWJyeW88

L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9ucy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5Q

ZXB0aWRlIEZyYWdtZW50cy8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5SZXRpbmEvY3l0

b2xvZ3kvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+VHJpdGl1bTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDAyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RGVjPC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTM1MC02MTI5IChQcmludCkmI3hEOzEzNTAtNjEy

OSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTI1NTc3NDk8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMTI1NTc3NDk8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxD

aXRlPjxBdXRob3I+QW1vcmltPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48UmVjTnVtPjM0Nzg8

L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM0Nzg8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5

cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1

YXYiIHRpbWVzdGFtcD0iMTUzNTkxMDIyNCI+MzQ3ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYt

dHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxh

dXRob3JzPjxhdXRob3I+QW1vcmltLCBKLiBBLjwvYXV0aG9yPjxhdXRob3I+Q2FuYXMsIFAuIE0u

PC9hdXRob3I+PGF1dGhvcj5Ub21lLCBBLiBSLjwvYXV0aG9yPjxhdXRob3I+Um9sbywgQS4gUC48

L2F1dGhvcj48YXV0aG9yPkFnb3N0aW5obywgUC48L2F1dGhvcj48YXV0aG9yPlBhbG1laXJhLCBD

LiBNLjwvYXV0aG9yPjxhdXRob3I+Q3VuaGEsIFIuIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+Q05DIC0gQ2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5k

IENlbGwgQmlvbG9neSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhLCBQb3J0dWdhbC4mI3hEO0RlcGFy

dG1lbnQgb2YgTGlmZSBTY2llbmNlcywgRmFjdWx0eSBvZiBTY2llbmNlcyBhbmQgVGVjaG5vbG9n

eSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhLCBQb3J0dWdhbC4mI3hEO0ZhY3VsdHkgb2YgTWVkaWNp

bmUsIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgUG9ydHVnYWwuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TWl0b2Nob25kcmlhIGluIEV4Y2l0YXRvcnkgYW5kIEluaGliaXRvcnkgU3luYXBz

ZXMgaGF2ZSBTaW1pbGFyIFN1c2NlcHRpYmlsaXR5IHRvIEFteWxvaWQtYmV0YSBQZXB0aWRlcyBN

b2RlbGluZyBBbHpoZWltZXImYXBvcztzIERpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+

SiBBbHpoZWltZXJzIERpczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxm

dWxsLXRpdGxlPkogQWx6aGVpbWVycyBEaXM8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdl

cz41MjUtNTM2PC9wYWdlcz48dm9sdW1lPjYwPC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGtl

eXdvcmRzPjxrZXl3b3JkPipBbHpoZWltZXIgRGlzZWFzZS9jaGVtaWNhbGx5IGluZHVjZWQvbWV0

YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVz

Lyp0b3hpY2l0eTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJy

YWluL2RydWcgZWZmZWN0cy9tZXRhYm9saXNtLypwYXRob2xvZ3kvdWx0cmFzdHJ1Y3R1cmU8L2tl

eXdvcmQ+PGtleXdvcmQ+Q2FzcGFzZSAzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+RGlz

ZWFzZSBNb2RlbHMsIEFuaW1hbDwva2V5d29yZD48a2V5d29yZD5FeHBsb3JhdG9yeSBCZWhhdmlv

ci9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZSBFeHByZXNzaW9uIFJlZ3VsYXRp

b24vZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkh5ZHJvZ2VuIFBlcm94aWRlL21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NZW1icmFuZSBQ

b3RlbnRpYWwsIE1pdG9jaG9uZHJpYWwvZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPk1p

dG9jaG9uZHJpYS9tZXRhYm9saXNtLypwYXRob2xvZ3kvdWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+

PGtleXdvcmQ+UGVwdGlkZSBGcmFnbWVudHMvKnRveGljaXR5PC9rZXl3b3JkPjxrZXl3b3JkPlJh

dHM8L2tleXdvcmQ+PGtleXdvcmQ+UmF0cywgV2lzdGFyPC9rZXl3b3JkPjxrZXl3b3JkPlJlYWN0

aXZlIE94eWdlbiBTcGVjaWVzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UmhvZGFtaW5l

cy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlN5bmFwc2VzL2RydWcgZWZmZWN0cy9tZXRh

Ym9saXNtLypwYXRob2xvZ3kvdWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+PGtleXdvcmQ+U3luYXB0

b3NvbWVzL21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlRpbWUgRmFjdG9y

czwva2V5d29yZD48a2V5d29yZD5WZXNpY3VsYXIgR2x1dGFtYXRlIFRyYW5zcG9ydCBQcm90ZWlu

IDEvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+VmVzaWN1bGFyIEluaGliaXRvcnkgQW1p

bm8gQWNpZCBUcmFuc3BvcnQgUHJvdGVpbnMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+

QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkdhYmE8L2tleXdvcmQ+

PGtleXdvcmQ+Y2FzcGFzZSAzPC9rZXl3b3JkPjxrZXl3b3JkPmdsdXRhbWF0ZTwva2V5d29yZD48

a2V5d29yZD5oaXBwb2NhbXB1czwva2V5d29yZD48a2V5d29yZD5tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPm1pdG9jaG9uZHJpYTwva2V5d29yZD48a2V5d29yZD5veHlnZW4gcmFkaWNhbHM8

L2tleXdvcmQ+PGtleXdvcmQ+c3luYXBzZTwva2V5d29yZD48a2V5d29yZD5zeW5hcHRvc29tZXM8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48L2RhdGVzPjxpc2Ju

PjE4NzUtODkwOCAoRWxlY3Ryb25pYykmI3hEOzEzODctMjg3NyAoTGlua2luZyk8L2lzYm4+PGFj

Y2Vzc2lvbi1udW0+Mjg4Njk0NzI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48

dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjg4Njk0NzI8L3VybD48L3Jl

bGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjMyMzMvSkFELTE3

MDM1NjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRo

b3I+RmFuZzwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051bT4zNDc5PC9SZWNOdW0+PHJl

Y29yZD48cmVjLW51bWJlcj4zNDc5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3Rh

bXA9IjE1MzU5MTAyNzkiPjM0Nzk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkZhbmcsIEQuPC9hdXRob3I+PGF1dGhvcj5ZYW4sIFMuPC9hdXRob3I+PGF1dGhvcj5ZdSwg

US48L2F1dGhvcj48YXV0aG9yPkNoZW4sIEQuPC9hdXRob3I+PGF1dGhvcj5ZYW4sIFMuIFMuPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBv

ZiBQaGFybWFjb2xvZ3kgYW5kIFRveGljb2xvZ3ksIGFuZCBIaWd1Y2hpIEJpb3NjaWVuY2UgQ2Vu

dGVyLCBTY2hvb2wgb2YgUGhhcm1hY29sb2d5LCBVbml2ZXJzaXR5IG9mIEthbnNhcywgTGF3cmVu

Y2UsIEtTLCBVU0EuJiN4RDtTdGF0ZSBLZXkgTGFib3JhdG9yeSBvZiBPcmFsIERpc2Vhc2VzLCBX

ZXN0IENoaW5hIEhvc3BpdGFsIG9mIFN0b21hdG9sb2d5LCBTaWNodWFuIFVuaXZlcnNpdHksIENo

ZW5nIER1LCBDaGluYS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5NZm4yIGlzIFJlcXVp

cmVkIGZvciBNaXRvY2hvbmRyaWFsIERldmVsb3BtZW50IGFuZCBTeW5hcHNlIEZvcm1hdGlvbiBp

biBIdW1hbiBJbmR1Y2VkIFBsdXJpcG90ZW50IFN0ZW0gQ2VsbHMvaGlQU0MgRGVyaXZlZCBDb3J0

aWNhbCBOZXVyb25zPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlNjaSBSZXA8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5TY2kgUmVwPC9mdWxsLXRpdGxl

PjwvcGVyaW9kaWNhbD48cGFnZXM+MzE0NjI8L3BhZ2VzPjx2b2x1bWU+Njwvdm9sdW1lPjxrZXl3

b3Jkcz48a2V5d29yZD5BZGVub3NpbmUgVHJpcGhvc3BoYXRlL21ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+Qm9uZSBNYXJyb3cgQ2VsbHMvY3l0b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2Vs

bCBEaWZmZXJlbnRpYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVkPC9rZXl3

b3JkPjxrZXl3b3JkPkdUUCBQaG9zcGhvaHlkcm9sYXNlcy9hbnRhZ29uaXN0cyAmYW1wOyBpbmhp

Yml0b3JzL2dlbmV0aWNzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5

d29yZD48a2V5d29yZD5JbmR1Y2VkIFBsdXJpcG90ZW50IFN0ZW0gQ2VsbHMvY3l0b2xvZ3kvbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5NZW1icmFuZSBQb3RlbnRpYWxzPC9rZXl3b3JkPjxr

ZXl3b3JkPk1pdG9jaG9uZHJpYS8qbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+TWl0b2Nob25kcmlhbCBQcm90ZWlucy9hbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzL2dl

bmV0aWNzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvZ2VuZXNpczwva2V5d29y

ZD48a2V5d29yZD5OZXVyb25zL2N5dG9sb2d5LyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

PlBhdGNoLUNsYW1wIFRlY2huaXF1ZXM8L2tleXdvcmQ+PGtleXdvcmQ+Uk5BIEludGVyZmVyZW5j

ZTwva2V5d29yZD48a2V5d29yZD5STkEsIFNtYWxsIEludGVyZmVyaW5nL21ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+U3luYXBzZXMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+U3lu

YXB0b3BoeXNpbi9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlR1YnVsaW4vbWV0YWJvbGlz

bTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+

PGRhdGU+QXVnIDE4PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MjA0NS0yMzIyIChF

bGVjdHJvbmljKSYjeEQ7MjA0NS0yMzIyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4y

NzUzNTc5NjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3

dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNzUzNTc5NjwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48Y3VzdG9tMj5QTUM0OTg5MTQ4PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4xMDM4L3NyZXAzMTQ2MjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9D

aXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZWxvPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48UmVj

TnVtPjM0MTA8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4z

MDEsMzA5LDMxMDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM0MTA8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkwOTMyOSI+MzQxMDwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWVsbywgSi4gQi48L2F1dGhv

cj48YXV0aG9yPkFnb3N0aW5obywgUC48L2F1dGhvcj48YXV0aG9yPk9saXZlaXJhLCBDLiBSLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkNlbnRlciBmb3Ig

TmV1cm9zY2llbmNlcyBvZiBDb2ltYnJhLCBGYWN1bHR5IG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5

IG9mIENvaW1icmEsIDMwMDQtNTA0IENvaW1icmEsIFBvcnR1Z2FsLjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPkFteWxvaWQgYmV0YS1wZXB0aWRlIDI1LTM1IHJlZHVjZXMgWzNIXWFjZXR5

bGNob2xpbmUgcmVsZWFzZSBpbiByZXRpbmFsIG5ldXJvbnMuIEludm9sdmVtZW50IG9mIG1ldGFi

b2xpYyBkeXNmdW5jdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbXlsb2lkPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjIyMS04PC9wYWdlcz48dm9sdW1lPjk8L3ZvbHVtZT48

bnVtYmVyPjQ8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWNldHlsY2hvbGluZS8qbWV0YWJv

bGlzbTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvKnBoeXNpb2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5DaGljayBFbWJyeW88

L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9ucy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5Q

ZXB0aWRlIEZyYWdtZW50cy8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5SZXRpbmEvY3l0

b2xvZ3kvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+VHJpdGl1bTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDAyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RGVjPC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTM1MC02MTI5IChQcmludCkmI3hEOzEzNTAtNjEy

OSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTI1NTc3NDk8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMTI1NTc3NDk8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxD

aXRlPjxBdXRob3I+QW1vcmltPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48UmVjTnVtPjM0Nzg8

L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM0Nzg8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5

cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1

YXYiIHRpbWVzdGFtcD0iMTUzNTkxMDIyNCI+MzQ3ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYt

dHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxh

dXRob3JzPjxhdXRob3I+QW1vcmltLCBKLiBBLjwvYXV0aG9yPjxhdXRob3I+Q2FuYXMsIFAuIE0u

PC9hdXRob3I+PGF1dGhvcj5Ub21lLCBBLiBSLjwvYXV0aG9yPjxhdXRob3I+Um9sbywgQS4gUC48

L2F1dGhvcj48YXV0aG9yPkFnb3N0aW5obywgUC48L2F1dGhvcj48YXV0aG9yPlBhbG1laXJhLCBD

LiBNLjwvYXV0aG9yPjxhdXRob3I+Q3VuaGEsIFIuIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+Q05DIC0gQ2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5k

IENlbGwgQmlvbG9neSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhLCBQb3J0dWdhbC4mI3hEO0RlcGFy

dG1lbnQgb2YgTGlmZSBTY2llbmNlcywgRmFjdWx0eSBvZiBTY2llbmNlcyBhbmQgVGVjaG5vbG9n

eSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhLCBQb3J0dWdhbC4mI3hEO0ZhY3VsdHkgb2YgTWVkaWNp

bmUsIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgUG9ydHVnYWwuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TWl0b2Nob25kcmlhIGluIEV4Y2l0YXRvcnkgYW5kIEluaGliaXRvcnkgU3luYXBz

ZXMgaGF2ZSBTaW1pbGFyIFN1c2NlcHRpYmlsaXR5IHRvIEFteWxvaWQtYmV0YSBQZXB0aWRlcyBN

b2RlbGluZyBBbHpoZWltZXImYXBvcztzIERpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+

SiBBbHpoZWltZXJzIERpczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxm

dWxsLXRpdGxlPkogQWx6aGVpbWVycyBEaXM8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdl

cz41MjUtNTM2PC9wYWdlcz48dm9sdW1lPjYwPC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGtl

eXdvcmRzPjxrZXl3b3JkPipBbHpoZWltZXIgRGlzZWFzZS9jaGVtaWNhbGx5IGluZHVjZWQvbWV0

YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVz

Lyp0b3hpY2l0eTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJy

YWluL2RydWcgZWZmZWN0cy9tZXRhYm9saXNtLypwYXRob2xvZ3kvdWx0cmFzdHJ1Y3R1cmU8L2tl

eXdvcmQ+PGtleXdvcmQ+Q2FzcGFzZSAzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+RGlz

ZWFzZSBNb2RlbHMsIEFuaW1hbDwva2V5d29yZD48a2V5d29yZD5FeHBsb3JhdG9yeSBCZWhhdmlv

ci9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZSBFeHByZXNzaW9uIFJlZ3VsYXRp

b24vZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkh5ZHJvZ2VuIFBlcm94aWRlL21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NZW1icmFuZSBQ

b3RlbnRpYWwsIE1pdG9jaG9uZHJpYWwvZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPk1p

dG9jaG9uZHJpYS9tZXRhYm9saXNtLypwYXRob2xvZ3kvdWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+

PGtleXdvcmQ+UGVwdGlkZSBGcmFnbWVudHMvKnRveGljaXR5PC9rZXl3b3JkPjxrZXl3b3JkPlJh

dHM8L2tleXdvcmQ+PGtleXdvcmQ+UmF0cywgV2lzdGFyPC9rZXl3b3JkPjxrZXl3b3JkPlJlYWN0

aXZlIE94eWdlbiBTcGVjaWVzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UmhvZGFtaW5l

cy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlN5bmFwc2VzL2RydWcgZWZmZWN0cy9tZXRh

Ym9saXNtLypwYXRob2xvZ3kvdWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+PGtleXdvcmQ+U3luYXB0

b3NvbWVzL21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlRpbWUgRmFjdG9y

czwva2V5d29yZD48a2V5d29yZD5WZXNpY3VsYXIgR2x1dGFtYXRlIFRyYW5zcG9ydCBQcm90ZWlu

IDEvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+VmVzaWN1bGFyIEluaGliaXRvcnkgQW1p

bm8gQWNpZCBUcmFuc3BvcnQgUHJvdGVpbnMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+

QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkdhYmE8L2tleXdvcmQ+

PGtleXdvcmQ+Y2FzcGFzZSAzPC9rZXl3b3JkPjxrZXl3b3JkPmdsdXRhbWF0ZTwva2V5d29yZD48

a2V5d29yZD5oaXBwb2NhbXB1czwva2V5d29yZD48a2V5d29yZD5tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPm1pdG9jaG9uZHJpYTwva2V5d29yZD48a2V5d29yZD5veHlnZW4gcmFkaWNhbHM8

L2tleXdvcmQ+PGtleXdvcmQ+c3luYXBzZTwva2V5d29yZD48a2V5d29yZD5zeW5hcHRvc29tZXM8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48L2RhdGVzPjxpc2Ju

PjE4NzUtODkwOCAoRWxlY3Ryb25pYykmI3hEOzEzODctMjg3NyAoTGlua2luZyk8L2lzYm4+PGFj

Y2Vzc2lvbi1udW0+Mjg4Njk0NzI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48

dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjg4Njk0NzI8L3VybD48L3Jl

bGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjMyMzMvSkFELTE3

MDM1NjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRo

b3I+RmFuZzwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051bT4zNDc5PC9SZWNOdW0+PHJl

Y29yZD48cmVjLW51bWJlcj4zNDc5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3Rh

bXA9IjE1MzU5MTAyNzkiPjM0Nzk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkZhbmcsIEQuPC9hdXRob3I+PGF1dGhvcj5ZYW4sIFMuPC9hdXRob3I+PGF1dGhvcj5ZdSwg

US48L2F1dGhvcj48YXV0aG9yPkNoZW4sIEQuPC9hdXRob3I+PGF1dGhvcj5ZYW4sIFMuIFMuPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBv

ZiBQaGFybWFjb2xvZ3kgYW5kIFRveGljb2xvZ3ksIGFuZCBIaWd1Y2hpIEJpb3NjaWVuY2UgQ2Vu

dGVyLCBTY2hvb2wgb2YgUGhhcm1hY29sb2d5LCBVbml2ZXJzaXR5IG9mIEthbnNhcywgTGF3cmVu

Y2UsIEtTLCBVU0EuJiN4RDtTdGF0ZSBLZXkgTGFib3JhdG9yeSBvZiBPcmFsIERpc2Vhc2VzLCBX

ZXN0IENoaW5hIEhvc3BpdGFsIG9mIFN0b21hdG9sb2d5LCBTaWNodWFuIFVuaXZlcnNpdHksIENo

ZW5nIER1LCBDaGluYS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5NZm4yIGlzIFJlcXVp

cmVkIGZvciBNaXRvY2hvbmRyaWFsIERldmVsb3BtZW50IGFuZCBTeW5hcHNlIEZvcm1hdGlvbiBp

biBIdW1hbiBJbmR1Y2VkIFBsdXJpcG90ZW50IFN0ZW0gQ2VsbHMvaGlQU0MgRGVyaXZlZCBDb3J0

aWNhbCBOZXVyb25zPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlNjaSBSZXA8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5TY2kgUmVwPC9mdWxsLXRpdGxl

PjwvcGVyaW9kaWNhbD48cGFnZXM+MzE0NjI8L3BhZ2VzPjx2b2x1bWU+Njwvdm9sdW1lPjxrZXl3

b3Jkcz48a2V5d29yZD5BZGVub3NpbmUgVHJpcGhvc3BoYXRlL21ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+Qm9uZSBNYXJyb3cgQ2VsbHMvY3l0b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2Vs

bCBEaWZmZXJlbnRpYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVkPC9rZXl3

b3JkPjxrZXl3b3JkPkdUUCBQaG9zcGhvaHlkcm9sYXNlcy9hbnRhZ29uaXN0cyAmYW1wOyBpbmhp

Yml0b3JzL2dlbmV0aWNzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5

d29yZD48a2V5d29yZD5JbmR1Y2VkIFBsdXJpcG90ZW50IFN0ZW0gQ2VsbHMvY3l0b2xvZ3kvbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5NZW1icmFuZSBQb3RlbnRpYWxzPC9rZXl3b3JkPjxr

ZXl3b3JkPk1pdG9jaG9uZHJpYS8qbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+TWl0b2Nob25kcmlhbCBQcm90ZWlucy9hbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzL2dl

bmV0aWNzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvZ2VuZXNpczwva2V5d29y

ZD48a2V5d29yZD5OZXVyb25zL2N5dG9sb2d5LyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

PlBhdGNoLUNsYW1wIFRlY2huaXF1ZXM8L2tleXdvcmQ+PGtleXdvcmQ+Uk5BIEludGVyZmVyZW5j

ZTwva2V5d29yZD48a2V5d29yZD5STkEsIFNtYWxsIEludGVyZmVyaW5nL21ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+U3luYXBzZXMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+U3lu

YXB0b3BoeXNpbi9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlR1YnVsaW4vbWV0YWJvbGlz

bTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+

PGRhdGU+QXVnIDE4PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MjA0NS0yMzIyIChF

bGVjdHJvbmljKSYjeEQ7MjA0NS0yMzIyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4y

NzUzNTc5NjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3

dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNzUzNTc5NjwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48Y3VzdG9tMj5QTUM0OTg5MTQ4PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4xMDM4L3NyZXAzMTQ2MjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9D

aXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 301,309,310. Moreover, the correlation between early deficits in synaptic mitochondria and synaptic loss in AD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYW48L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNO

dW0+MzQ5MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjI5

OSwzMTE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zNDkyPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTAzOTgiPjM0OTI8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkdhbiwgWC48L2F1dGhvcj48YXV0aG9y

Pkh1YW5nLCBTLjwvYXV0aG9yPjxhdXRob3I+V3UsIEwuPC9hdXRob3I+PGF1dGhvcj5XYW5nLCBZ

LjwvYXV0aG9yPjxhdXRob3I+SHUsIEcuPC9hdXRob3I+PGF1dGhvcj5MaSwgRy48L2F1dGhvcj48

YXV0aG9yPlpoYW5nLCBILjwvYXV0aG9yPjxhdXRob3I+WXUsIEguPC9hdXRob3I+PGF1dGhvcj5T

d2VyZGxvdywgUi4gSC48L2F1dGhvcj48YXV0aG9yPkNoZW4sIEouIFguPC9hdXRob3I+PGF1dGhv

cj5ZYW4sIFMuIFMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJl

c3M+RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xvZ3kgYW5kIFRveGljb2xvZ3ksIGFuZCBIaWd1Y2hp

IEJpb3NjaWVuY2UgQ2VudGVyLCBTY2hvb2wgb2YgUGhhcm1hY3ksIFVuaXZlcnNpdHkgb2YgS2Fu

c2FzLCBMYXdyZW5jZSwgS1MgNjYwNDcsIFVTQTsgU3RhdGUgS2V5IExhYm9yYXRvcnkgb2YgT3Jh

bCBEaXNlYXNlcywgV2VzdCBDaGluYSBIb3NwaXRhbCBvZiBTdG9tYXRvbG9neSwgU2ljaHVhbiBV

bml2ZXJzaXR5LCBDaGVuZyBEdSA2MTAwNDEsIENoaW5hLiYjeEQ7RGVwYXJ0bWVudCBvZiBQaGFy

bWFjb2xvZ3kgYW5kIFRveGljb2xvZ3ksIGFuZCBIaWd1Y2hpIEJpb3NjaWVuY2UgQ2VudGVyLCBT

Y2hvb2wgb2YgUGhhcm1hY3ksIFVuaXZlcnNpdHkgb2YgS2Fuc2FzLCBMYXdyZW5jZSwgS1MgNjYw

NDcsIFVTQS4mI3hEO1N0YXRlIEtleSBMYWJvcmF0b3J5IG9mIE9yYWwgRGlzZWFzZXMsIFdlc3Qg

Q2hpbmEgSG9zcGl0YWwgb2YgU3RvbWF0b2xvZ3ksIFNpY2h1YW4gVW5pdmVyc2l0eSwgQ2hlbmcg

RHUgNjEwMDQxLCBDaGluYS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5

IG9mIEthbnNhcyBNZWRpY2FsIENlbnRlciwgS2Fuc2FzIENpdHksIEtTIDY2MTYwLCBVU0EuJiN4

RDtEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgTWVtb3JpYWwgU2xvYW4tS2V0dGVyaW5nIENhbmNl

ciBDZW50ZXIsIE5ldyBZb3JrLCBOWSAxMDAzLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIFBoYXJt

YWNvbG9neSBhbmQgVG94aWNvbG9neSwgYW5kIEhpZ3VjaGkgQmlvc2NpZW5jZSBDZW50ZXIsIFNj

aG9vbCBvZiBQaGFybWFjeSwgVW5pdmVyc2l0eSBvZiBLYW5zYXMsIExhd3JlbmNlLCBLUyA2NjA0

NywgVVNBLiBFbGVjdHJvbmljIGFkZHJlc3M6IHNoaWR1QGt1LmVkdS48L2F1dGgtYWRkcmVzcz48

dGl0bGVzPjx0aXRsZT5JbmhpYml0aW9uIG9mIEVSSy1ETFAxIHNpZ25hbGluZyBhbmQgbWl0b2No

b25kcmlhbCBkaXZpc2lvbiBhbGxldmlhdGVzIG1pdG9jaG9uZHJpYWwgZHlzZnVuY3Rpb24gaW4g

QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGN5YnJpZCBjZWxsPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPkJpb2NoaW0gQmlvcGh5cyBBY3RhPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2Vz

PjIyMC0zMTwvcGFnZXM+PHZvbHVtZT4xODQyPC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGtl

eXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8

L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvZ2VuZXRpY3MvKm1ldGFib2xpc20v

cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFudGlveGlkYW50cy9waGFybWFjb2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+RXh0cmFjZWxsdWxhciBTaWduYWwtUmVndWxhdGVkIE1BUCBLaW5hc2Vz

LyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5H

VFAgUGhvc3Bob2h5ZHJvbGFzZXMvZ2VuZXRpY3MvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5YnJpZCBDZWxscy8qbWV0YWJvbGlzbS9wYXRo

b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vYmxvdHRpbmc8L2tleXdvcmQ+PGtleXdvcmQ+

TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWNyb3R1YnVsZS1Bc3NvY2lhdGVkIFByb3RlaW5zL2dl

bmV0aWNzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3Jk

PjxrZXl3b3JkPk1pdG9jaG9uZHJpYS9kcnVnIGVmZmVjdHMvZ2VuZXRpY3MvKm1ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2Nob25kcmlhbCBEeW5hbWljcy9kcnVnIGVmZmVjdHMvZ2Vu

ZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2Nob25kcmlhbCBQcm90ZWlucy9nZW5ldGljcy8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5NaXRvZ2VuLUFjdGl2YXRlZCBQcm90ZWluIEtp

bmFzZSAxL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2dlbi1BY3RpdmF0ZWQgUHJv

dGVpbiBLaW5hc2UgMy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1vZGVscywgQmlvbG9n

aWNhbDwva2V5d29yZD48a2V5d29yZD5NdXRhdGlvbjwva2V5d29yZD48a2V5d29yZD5OZXVyb25z

L21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlByb2J1Y29sL3BoYXJtYWNv

bG9neTwva2V5d29yZD48a2V5d29yZD5RdWluYXpvbGlub25lcy9waGFybWFjb2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+Uk5BIEludGVyZmVyZW5jZTwva2V5d29yZD48a2V5d29yZD5SZWFjdGl2ZSBP

eHlnZW4gU3BlY2llcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlNpZ25hbCBUcmFuc2R1

Y3Rpb24vZHJ1ZyBlZmZlY3RzL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkFkPC9rZXl3b3Jk

PjxrZXl3b3JkPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5BbXls

b2lkIGJldGEgcGVwdGlkZTwva2V5d29yZD48a2V5d29yZD5BYmV0YTwva2V5d29yZD48a2V5d29y

ZD5DY088L2tleXdvcmQ+PGtleXdvcmQ+Q3licmlkIGNlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPkN5

dG9jaHJvbWUgYyBveGlkYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkRscDE8L2tleXdvcmQ+PGtleXdv

cmQ+RHluYW1pbi1saWtlIHByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+RXJrPC9rZXl3b3JkPjxr

ZXl3b3JkPkV4dHJhY2VsbHVsYXIgc2lnbmFsLXJlZ3VsYXRlZCBraW5hc2U8L2tleXdvcmQ+PGtl

eXdvcmQ+SGQ8L2tleXdvcmQ+PGtleXdvcmQ+SHVudGluZ3RvbiBkaXNlYXNlPC9rZXl3b3JkPjxr

ZXl3b3JkPk1mbjI8L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2Nob25kcmlhbCBETkE8L2tleXdvcmQ+

PGtleXdvcmQ+TWl0b2Nob25kcmlhbCBmaXNzaW9uIGFuZCBmdXNpb248L2tleXdvcmQ+PGtleXdv

cmQ+TWl0b2Z1c2luIDI8L2tleXdvcmQ+PGtleXdvcmQ+UGQ8L2tleXdvcmQ+PGtleXdvcmQ+UGFy

a2luc29uIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Um9zPC9rZXl3b3JkPjxrZXl3b3JkPlJl

YWN0aXZlIG94eWdlbiBzcGVjaWVzPC9rZXl3b3JkPjxrZXl3b3JkPlRtcm08L2tleXdvcmQ+PGtl

eXdvcmQ+VGV0cmFtZXRoeWxyaG9kYW1pbmVtZXRoeWxlc3Rlcjwva2V5d29yZD48a2V5d29yZD5t

dEROQTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE0PC95ZWFyPjxwdWItZGF0

ZXM+PGRhdGU+RmViPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDAwNi0zMDAyIChQ

cmludCkmI3hEOzAwMDYtMzAwMiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjQyNTI2

MTQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNi

aS5ubG0ubmloLmdvdi9wdWJtZWQvMjQyNTI2MTQ8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGN1c3RvbTI+UE1DMzk5MTIzNTwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu

MTAxNi9qLmJiYWRpcy4yMDEzLjExLjAwOTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNv

cmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Q2Fsa2luczwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

PFJlY051bT4zMzQ2PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zMzQ2PC9yZWMtbnVtYmVy

Pjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBm

d3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MDkxNzUiPjMzNDY8L2tleT48L2ZvcmVp

Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv

bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkNhbGtpbnMsIE0uIEouPC9hdXRob3I+PGF1dGhv

cj5NYW5jemFrLCBNLjwvYXV0aG9yPjxhdXRob3I+TWFvLCBQLjwvYXV0aG9yPjxhdXRob3I+U2hp

cmVuZGViLCBVLjwvYXV0aG9yPjxhdXRob3I+UmVkZHksIFAuIEguPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+TmV1cm9nZW5ldGljcyBMYWJvcmF0b3J5LCBE

aXZpc2lvbiBvZiBOZXVyb3NjaWVuY2UsIE9yZWdvbiBOYXRpb25hbCBQcmltYXRlIFJlc2VhcmNo

IENlbnRlciwgT3JlZ29uIEhlYWx0aCAmYW1wOyBTY2llbmNlIFVuaXZlcnNpdHksIEJlYXZlcnRv

biwgT1IgOTcwMDYsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5JbXBhaXJlZCBt

aXRvY2hvbmRyaWFsIGJpb2dlbmVzaXMsIGRlZmVjdGl2ZSBheG9uYWwgdHJhbnNwb3J0IG9mIG1p

dG9jaG9uZHJpYSwgYWJub3JtYWwgbWl0b2Nob25kcmlhbCBkeW5hbWljcyBhbmQgc3luYXB0aWMg

ZGVnZW5lcmF0aW9uIGluIGEgbW91c2UgbW9kZWwgb2YgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNl

PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkh1bSBNb2wgR2VuZXQ8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5IdW0gTW9sIEdlbmV0PC9mdWxsLXRpdGxl

PjwvcGVyaW9kaWNhbD48cGFnZXM+NDUxNS0yOTwvcGFnZXM+PHZvbHVtZT4yMDwvdm9sdW1lPjxu

dW1iZXI+MjM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWRlbm9zaW5lIFRyaXBob3NwaGF0

ZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLyptZXRhYm9s

aXNtLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW4gUHJl

Y3Vyc29yL2NoZW1pc3RyeS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tl

eXdvcmQ+PGtleXdvcmQ+QXBvcHRvc2lzL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD4q

QXhvbmFsIFRyYW5zcG9ydC9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+QmxvdHRpbmcs

IFdlc3Rlcm48L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVkPC9rZXl3b3JkPjxrZXl3

b3JkPkN5Y2xvcGhpbGlucy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkRpc2Vhc2UgTW9k

ZWxzLCBBbmltYWw8L2tleXdvcmQ+PGtleXdvcmQ+RWxlY3Ryb24gVHJhbnNwb3J0IENvbXBsZXgg

SVYvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5HZW5lIEV4cHJlc3Npb24gUmVndWxhdGlv

bi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+SHlkcm9nZW4gUGVyb3hpZGUvbWV0YWJv

bGlzbTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pdG9jaG9uZHJp

YS9kcnVnIGVmZmVjdHMvKm1ldGFib2xpc20vKnBhdGhvbG9neS91bHRyYXN0cnVjdHVyZTwva2V5

d29yZD48a2V5d29yZD5Nb2xlY3VsYXIgV2VpZ2h0PC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJpdGVz

L2RydWcgZWZmZWN0cy9tZXRhYm9saXNtL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5PbGln

b3BlcHRpZGVzL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5QZXJveGlyZWRveGlucy9t

ZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlByb3RlaW4gU3RydWN0dXJlLCBRdWF0ZXJuYXJ5

PC9rZXl3b3JkPjxrZXl3b3JkPlJOQSwgTWVzc2VuZ2VyL2dlbmV0aWNzL21ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+U3luYXBzZXMvZHJ1ZyBlZmZlY3RzL21ldGFib2xpc20vKnBhdGhvbG9n

eTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWItZGF0ZXM+

PGRhdGU+RGVjIDE8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDYwLTIwODMgKEVs

ZWN0cm9uaWMpJiN4RDswOTY0LTY5MDYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIx

ODczMjYwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3

Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIxODczMjYwPC91cmw+PC9yZWxhdGVkLXVybHM+PC91

cmxzPjxjdXN0b20yPlBNQzMyMDk4MjQ8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjEwLjEwOTMvaG1nL2RkcjM4MTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9D

aXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYW48L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNO

dW0+MzQ5MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjI5

OSwzMTE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zNDkyPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTAzOTgiPjM0OTI8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkdhbiwgWC48L2F1dGhvcj48YXV0aG9y

Pkh1YW5nLCBTLjwvYXV0aG9yPjxhdXRob3I+V3UsIEwuPC9hdXRob3I+PGF1dGhvcj5XYW5nLCBZ

LjwvYXV0aG9yPjxhdXRob3I+SHUsIEcuPC9hdXRob3I+PGF1dGhvcj5MaSwgRy48L2F1dGhvcj48

YXV0aG9yPlpoYW5nLCBILjwvYXV0aG9yPjxhdXRob3I+WXUsIEguPC9hdXRob3I+PGF1dGhvcj5T

d2VyZGxvdywgUi4gSC48L2F1dGhvcj48YXV0aG9yPkNoZW4sIEouIFguPC9hdXRob3I+PGF1dGhv

cj5ZYW4sIFMuIFMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJl

c3M+RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xvZ3kgYW5kIFRveGljb2xvZ3ksIGFuZCBIaWd1Y2hp

IEJpb3NjaWVuY2UgQ2VudGVyLCBTY2hvb2wgb2YgUGhhcm1hY3ksIFVuaXZlcnNpdHkgb2YgS2Fu

c2FzLCBMYXdyZW5jZSwgS1MgNjYwNDcsIFVTQTsgU3RhdGUgS2V5IExhYm9yYXRvcnkgb2YgT3Jh

bCBEaXNlYXNlcywgV2VzdCBDaGluYSBIb3NwaXRhbCBvZiBTdG9tYXRvbG9neSwgU2ljaHVhbiBV

bml2ZXJzaXR5LCBDaGVuZyBEdSA2MTAwNDEsIENoaW5hLiYjeEQ7RGVwYXJ0bWVudCBvZiBQaGFy

bWFjb2xvZ3kgYW5kIFRveGljb2xvZ3ksIGFuZCBIaWd1Y2hpIEJpb3NjaWVuY2UgQ2VudGVyLCBT

Y2hvb2wgb2YgUGhhcm1hY3ksIFVuaXZlcnNpdHkgb2YgS2Fuc2FzLCBMYXdyZW5jZSwgS1MgNjYw

NDcsIFVTQS4mI3hEO1N0YXRlIEtleSBMYWJvcmF0b3J5IG9mIE9yYWwgRGlzZWFzZXMsIFdlc3Qg

Q2hpbmEgSG9zcGl0YWwgb2YgU3RvbWF0b2xvZ3ksIFNpY2h1YW4gVW5pdmVyc2l0eSwgQ2hlbmcg

RHUgNjEwMDQxLCBDaGluYS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5

IG9mIEthbnNhcyBNZWRpY2FsIENlbnRlciwgS2Fuc2FzIENpdHksIEtTIDY2MTYwLCBVU0EuJiN4

RDtEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgTWVtb3JpYWwgU2xvYW4tS2V0dGVyaW5nIENhbmNl

ciBDZW50ZXIsIE5ldyBZb3JrLCBOWSAxMDAzLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIFBoYXJt

YWNvbG9neSBhbmQgVG94aWNvbG9neSwgYW5kIEhpZ3VjaGkgQmlvc2NpZW5jZSBDZW50ZXIsIFNj

aG9vbCBvZiBQaGFybWFjeSwgVW5pdmVyc2l0eSBvZiBLYW5zYXMsIExhd3JlbmNlLCBLUyA2NjA0

NywgVVNBLiBFbGVjdHJvbmljIGFkZHJlc3M6IHNoaWR1QGt1LmVkdS48L2F1dGgtYWRkcmVzcz48

dGl0bGVzPjx0aXRsZT5JbmhpYml0aW9uIG9mIEVSSy1ETFAxIHNpZ25hbGluZyBhbmQgbWl0b2No

b25kcmlhbCBkaXZpc2lvbiBhbGxldmlhdGVzIG1pdG9jaG9uZHJpYWwgZHlzZnVuY3Rpb24gaW4g

QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGN5YnJpZCBjZWxsPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPkJpb2NoaW0gQmlvcGh5cyBBY3RhPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2Vz

PjIyMC0zMTwvcGFnZXM+PHZvbHVtZT4xODQyPC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGtl

eXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8

L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvZ2VuZXRpY3MvKm1ldGFib2xpc20v

cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFudGlveGlkYW50cy9waGFybWFjb2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+RXh0cmFjZWxsdWxhciBTaWduYWwtUmVndWxhdGVkIE1BUCBLaW5hc2Vz

LyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5H

VFAgUGhvc3Bob2h5ZHJvbGFzZXMvZ2VuZXRpY3MvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5YnJpZCBDZWxscy8qbWV0YWJvbGlzbS9wYXRo

b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vYmxvdHRpbmc8L2tleXdvcmQ+PGtleXdvcmQ+

TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWNyb3R1YnVsZS1Bc3NvY2lhdGVkIFByb3RlaW5zL2dl

bmV0aWNzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3Jk

PjxrZXl3b3JkPk1pdG9jaG9uZHJpYS9kcnVnIGVmZmVjdHMvZ2VuZXRpY3MvKm1ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2Nob25kcmlhbCBEeW5hbWljcy9kcnVnIGVmZmVjdHMvZ2Vu

ZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2Nob25kcmlhbCBQcm90ZWlucy9nZW5ldGljcy8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5NaXRvZ2VuLUFjdGl2YXRlZCBQcm90ZWluIEtp

bmFzZSAxL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2dlbi1BY3RpdmF0ZWQgUHJv

dGVpbiBLaW5hc2UgMy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1vZGVscywgQmlvbG9n

aWNhbDwva2V5d29yZD48a2V5d29yZD5NdXRhdGlvbjwva2V5d29yZD48a2V5d29yZD5OZXVyb25z

L21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlByb2J1Y29sL3BoYXJtYWNv

bG9neTwva2V5d29yZD48a2V5d29yZD5RdWluYXpvbGlub25lcy9waGFybWFjb2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+Uk5BIEludGVyZmVyZW5jZTwva2V5d29yZD48a2V5d29yZD5SZWFjdGl2ZSBP

eHlnZW4gU3BlY2llcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlNpZ25hbCBUcmFuc2R1

Y3Rpb24vZHJ1ZyBlZmZlY3RzL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkFkPC9rZXl3b3Jk

PjxrZXl3b3JkPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5BbXls

b2lkIGJldGEgcGVwdGlkZTwva2V5d29yZD48a2V5d29yZD5BYmV0YTwva2V5d29yZD48a2V5d29y

ZD5DY088L2tleXdvcmQ+PGtleXdvcmQ+Q3licmlkIGNlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPkN5

dG9jaHJvbWUgYyBveGlkYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkRscDE8L2tleXdvcmQ+PGtleXdv

cmQ+RHluYW1pbi1saWtlIHByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+RXJrPC9rZXl3b3JkPjxr

ZXl3b3JkPkV4dHJhY2VsbHVsYXIgc2lnbmFsLXJlZ3VsYXRlZCBraW5hc2U8L2tleXdvcmQ+PGtl

eXdvcmQ+SGQ8L2tleXdvcmQ+PGtleXdvcmQ+SHVudGluZ3RvbiBkaXNlYXNlPC9rZXl3b3JkPjxr

ZXl3b3JkPk1mbjI8L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2Nob25kcmlhbCBETkE8L2tleXdvcmQ+

PGtleXdvcmQ+TWl0b2Nob25kcmlhbCBmaXNzaW9uIGFuZCBmdXNpb248L2tleXdvcmQ+PGtleXdv

cmQ+TWl0b2Z1c2luIDI8L2tleXdvcmQ+PGtleXdvcmQ+UGQ8L2tleXdvcmQ+PGtleXdvcmQ+UGFy

a2luc29uIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Um9zPC9rZXl3b3JkPjxrZXl3b3JkPlJl

YWN0aXZlIG94eWdlbiBzcGVjaWVzPC9rZXl3b3JkPjxrZXl3b3JkPlRtcm08L2tleXdvcmQ+PGtl

eXdvcmQ+VGV0cmFtZXRoeWxyaG9kYW1pbmVtZXRoeWxlc3Rlcjwva2V5d29yZD48a2V5d29yZD5t

dEROQTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE0PC95ZWFyPjxwdWItZGF0

ZXM+PGRhdGU+RmViPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDAwNi0zMDAyIChQ

cmludCkmI3hEOzAwMDYtMzAwMiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjQyNTI2

MTQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNi

aS5ubG0ubmloLmdvdi9wdWJtZWQvMjQyNTI2MTQ8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGN1c3RvbTI+UE1DMzk5MTIzNTwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu

MTAxNi9qLmJiYWRpcy4yMDEzLjExLjAwOTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNv

cmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Q2Fsa2luczwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

PFJlY051bT4zMzQ2PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zMzQ2PC9yZWMtbnVtYmVy

Pjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBm

d3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MDkxNzUiPjMzNDY8L2tleT48L2ZvcmVp

Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv

bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkNhbGtpbnMsIE0uIEouPC9hdXRob3I+PGF1dGhv

cj5NYW5jemFrLCBNLjwvYXV0aG9yPjxhdXRob3I+TWFvLCBQLjwvYXV0aG9yPjxhdXRob3I+U2hp

cmVuZGViLCBVLjwvYXV0aG9yPjxhdXRob3I+UmVkZHksIFAuIEguPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+TmV1cm9nZW5ldGljcyBMYWJvcmF0b3J5LCBE

aXZpc2lvbiBvZiBOZXVyb3NjaWVuY2UsIE9yZWdvbiBOYXRpb25hbCBQcmltYXRlIFJlc2VhcmNo

IENlbnRlciwgT3JlZ29uIEhlYWx0aCAmYW1wOyBTY2llbmNlIFVuaXZlcnNpdHksIEJlYXZlcnRv

biwgT1IgOTcwMDYsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5JbXBhaXJlZCBt

aXRvY2hvbmRyaWFsIGJpb2dlbmVzaXMsIGRlZmVjdGl2ZSBheG9uYWwgdHJhbnNwb3J0IG9mIG1p

dG9jaG9uZHJpYSwgYWJub3JtYWwgbWl0b2Nob25kcmlhbCBkeW5hbWljcyBhbmQgc3luYXB0aWMg

ZGVnZW5lcmF0aW9uIGluIGEgbW91c2UgbW9kZWwgb2YgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNl

PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkh1bSBNb2wgR2VuZXQ8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5IdW0gTW9sIEdlbmV0PC9mdWxsLXRpdGxl

PjwvcGVyaW9kaWNhbD48cGFnZXM+NDUxNS0yOTwvcGFnZXM+PHZvbHVtZT4yMDwvdm9sdW1lPjxu

dW1iZXI+MjM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWRlbm9zaW5lIFRyaXBob3NwaGF0

ZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLyptZXRhYm9s

aXNtLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW4gUHJl

Y3Vyc29yL2NoZW1pc3RyeS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tl

eXdvcmQ+PGtleXdvcmQ+QXBvcHRvc2lzL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD4q

QXhvbmFsIFRyYW5zcG9ydC9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+QmxvdHRpbmcs

IFdlc3Rlcm48L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVkPC9rZXl3b3JkPjxrZXl3

b3JkPkN5Y2xvcGhpbGlucy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkRpc2Vhc2UgTW9k

ZWxzLCBBbmltYWw8L2tleXdvcmQ+PGtleXdvcmQ+RWxlY3Ryb24gVHJhbnNwb3J0IENvbXBsZXgg

SVYvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5HZW5lIEV4cHJlc3Npb24gUmVndWxhdGlv

bi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+SHlkcm9nZW4gUGVyb3hpZGUvbWV0YWJv

bGlzbTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pdG9jaG9uZHJp

YS9kcnVnIGVmZmVjdHMvKm1ldGFib2xpc20vKnBhdGhvbG9neS91bHRyYXN0cnVjdHVyZTwva2V5

d29yZD48a2V5d29yZD5Nb2xlY3VsYXIgV2VpZ2h0PC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJpdGVz

L2RydWcgZWZmZWN0cy9tZXRhYm9saXNtL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5PbGln

b3BlcHRpZGVzL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5QZXJveGlyZWRveGlucy9t

ZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlByb3RlaW4gU3RydWN0dXJlLCBRdWF0ZXJuYXJ5

PC9rZXl3b3JkPjxrZXl3b3JkPlJOQSwgTWVzc2VuZ2VyL2dlbmV0aWNzL21ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+U3luYXBzZXMvZHJ1ZyBlZmZlY3RzL21ldGFib2xpc20vKnBhdGhvbG9n

eTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWItZGF0ZXM+

PGRhdGU+RGVjIDE8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDYwLTIwODMgKEVs

ZWN0cm9uaWMpJiN4RDswOTY0LTY5MDYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIx

ODczMjYwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3

Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIxODczMjYwPC91cmw+PC9yZWxhdGVkLXVybHM+PC91

cmxzPjxjdXN0b20yPlBNQzMyMDk4MjQ8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjEwLjEwOTMvaG1nL2RkcjM4MTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9D

aXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 299,311 reinforce the notion that brain glucose (energy) hypometabolism may constitute an early event in disease pathogenesis, starting decades before its diagnosis (probably during midlife) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJlY051

bT4zNDk0PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+MzEy

LDMxMzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM0OTQ8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxMDUxNiI+MzQ5NDwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RHUsIEguPC9hdXRob3I+PGF1dGhvcj5H

dW8sIEwuPC9hdXRob3I+PGF1dGhvcj5ZYW4sIFMuPC9hdXRob3I+PGF1dGhvcj5Tb3N1bm92LCBB

LiBBLjwvYXV0aG9yPjxhdXRob3I+TWNLaGFubiwgRy4gTS48L2F1dGhvcj48YXV0aG9yPllhbiwg

Uy4gUy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBh

cnRtZW50IG9mIFN1cmdlcnksIENvbGxlZ2Ugb2YgUGh5c2ljaWFucyBhbmQgU3VyZ2VvbnMsIENv

bHVtYmlhIFVuaXZlcnNpdHksIE5ldyBZb3JrLCBOWSAxMDAzMiwgVVNBLjwvYXV0aC1hZGRyZXNz

Pjx0aXRsZXM+PHRpdGxlPkVhcmx5IGRlZmljaXRzIGluIHN5bmFwdGljIG1pdG9jaG9uZHJpYSBp

biBhbiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgbW91c2UgbW9kZWw8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9zZWNvbmRhcnktdGl0bGU+PC90aXRs

ZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9mdWxs

LXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTg2NzAtNTwvcGFnZXM+PHZvbHVtZT4xMDc8L3Zv

bHVtZT48bnVtYmVyPjQzPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNl

YXNlLypldGlvbG9neS9nZW5ldGljcy8qbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW4gUHJlY3Vyc29yL2dlbmV0aWNzLyptZXRhYm9saXNt

PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QXhvbnMvbWV0YWJv

bGlzbS91bHRyYXN0cnVjdHVyZTwva2V5d29yZD48a2V5d29yZD5EaXNlYXNlIE1vZGVscywgQW5p

bWFsPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3

b3JkPjxrZXl3b3JkPk1pY2UsIFRyYW5zZ2VuaWM8L2tleXdvcmQ+PGtleXdvcmQ+TWljcm9zY29w

eSwgSW1tdW5vZWxlY3Ryb248L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2Nob25kcmlhLyptZXRhYm9s

aXNtL3VsdHJhc3RydWN0dXJlPC9rZXl3b3JkPjxrZXl3b3JkPk1pdG9jaG9uZHJpYWwgTWVtYnJh

bmUgVHJhbnNwb3J0IFByb3RlaW5zL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TXV0YW50

IFByb3RlaW5zL2dlbmV0aWNzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+T3hpZGF0aXZl

IFN0cmVzczwva2V5d29yZD48a2V5d29yZD5SZWNvbWJpbmFudCBQcm90ZWlucy9nZW5ldGljcy9t

ZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlN5bmFwc2VzLyptZXRhYm9saXNtL3VsdHJhc3Ry

dWN0dXJlPC9rZXl3b3JkPjxrZXl3b3JkPlRpbWUgRmFjdG9yczwva2V5d29yZD48L2tleXdvcmRz

PjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+T2N0IDI2PC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA5MS02NDkwIChFbGVjdHJvbmljKSYjeEQ7MDAyNy04

NDI0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMDkzNzg5NDwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8yMDkzNzg5NDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUMyOTcy

OTIyPC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDczL3BuYXMuMTAwNjU4

NjEwNzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRo

b3I+VG9ydGVsbGk8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNOdW0+MzUwMTwvUmVjTnVt

PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzUwMTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg

YXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGlt

ZXN0YW1wPSIxNTM1OTEwNTUyIj4zNTAxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5Ub3J0ZWxsaSwgUi48L2F1dGhvcj48YXV0aG9yPkxvenVwb25lLCBNLjwvYXV0aG9y

PjxhdXRob3I+R3VlcnJhLCBWLjwvYXV0aG9yPjxhdXRob3I+QmFydWxsaSwgTS4gUi48L2F1dGhv

cj48YXV0aG9yPkltYmltYm8sIEIuIFAuPC9hdXRob3I+PGF1dGhvcj5DYXBvenpvLCBSLjwvYXV0

aG9yPjxhdXRob3I+R3Jhc3NvLCBBLjwvYXV0aG9yPjxhdXRob3I+VHVyc2ksIE0uPC9hdXRob3I+

PGF1dGhvcj5EaSBEaW8sIEMuPC9hdXRob3I+PGF1dGhvcj5TYXJkb25lLCBSLjwvYXV0aG9yPjxh

dXRob3I+R2lhbm5lbGxpLCBHLjwvYXV0aG9yPjxhdXRob3I+U2VyaXBhLCBELjwvYXV0aG9yPjxh

dXRob3I+TWlzY2lhZ25hLCBHLjwvYXV0aG9yPjxhdXRob3I+UGFuemEsIEYuPC9hdXRob3I+PGF1

dGhvcj5Mb2dyb3NjaW5vLCBHLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0

aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgQ2xpbmljYWwgUmVzZWFyY2ggaW4gTmV1cm9sb2d5LCBV

bml0IG9mIE5ldXJvZGVnZW5lcmF0aXZlIERpc2Vhc2UsIFVuaXZlcnNpdHkgb2YgQmFyaSAmcXVv

dDtBbGRvIE1vcm8mcXVvdDsgYXQgJnF1b3Q7UGlhIEZvbmRhemlvbmUgQ2FyZC4gRy4gUGFuaWNv

JnF1b3Q7LCBUcmljYXNlLCBMZWNjZSwgSXRhbHkuJiN4RDtEZXBhcnRtZW50IG9mIEJhc2ljIE1l

ZGljaW5lLCBOZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlIFVuaXQsIE5ldXJvc2NpZW5jZSwgYW5k

IFNlbnNlIE9yZ2FucywgVW5pdmVyc2l0eSBvZiBCYXJpIEFsZG8gTW9ybywgQmFyaSwgSXRhbHku

JiN4RDtOYXRpb25hbCBJbnN0aXR1dGUgb2YgR2FzdHJvZW50ZXJvbG9neSAmcXVvdDtTYXZlcmlv

IGRlIEJlbGxpcyZxdW90OywgUmVzZWFyY2ggSG9zcGl0YWwsIENhc3RlbGxhbmEgR3JvdHRlIEJh

cmksIEl0YWx5LiYjeEQ7RGVwYXJ0bWVudCBvZiBSZXNlYXJjaCAmYW1wOyBEZXZlbG9wbWVudCwg

Q2hpZXNpIEZhcm1hY2V1dGljaSwgUGFybWEsIEl0YWx5LiYjeEQ7RGVwYXJ0bWVudCBvZiBNZWRp

Y2FsIFNjaWVuY2VzLCBHZXJpYXRyaWMgVW5pdCBhbmQgR2Vyb250b2xvZ3ktR2VyaWF0cmljcyBS

ZXNlYXJjaCBMYWJvcmF0b3J5LCBJUkNDUyBDYXNhIFNvbGxpZXZvIGRlbGxhIFNvZmZlcmVuemEs

IFNhbiBHaW92YW5uaSBSb3RvbmRvLCBGb2dnaWEsIEl0YWx5LjwvYXV0aC1hZGRyZXNzPjx0aXRs

ZXM+PHRpdGxlPk1pZGxpZmUgTWV0YWJvbGljIFByb2ZpbGUgYW5kIHRoZSBSaXNrIG9mIExhdGUt

TGlmZSBDb2duaXRpdmUgRGVjbGluZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEFsemhlaW1l

cnMgRGlzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+

SiBBbHpoZWltZXJzIERpczwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjEyMS0xMzA8

L3BhZ2VzPjx2b2x1bWU+NTk8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48a2V5d29yZHM+PGtl

eXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48

a2V5d29yZD5BbmFseXNpcyBvZiBWYXJpYW5jZTwva2V5d29yZD48a2V5d29yZD5CbG9vZCBQcmVz

c3VyZS9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sL2Jsb29kPC9rZXl3

b3JkPjxrZXl3b3JkPkNvZ25pdGl2ZSBEeXNmdW5jdGlvbi8qbWV0YWJvbGlzbTwva2V5d29yZD48

a2V5d29yZD5Db2hvcnQgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5GYXN0aW5nL2Jsb29kPC9r

ZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+

PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NZW50YWwgU3RhdHVzIFNjaGVkdWxlPC9r

ZXl3b3JkPjxrZXl3b3JkPipNZXRhYm9sb21lPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2Vk

PC9rZXl3b3JkPjxrZXl3b3JkPlJhZGlvaW1tdW5vYXNzYXk8L2tleXdvcmQ+PGtleXdvcmQ+Umlz

ayBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5

d29yZD48a2V5d29yZD5HcmVhdEFHRSBTdHVkeTwva2V5d29yZD48a2V5d29yZD5jb2duaXRpdmUg

ZGVjbGluZTwva2V5d29yZD48a2V5d29yZD5kZW1lbnRpYSByaXNrIHNjb3Jlczwva2V5d29yZD48

a2V5d29yZD5kaWFiZXRlcyBtZWxsaXR1czwva2V5d29yZD48a2V5d29yZD5mYXN0aW5nIGdseWNl

bWlhPC9rZXl3b3JkPjxrZXl3b3JkPmluc3VsaW4gcmVzaXN0YW5jZTwva2V5d29yZD48a2V5d29y

ZD5tZXRhYm9saWMgc3luZHJvbWU8L2tleXdvcmQ+PGtleXdvcmQ+bnV0cml0aW9uPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3llYXI+PC9kYXRlcz48aXNibj4xODc1LTg5

MDggKEVsZWN0cm9uaWMpJiN4RDsxMzg3LTI4NzcgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24t

bnVtPjI4NTgyODYyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRw

Oi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI4NTgyODYyPC91cmw+PC9yZWxhdGVkLXVy

bHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4zMjMzL0pBRC0xNzAxNTM8L2Vs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJlY051

bT4zNDk0PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+MzEy

LDMxMzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM0OTQ8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxMDUxNiI+MzQ5NDwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RHUsIEguPC9hdXRob3I+PGF1dGhvcj5H

dW8sIEwuPC9hdXRob3I+PGF1dGhvcj5ZYW4sIFMuPC9hdXRob3I+PGF1dGhvcj5Tb3N1bm92LCBB

LiBBLjwvYXV0aG9yPjxhdXRob3I+TWNLaGFubiwgRy4gTS48L2F1dGhvcj48YXV0aG9yPllhbiwg

Uy4gUy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBh

cnRtZW50IG9mIFN1cmdlcnksIENvbGxlZ2Ugb2YgUGh5c2ljaWFucyBhbmQgU3VyZ2VvbnMsIENv

bHVtYmlhIFVuaXZlcnNpdHksIE5ldyBZb3JrLCBOWSAxMDAzMiwgVVNBLjwvYXV0aC1hZGRyZXNz

Pjx0aXRsZXM+PHRpdGxlPkVhcmx5IGRlZmljaXRzIGluIHN5bmFwdGljIG1pdG9jaG9uZHJpYSBp

biBhbiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgbW91c2UgbW9kZWw8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9zZWNvbmRhcnktdGl0bGU+PC90aXRs

ZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9mdWxs

LXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTg2NzAtNTwvcGFnZXM+PHZvbHVtZT4xMDc8L3Zv

bHVtZT48bnVtYmVyPjQzPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNl

YXNlLypldGlvbG9neS9nZW5ldGljcy8qbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW4gUHJlY3Vyc29yL2dlbmV0aWNzLyptZXRhYm9saXNt

PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QXhvbnMvbWV0YWJv

bGlzbS91bHRyYXN0cnVjdHVyZTwva2V5d29yZD48a2V5d29yZD5EaXNlYXNlIE1vZGVscywgQW5p

bWFsPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3

b3JkPjxrZXl3b3JkPk1pY2UsIFRyYW5zZ2VuaWM8L2tleXdvcmQ+PGtleXdvcmQ+TWljcm9zY29w

eSwgSW1tdW5vZWxlY3Ryb248L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2Nob25kcmlhLyptZXRhYm9s

aXNtL3VsdHJhc3RydWN0dXJlPC9rZXl3b3JkPjxrZXl3b3JkPk1pdG9jaG9uZHJpYWwgTWVtYnJh

bmUgVHJhbnNwb3J0IFByb3RlaW5zL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TXV0YW50

IFByb3RlaW5zL2dlbmV0aWNzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+T3hpZGF0aXZl

IFN0cmVzczwva2V5d29yZD48a2V5d29yZD5SZWNvbWJpbmFudCBQcm90ZWlucy9nZW5ldGljcy9t

ZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlN5bmFwc2VzLyptZXRhYm9saXNtL3VsdHJhc3Ry

dWN0dXJlPC9rZXl3b3JkPjxrZXl3b3JkPlRpbWUgRmFjdG9yczwva2V5d29yZD48L2tleXdvcmRz

PjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+T2N0IDI2PC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA5MS02NDkwIChFbGVjdHJvbmljKSYjeEQ7MDAyNy04

NDI0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMDkzNzg5NDwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8yMDkzNzg5NDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUMyOTcy

OTIyPC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDczL3BuYXMuMTAwNjU4

NjEwNzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRo

b3I+VG9ydGVsbGk8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNOdW0+MzUwMTwvUmVjTnVt

PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzUwMTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg

YXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGlt

ZXN0YW1wPSIxNTM1OTEwNTUyIj4zNTAxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5Ub3J0ZWxsaSwgUi48L2F1dGhvcj48YXV0aG9yPkxvenVwb25lLCBNLjwvYXV0aG9y

PjxhdXRob3I+R3VlcnJhLCBWLjwvYXV0aG9yPjxhdXRob3I+QmFydWxsaSwgTS4gUi48L2F1dGhv

cj48YXV0aG9yPkltYmltYm8sIEIuIFAuPC9hdXRob3I+PGF1dGhvcj5DYXBvenpvLCBSLjwvYXV0

aG9yPjxhdXRob3I+R3Jhc3NvLCBBLjwvYXV0aG9yPjxhdXRob3I+VHVyc2ksIE0uPC9hdXRob3I+

PGF1dGhvcj5EaSBEaW8sIEMuPC9hdXRob3I+PGF1dGhvcj5TYXJkb25lLCBSLjwvYXV0aG9yPjxh

dXRob3I+R2lhbm5lbGxpLCBHLjwvYXV0aG9yPjxhdXRob3I+U2VyaXBhLCBELjwvYXV0aG9yPjxh

dXRob3I+TWlzY2lhZ25hLCBHLjwvYXV0aG9yPjxhdXRob3I+UGFuemEsIEYuPC9hdXRob3I+PGF1

dGhvcj5Mb2dyb3NjaW5vLCBHLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0

aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgQ2xpbmljYWwgUmVzZWFyY2ggaW4gTmV1cm9sb2d5LCBV

bml0IG9mIE5ldXJvZGVnZW5lcmF0aXZlIERpc2Vhc2UsIFVuaXZlcnNpdHkgb2YgQmFyaSAmcXVv

dDtBbGRvIE1vcm8mcXVvdDsgYXQgJnF1b3Q7UGlhIEZvbmRhemlvbmUgQ2FyZC4gRy4gUGFuaWNv

JnF1b3Q7LCBUcmljYXNlLCBMZWNjZSwgSXRhbHkuJiN4RDtEZXBhcnRtZW50IG9mIEJhc2ljIE1l

ZGljaW5lLCBOZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlIFVuaXQsIE5ldXJvc2NpZW5jZSwgYW5k

IFNlbnNlIE9yZ2FucywgVW5pdmVyc2l0eSBvZiBCYXJpIEFsZG8gTW9ybywgQmFyaSwgSXRhbHku

JiN4RDtOYXRpb25hbCBJbnN0aXR1dGUgb2YgR2FzdHJvZW50ZXJvbG9neSAmcXVvdDtTYXZlcmlv

IGRlIEJlbGxpcyZxdW90OywgUmVzZWFyY2ggSG9zcGl0YWwsIENhc3RlbGxhbmEgR3JvdHRlIEJh

cmksIEl0YWx5LiYjeEQ7RGVwYXJ0bWVudCBvZiBSZXNlYXJjaCAmYW1wOyBEZXZlbG9wbWVudCwg

Q2hpZXNpIEZhcm1hY2V1dGljaSwgUGFybWEsIEl0YWx5LiYjeEQ7RGVwYXJ0bWVudCBvZiBNZWRp

Y2FsIFNjaWVuY2VzLCBHZXJpYXRyaWMgVW5pdCBhbmQgR2Vyb250b2xvZ3ktR2VyaWF0cmljcyBS

ZXNlYXJjaCBMYWJvcmF0b3J5LCBJUkNDUyBDYXNhIFNvbGxpZXZvIGRlbGxhIFNvZmZlcmVuemEs

IFNhbiBHaW92YW5uaSBSb3RvbmRvLCBGb2dnaWEsIEl0YWx5LjwvYXV0aC1hZGRyZXNzPjx0aXRs

ZXM+PHRpdGxlPk1pZGxpZmUgTWV0YWJvbGljIFByb2ZpbGUgYW5kIHRoZSBSaXNrIG9mIExhdGUt

TGlmZSBDb2duaXRpdmUgRGVjbGluZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEFsemhlaW1l

cnMgRGlzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+

SiBBbHpoZWltZXJzIERpczwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjEyMS0xMzA8

L3BhZ2VzPjx2b2x1bWU+NTk8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48a2V5d29yZHM+PGtl

eXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48

a2V5d29yZD5BbmFseXNpcyBvZiBWYXJpYW5jZTwva2V5d29yZD48a2V5d29yZD5CbG9vZCBQcmVz

c3VyZS9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sL2Jsb29kPC9rZXl3

b3JkPjxrZXl3b3JkPkNvZ25pdGl2ZSBEeXNmdW5jdGlvbi8qbWV0YWJvbGlzbTwva2V5d29yZD48

a2V5d29yZD5Db2hvcnQgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5GYXN0aW5nL2Jsb29kPC9r

ZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+

PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NZW50YWwgU3RhdHVzIFNjaGVkdWxlPC9r

ZXl3b3JkPjxrZXl3b3JkPipNZXRhYm9sb21lPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2Vk

PC9rZXl3b3JkPjxrZXl3b3JkPlJhZGlvaW1tdW5vYXNzYXk8L2tleXdvcmQ+PGtleXdvcmQ+Umlz

ayBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5

d29yZD48a2V5d29yZD5HcmVhdEFHRSBTdHVkeTwva2V5d29yZD48a2V5d29yZD5jb2duaXRpdmUg

ZGVjbGluZTwva2V5d29yZD48a2V5d29yZD5kZW1lbnRpYSByaXNrIHNjb3Jlczwva2V5d29yZD48

a2V5d29yZD5kaWFiZXRlcyBtZWxsaXR1czwva2V5d29yZD48a2V5d29yZD5mYXN0aW5nIGdseWNl

bWlhPC9rZXl3b3JkPjxrZXl3b3JkPmluc3VsaW4gcmVzaXN0YW5jZTwva2V5d29yZD48a2V5d29y

ZD5tZXRhYm9saWMgc3luZHJvbWU8L2tleXdvcmQ+PGtleXdvcmQ+bnV0cml0aW9uPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3llYXI+PC9kYXRlcz48aXNibj4xODc1LTg5

MDggKEVsZWN0cm9uaWMpJiN4RDsxMzg3LTI4NzcgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24t

bnVtPjI4NTgyODYyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRw

Oi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI4NTgyODYyPC91cmw+PC9yZWxhdGVkLXVy

bHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4zMjMzL0pBRC0xNzAxNTM8L2Vs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 312,313. This may impair neuronal insulin signaling, creating a vicious cycle of Aβ- and hyperphosphorylated Tau-mediated injury PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3Njb25pPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48

UmVjTnVtPjM1NTM8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMTQsMzE1PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzU1Mzwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTEyOTQyIj4zNTUzPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Nb3Njb25pLCBMLjwvYXV0aG9y

PjxhdXRob3I+TXVycmF5LCBKLjwvYXV0aG9yPjxhdXRob3I+VHN1aSwgVy4gSC48L2F1dGhvcj48

YXV0aG9yPkxpLCBZLjwvYXV0aG9yPjxhdXRob3I+U3BlY3RvciwgTi48L2F1dGhvcj48YXV0aG9y

PkdvbGRvd3NreSwgQS48L2F1dGhvcj48YXV0aG9yPldpbGxpYW1zLCBTLjwvYXV0aG9yPjxhdXRo

b3I+T3NvcmlvLCBSLjwvYXV0aG9yPjxhdXRob3I+TWNIdWdoLCBQLjwvYXV0aG9yPjxhdXRob3I+

R2xvZHppaywgTC48L2F1dGhvcj48YXV0aG9yPlZhbGxhYmhham9zdWxhLCBTLjwvYXV0aG9yPjxh

dXRob3I+ZGUgTGVvbiwgTS4gSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1

dGgtYWRkcmVzcz5Gcm9tIHRoZSBOZXcgWW9yayBVbml2ZXJzaXR5IFNjaG9vbCBvZiBNZWRpY2lu

ZSAoTC5NLiwgSi5NLiwgVy5ILlQuLCBZLkwuLCBOLlMuLCBBLkcuLCBTLlcuLCBSLk8uLCBQLk0u

LCBMLkcuLCBNLkouZC5MLik7IGFuZCBXZWlsbCBDb3JuZWxsIE1lZGljYWwgQ29sbGVnZSAoUy5W

LiksIE5ldyBZb3JrLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkJyYWluIGltYWdpbmcg

b2YgY29nbml0aXZlbHkgbm9ybWFsIGluZGl2aWR1YWxzIHdpdGggMiBwYXJlbnRzIGFmZmVjdGVk

IGJ5IGxhdGUtb25zZXQgQUQ8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmV1cm9sb2d5PC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmV1cm9sb2d5PC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NzUyLTYwPC9wYWdlcz48dm9sdW1lPjgyPC92

b2x1bWU+PG51bWJlcj45PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3Jk

PjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvZGlhZ25v

c3RpYyBpbWFnaW5nLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QXRyb3BoeS9kaWFnbm9z

dGljIGltYWdpbmcvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL2RpYWdub3N0aWMg

aW1hZ2luZy8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluIE1hcHBpbmc8L2tleXdv

cmQ+PGtleXdvcmQ+KkNoaWxkIG9mIEltcGFpcmVkIFBhcmVudHM8L2tleXdvcmQ+PGtleXdvcmQ+

RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NYWduZXRp

YyBSZXNvbmFuY2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3

b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlJhZGlvbnVjbGlkZSBJbWFnaW5nPC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5NYXIgNDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1MjYtNjMyWCAoRWxlY3Ry

b25pYykmI3hEOzAwMjgtMzg3OCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjQ1MjM0

ODE8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNi

aS5ubG0ubmloLmdvdi9wdWJtZWQvMjQ1MjM0ODE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGN1c3RvbTI+UE1DMzk0NTY1MTwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu

MTIxMi9XTkwuMDAwMDAwMDAwMDAwMDE4MTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNv

cmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+VmVyZGlsZTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+

PFJlY051bT4zNTY4PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zNTY4PC9yZWMtbnVtYmVy

Pjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBm

d3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTQ0MDQiPjM1Njg8L2tleT48L2ZvcmVp

Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv

bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlZlcmRpbGUsIEcuPC9hdXRob3I+PGF1dGhvcj5G

dWxsZXIsIFMuIEouPC9hdXRob3I+PGF1dGhvcj5NYXJ0aW5zLCBSLiBOLjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlNjaG9vbCBvZiBCaW9tZWRpY2FsIFNj

aWVuY2VzLCBDSElSSSBCaW9zY2llbmNlcywgQ3VydGluIFVuaXZlcnNpdHksIEJlbnRsZXksIFdl

c3Rlcm4gQXVzdHJhbGlhIDYxMDIsIEF1c3RyYWxpYTsgQ2VudHJlIG9mIEV4Y2VsbGVuY2UgZm9y

IEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZSBSZXNlYXJjaCBhbmQgQ2FyZSwgU2Nob29sIG9mIE1l

ZGljYWwgU2NpZW5jZXMsIEVkaXRoIENvd2FuIFVuaXZlcnNpdHksIEpvb25kYWx1cCwgV2VzdGVy

biBBdXN0cmFsaWEgNjAyNywgQXVzdHJhbGlhOyBTaXIgSmFtZXMgTWNDdXNrZXIgQWx6aGVpbWVy

JmFwb3M7cyBEaXNlYXNlIFJlc2VhcmNoIFVuaXQsIFNjaG9vbCBvZiBQc3ljaGlhdHJ5IGFuZCBD

bGluaWNhbCBOZXVyb3NjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIFdlc3Rlcm4gQXVzdHJhbGlhLCBD

cmF3bGV5LCBXZXN0ZXJuIEF1c3RyYWxpYSA2MDA5LCBBdXN0cmFsaWEuJiN4RDtTaXIgSmFtZXMg

TWNDdXNrZXIgQWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlIFJlc2VhcmNoIFVuaXQsIFNjaG9vbCBv

ZiBQc3ljaGlhdHJ5IGFuZCBDbGluaWNhbCBOZXVyb3NjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIFdl

c3Rlcm4gQXVzdHJhbGlhLCBDcmF3bGV5LCBXZXN0ZXJuIEF1c3RyYWxpYSA2MDA5LCBBdXN0cmFs

aWEuJiN4RDtTY2hvb2wgb2YgQmlvbWVkaWNhbCBTY2llbmNlcywgQ0hJUkkgQmlvc2NpZW5jZXMs

IEN1cnRpbiBVbml2ZXJzaXR5LCBCZW50bGV5LCBXZXN0ZXJuIEF1c3RyYWxpYSA2MTAyLCBBdXN0

cmFsaWE7IENlbnRyZSBvZiBFeGNlbGxlbmNlIGZvciBBbHpoZWltZXImYXBvcztzIERpc2Vhc2Ug

UmVzZWFyY2ggYW5kIENhcmUsIFNjaG9vbCBvZiBNZWRpY2FsIFNjaWVuY2VzLCBFZGl0aCBDb3dh

biBVbml2ZXJzaXR5LCBKb29uZGFsdXAsIFdlc3Rlcm4gQXVzdHJhbGlhIDYwMjcsIEF1c3RyYWxp

YTsgU2lyIEphbWVzIE1jQ3Vza2VyIEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZSBSZXNlYXJjaCBV

bml0LCBTY2hvb2wgb2YgUHN5Y2hpYXRyeSBhbmQgQ2xpbmljYWwgTmV1cm9zY2llbmNlcywgVW5p

dmVyc2l0eSBvZiBXZXN0ZXJuIEF1c3RyYWxpYSwgQ3Jhd2xleSwgV2VzdGVybiBBdXN0cmFsaWEg

NjAwOSwgQXVzdHJhbGlhLiBFbGVjdHJvbmljIGFkZHJlc3M6IHIubWFydGluc0BlY3UuZWR1LmF1

LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSByb2xlIG9mIHR5cGUgMiBkaWFiZXRl

cyBpbiBuZXVyb2RlZ2VuZXJhdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb2Jpb2wg

RGlzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmV1

cm9iaW9sIERpczwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIyLTM4PC9wYWdlcz48

dm9sdW1lPjg0PC92b2x1bWU+PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtl

eXdvcmQ+QnJhaW4vbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBNZWxsaXR1

cywgVHlwZSAyLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48

a2V5d29yZD5OZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcy8qbWV0YWJvbGlzbTwva2V5d29yZD48

a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+QW15bGlu

PC9rZXl3b3JkPjxrZXl3b3JkPkJldGEgYW15bG9pZDwva2V5d29yZD48a2V5d29yZD5EaWFiZXRl

czwva2V5d29yZD48a2V5d29yZD5OZXVyb2RlZ2VuZXJhdGlvbjwva2V5d29yZD48a2V5d29yZD5U

YXU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNTwveWVhcj48cHViLWRhdGVz

PjxkYXRlPkRlYzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjEwOTUtOTUzWCAoRWxl

Y3Ryb25pYykmI3hEOzA5NjktOTk2MSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjU5

MjYzNDk8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjU5MjYzNDk8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uYmQuMjAxNS4wNC4wMDg8L2Vs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3Njb25pPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48

UmVjTnVtPjM1NTM8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMTQsMzE1PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzU1Mzwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTEyOTQyIj4zNTUzPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Nb3Njb25pLCBMLjwvYXV0aG9y

PjxhdXRob3I+TXVycmF5LCBKLjwvYXV0aG9yPjxhdXRob3I+VHN1aSwgVy4gSC48L2F1dGhvcj48

YXV0aG9yPkxpLCBZLjwvYXV0aG9yPjxhdXRob3I+U3BlY3RvciwgTi48L2F1dGhvcj48YXV0aG9y

PkdvbGRvd3NreSwgQS48L2F1dGhvcj48YXV0aG9yPldpbGxpYW1zLCBTLjwvYXV0aG9yPjxhdXRo

b3I+T3NvcmlvLCBSLjwvYXV0aG9yPjxhdXRob3I+TWNIdWdoLCBQLjwvYXV0aG9yPjxhdXRob3I+

R2xvZHppaywgTC48L2F1dGhvcj48YXV0aG9yPlZhbGxhYmhham9zdWxhLCBTLjwvYXV0aG9yPjxh

dXRob3I+ZGUgTGVvbiwgTS4gSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1

dGgtYWRkcmVzcz5Gcm9tIHRoZSBOZXcgWW9yayBVbml2ZXJzaXR5IFNjaG9vbCBvZiBNZWRpY2lu

ZSAoTC5NLiwgSi5NLiwgVy5ILlQuLCBZLkwuLCBOLlMuLCBBLkcuLCBTLlcuLCBSLk8uLCBQLk0u

LCBMLkcuLCBNLkouZC5MLik7IGFuZCBXZWlsbCBDb3JuZWxsIE1lZGljYWwgQ29sbGVnZSAoUy5W

LiksIE5ldyBZb3JrLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkJyYWluIGltYWdpbmcg

b2YgY29nbml0aXZlbHkgbm9ybWFsIGluZGl2aWR1YWxzIHdpdGggMiBwYXJlbnRzIGFmZmVjdGVk

IGJ5IGxhdGUtb25zZXQgQUQ8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmV1cm9sb2d5PC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmV1cm9sb2d5PC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NzUyLTYwPC9wYWdlcz48dm9sdW1lPjgyPC92

b2x1bWU+PG51bWJlcj45PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3Jk

PjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvZGlhZ25v

c3RpYyBpbWFnaW5nLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QXRyb3BoeS9kaWFnbm9z

dGljIGltYWdpbmcvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL2RpYWdub3N0aWMg

aW1hZ2luZy8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluIE1hcHBpbmc8L2tleXdv

cmQ+PGtleXdvcmQ+KkNoaWxkIG9mIEltcGFpcmVkIFBhcmVudHM8L2tleXdvcmQ+PGtleXdvcmQ+

RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NYWduZXRp

YyBSZXNvbmFuY2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3

b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlJhZGlvbnVjbGlkZSBJbWFnaW5nPC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5NYXIgNDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1MjYtNjMyWCAoRWxlY3Ry

b25pYykmI3hEOzAwMjgtMzg3OCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjQ1MjM0

ODE8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNi

aS5ubG0ubmloLmdvdi9wdWJtZWQvMjQ1MjM0ODE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGN1c3RvbTI+UE1DMzk0NTY1MTwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu

MTIxMi9XTkwuMDAwMDAwMDAwMDAwMDE4MTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNv

cmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+VmVyZGlsZTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+

PFJlY051bT4zNTY4PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zNTY4PC9yZWMtbnVtYmVy

Pjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBm

d3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTQ0MDQiPjM1Njg8L2tleT48L2ZvcmVp

Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv

bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlZlcmRpbGUsIEcuPC9hdXRob3I+PGF1dGhvcj5G

dWxsZXIsIFMuIEouPC9hdXRob3I+PGF1dGhvcj5NYXJ0aW5zLCBSLiBOLjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlNjaG9vbCBvZiBCaW9tZWRpY2FsIFNj

aWVuY2VzLCBDSElSSSBCaW9zY2llbmNlcywgQ3VydGluIFVuaXZlcnNpdHksIEJlbnRsZXksIFdl

c3Rlcm4gQXVzdHJhbGlhIDYxMDIsIEF1c3RyYWxpYTsgQ2VudHJlIG9mIEV4Y2VsbGVuY2UgZm9y

IEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZSBSZXNlYXJjaCBhbmQgQ2FyZSwgU2Nob29sIG9mIE1l

ZGljYWwgU2NpZW5jZXMsIEVkaXRoIENvd2FuIFVuaXZlcnNpdHksIEpvb25kYWx1cCwgV2VzdGVy

biBBdXN0cmFsaWEgNjAyNywgQXVzdHJhbGlhOyBTaXIgSmFtZXMgTWNDdXNrZXIgQWx6aGVpbWVy

JmFwb3M7cyBEaXNlYXNlIFJlc2VhcmNoIFVuaXQsIFNjaG9vbCBvZiBQc3ljaGlhdHJ5IGFuZCBD

bGluaWNhbCBOZXVyb3NjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIFdlc3Rlcm4gQXVzdHJhbGlhLCBD

cmF3bGV5LCBXZXN0ZXJuIEF1c3RyYWxpYSA2MDA5LCBBdXN0cmFsaWEuJiN4RDtTaXIgSmFtZXMg

TWNDdXNrZXIgQWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlIFJlc2VhcmNoIFVuaXQsIFNjaG9vbCBv

ZiBQc3ljaGlhdHJ5IGFuZCBDbGluaWNhbCBOZXVyb3NjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIFdl

c3Rlcm4gQXVzdHJhbGlhLCBDcmF3bGV5LCBXZXN0ZXJuIEF1c3RyYWxpYSA2MDA5LCBBdXN0cmFs

aWEuJiN4RDtTY2hvb2wgb2YgQmlvbWVkaWNhbCBTY2llbmNlcywgQ0hJUkkgQmlvc2NpZW5jZXMs

IEN1cnRpbiBVbml2ZXJzaXR5LCBCZW50bGV5LCBXZXN0ZXJuIEF1c3RyYWxpYSA2MTAyLCBBdXN0

cmFsaWE7IENlbnRyZSBvZiBFeGNlbGxlbmNlIGZvciBBbHpoZWltZXImYXBvcztzIERpc2Vhc2Ug

UmVzZWFyY2ggYW5kIENhcmUsIFNjaG9vbCBvZiBNZWRpY2FsIFNjaWVuY2VzLCBFZGl0aCBDb3dh

biBVbml2ZXJzaXR5LCBKb29uZGFsdXAsIFdlc3Rlcm4gQXVzdHJhbGlhIDYwMjcsIEF1c3RyYWxp

YTsgU2lyIEphbWVzIE1jQ3Vza2VyIEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZSBSZXNlYXJjaCBV

bml0LCBTY2hvb2wgb2YgUHN5Y2hpYXRyeSBhbmQgQ2xpbmljYWwgTmV1cm9zY2llbmNlcywgVW5p

dmVyc2l0eSBvZiBXZXN0ZXJuIEF1c3RyYWxpYSwgQ3Jhd2xleSwgV2VzdGVybiBBdXN0cmFsaWEg

NjAwOSwgQXVzdHJhbGlhLiBFbGVjdHJvbmljIGFkZHJlc3M6IHIubWFydGluc0BlY3UuZWR1LmF1

LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSByb2xlIG9mIHR5cGUgMiBkaWFiZXRl

cyBpbiBuZXVyb2RlZ2VuZXJhdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb2Jpb2wg

RGlzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmV1

cm9iaW9sIERpczwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIyLTM4PC9wYWdlcz48

dm9sdW1lPjg0PC92b2x1bWU+PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtl

eXdvcmQ+QnJhaW4vbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBNZWxsaXR1

cywgVHlwZSAyLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48

a2V5d29yZD5OZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcy8qbWV0YWJvbGlzbTwva2V5d29yZD48

a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+QW15bGlu

PC9rZXl3b3JkPjxrZXl3b3JkPkJldGEgYW15bG9pZDwva2V5d29yZD48a2V5d29yZD5EaWFiZXRl

czwva2V5d29yZD48a2V5d29yZD5OZXVyb2RlZ2VuZXJhdGlvbjwva2V5d29yZD48a2V5d29yZD5U

YXU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNTwveWVhcj48cHViLWRhdGVz

PjxkYXRlPkRlYzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjEwOTUtOTUzWCAoRWxl

Y3Ryb25pYykmI3hEOzA5NjktOTk2MSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjU5

MjYzNDk8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjU5MjYzNDk8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uYmQuMjAxNS4wNC4wMDg8L2Vs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 314,315.Although this is not the aim herein, there are extensive differences (even at the level of gene expression) between male and female brain (metabolism) upon aging and/or AD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGFvPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVj

TnVtPjEwMDc8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4y

OTAsMzE2PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTAwNzwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyODY1NjQwIj4xMDA3PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5aaGFvLCBMaXFpbjwvYXV0aG9yPjxh

dXRob3I+TWFvLCBaaXN1PC9hdXRob3I+PGF1dGhvcj5Xb29keSwgU2FyYWggSy48L2F1dGhvcj48

YXV0aG9yPkJyaW50b24sIFJvYmVydGEgRC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PHRpdGxlcz48dGl0bGU+U2V4IGRpZmZlcmVuY2VzIGluIG1ldGFib2xpYyBhZ2luZyBvZiB0

aGUgYnJhaW46IGluc2lnaHRzIGludG8gZmVtYWxlIHN1c2NlcHRpYmlsaXR5IHRvIEFsemhlaW1l

ciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb2Jpb2xvZ3kgb2Yg

QWdpbmc8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NjktNzk8L3BhZ2VzPjx2b2x1

bWU+NDI8L3ZvbHVtZT48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIw

MTYvMDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9w

dWJsaXNoZXI+PGlzYm4+MDE5Ny00NTgwPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2oubmV1cm9iaW9sYWdpbmcuMjAxNi4wMi4wMTE8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYv

ai5uZXVyb2Jpb2xhZ2luZy4yMDE2LjAyLjAxMTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9y

ZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+VmVyZGlsZTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1ll

YXI+PFJlY051bT4zNTczPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zNTczPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTQ0OTciPjM1NzM8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlZlcmRpbGUsIEcuPC9hdXRob3I+PGF1dGhv

cj5MYXdzLCBTLiBNLjwvYXV0aG9yPjxhdXRob3I+SGVubGV5LCBELjwvYXV0aG9yPjxhdXRob3I+

QW1lcywgRC48L2F1dGhvcj48YXV0aG9yPkJ1c2gsIEEuIEkuPC9hdXRob3I+PGF1dGhvcj5FbGxp

cywgSy4gQS48L2F1dGhvcj48YXV0aG9yPkZhdXgsIE4uIEcuPC9hdXRob3I+PGF1dGhvcj5HdXB0

YSwgVi4gQi48L2F1dGhvcj48YXV0aG9yPkxpLCBRLiBYLjwvYXV0aG9yPjxhdXRob3I+TWFzdGVy

cywgQy4gTC48L2F1dGhvcj48YXV0aG9yPlBpa2UsIEsuIEUuPC9hdXRob3I+PGF1dGhvcj5Sb3dl

LCBDLiBDLjwvYXV0aG9yPjxhdXRob3I+U3pvZWtlLCBDLjwvYXV0aG9yPjxhdXRob3I+VGFkZGVp

LCBLLjwvYXV0aG9yPjxhdXRob3I+VmlsbGVtYWduZSwgVi4gTC48L2F1dGhvcj48YXV0aG9yPk1h

cnRpbnMsIFIuIE4uPC9hdXRob3I+PGF1dGhvcj5BaWJsIFJlc2VhcmNoIEdyb3VwPC9hdXRob3I+

PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+MV0gQ2VudHJlIG9mIEV4Y2Vs

bGVuY2UgZm9yIEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZSBSZXNlYXJjaCAmYW1wOyBDYXJlLCBT

Y2hvb2wgb2YgTWVkaWNhbCBTY2llbmNlcywgRWRpdGggQ293YW4gVW5pdmVyc2l0eSwgSm9vbmRh

bHVwLCBXZXN0ZXJuIEF1c3RyYWxpYSwgQXVzdHJhbGlhIFsyXSBTaXIgSmFtZXMgTWNDdXNrZXIg

QWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlIFJlc2VhcmNoIFVuaXQgKEhvbGx5d29vZCBQcml2YXRl

IEhvc3BpdGFsKSwgUGVydGgsIFdlc3Rlcm4gQXVzdHJhbGlhLCBBdXN0cmFsaWEuJiN4RDsxXSBD

ZW50cmUgb2YgRXhjZWxsZW5jZSBmb3IgQWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlIFJlc2VhcmNo

ICZhbXA7IENhcmUsIFNjaG9vbCBvZiBNZWRpY2FsIFNjaWVuY2VzLCBFZGl0aCBDb3dhbiBVbml2

ZXJzaXR5LCBKb29uZGFsdXAsIFdlc3Rlcm4gQXVzdHJhbGlhLCBBdXN0cmFsaWEgWzJdIFNpciBK

YW1lcyBNY0N1c2tlciBBbHpoZWltZXImYXBvcztzIERpc2Vhc2UgUmVzZWFyY2ggVW5pdCAoSG9s

bHl3b29kIFByaXZhdGUgSG9zcGl0YWwpLCBQZXJ0aCwgV2VzdGVybiBBdXN0cmFsaWEsIEF1c3Ry

YWxpYSBbM10gQ28tb3BlcmF0aXZlIFJlc2VhcmNoIENlbnRyZSBmb3IgTWVudGFsIEhlYWx0aCwg

aHR0cDovL3d3dy5tZW50YWxoZWFsdGhjcmMuY29tLiYjeEQ7MV0gRGVwYXJ0bWVudCBvZiBFbmRv

Y3Jpbm9sb2d5IGFuZCBEaWFiZXRlcywgU2lyIENoYXJsZXMgR2FpcmRuZXIgSG9zcGl0YWwsIE5l

ZGxhbmRzLCBXZXN0ZXJuIEF1c3RyYWxpYSwgQXVzdHJhbGlhIFsyXSBTY2hvb2wgb2YgTWVkaWNp

bmUgYW5kIFBoYXJtYWNvbG9neSwgVW5pdmVyc2l0eSBvZiBXZXN0ZXJuIEF1c3RyYWxpYSwgQ3Jh

d2xleSwgV2VzdGVybiBBdXN0cmFsaWEsIEF1c3RyYWxpYS4mI3hEOzFdIEFjYWRlbWljIFVuaXQg

Zm9yIFBzeWNoaWF0cnkgb2YgT2xkIEFnZSwgRGVwYXJ0bWVudCBvZiBQc3ljaGlhdHJ5LCBUaGUg

VW5pdmVyc2l0eSBvZiBNZWxib3VybmUsIFN0IFZpbmNlbnQmYXBvcztzIEFnZWQgUHN5Y2hpYXRy

eSBTZXJ2aWNlLCBTdCBHZW9yZ2UmYXBvcztzIEhvc3BpdGFsLCBNZWxib3VybmUsIFZpY3Rvcmlh

LCBBdXN0cmFsaWEgWzJdIE5hdGlvbmFsIEFnZWluZyBSZXNlYXJjaCBJbnN0aXR1dGUsIFBhcmt2

aWxsZSwgVmljdG9yaWEsIEF1c3RyYWxpYS4mI3hEOzFdIENvLW9wZXJhdGl2ZSBSZXNlYXJjaCBD

ZW50cmUgZm9yIE1lbnRhbCBIZWFsdGgsIGh0dHA6Ly93d3cubWVudGFsaGVhbHRoY3JjLmNvbSBb

Ml0gTWVudGFsIEhlYWx0aCBSZXNlYXJjaCBJbnN0aXR1dGUsIFRoZSBVbml2ZXJzaXR5IG9mIE1l

bGJvdXJuZSwgUGFya3ZpbGxlLCBWaWN0b3JpYSwgQXVzdHJhbGlhIFszXSBDZW50cmUgZm9yIE5l

dXJvc2NpZW5jZSwgVGhlIFVuaXZlcnNpdHkgb2YgTWVsYm91cm5lLCBQYXJrdmlsbGUsIFZpY3Rv

cmlhLCBBdXN0cmFsaWEuJiN4RDsxXSBBY2FkZW1pYyBVbml0IGZvciBQc3ljaGlhdHJ5IG9mIE9s

ZCBBZ2UsIERlcGFydG1lbnQgb2YgUHN5Y2hpYXRyeSwgVGhlIFVuaXZlcnNpdHkgb2YgTWVsYm91

cm5lLCBTdCBWaW5jZW50JmFwb3M7cyBBZ2VkIFBzeWNoaWF0cnkgU2VydmljZSwgU3QgR2Vvcmdl

JmFwb3M7cyBIb3NwaXRhbCwgTWVsYm91cm5lLCBWaWN0b3JpYSwgQXVzdHJhbGlhIFsyXSBOYXRp

b25hbCBBZ2VpbmcgUmVzZWFyY2ggSW5zdGl0dXRlLCBQYXJrdmlsbGUsIFZpY3RvcmlhLCBBdXN0

cmFsaWEgWzNdIE1lbnRhbCBIZWFsdGggUmVzZWFyY2ggSW5zdGl0dXRlLCBUaGUgVW5pdmVyc2l0

eSBvZiBNZWxib3VybmUsIFBhcmt2aWxsZSwgVmljdG9yaWEsIEF1c3RyYWxpYS4mI3hEOzFdIE1l

bnRhbCBIZWFsdGggUmVzZWFyY2ggSW5zdGl0dXRlLCBUaGUgVW5pdmVyc2l0eSBvZiBNZWxib3Vy

bmUsIFBhcmt2aWxsZSwgVmljdG9yaWEsIEF1c3RyYWxpYSBbMl0gQ2VudHJlIGZvciBOZXVyb3Nj

aWVuY2UsIFRoZSBVbml2ZXJzaXR5IG9mIE1lbGJvdXJuZSwgUGFya3ZpbGxlLCBWaWN0b3JpYSwg

QXVzdHJhbGlhLiYjeEQ7MV0gTWVudGFsIEhlYWx0aCBSZXNlYXJjaCBJbnN0aXR1dGUsIFRoZSBV

bml2ZXJzaXR5IG9mIE1lbGJvdXJuZSwgUGFya3ZpbGxlLCBWaWN0b3JpYSwgQXVzdHJhbGlhIFsy

XSBEZXBhcnRtZW50IG9mIFBhdGhvbG9neSwgVGhlIFVuaXZlcnNpdHkgb2YgTWVsYm91cm5lLCBQ

YXJrdmlsbGUsIFZpY3RvcmlhLCBBdXN0cmFsaWEuJiN4RDsxXSBNZW50YWwgSGVhbHRoIFJlc2Vh

cmNoIEluc3RpdHV0ZSwgVGhlIFVuaXZlcnNpdHkgb2YgTWVsYm91cm5lLCBQYXJrdmlsbGUsIFZp

Y3RvcmlhLCBBdXN0cmFsaWEgWzJdIENlbnRyZSBmb3IgTmV1cm9zY2llbmNlLCBUaGUgVW5pdmVy

c2l0eSBvZiBNZWxib3VybmUsIFBhcmt2aWxsZSwgVmljdG9yaWEsIEF1c3RyYWxpYSBbM10gRGVw

YXJ0bWVudCBvZiBOdWNsZWFyIE1lZGljaW5lICZhbXA7IENlbnRyZSBmb3IgUEVULCBBdXN0aW4g

SGVhbHRoLCBIZWlkZWxiZXJnLCBWaWN0b3JpYSwgQXVzdHJhbGlhIFs0XSBTY2hvb2wgb2YgUHN5

Y2hvbG9naWNhbCBTY2llbmNlLCBMYSBUcm9iZSBVbml2ZXJzaXR5LCBCdW5kb29yYSwgVmljdG9y

aWEgQXVzdHJhbGlhLiYjeEQ7RGVwYXJ0bWVudCBvZiBOdWNsZWFyIE1lZGljaW5lICZhbXA7IENl

bnRyZSBmb3IgUEVULCBBdXN0aW4gSGVhbHRoLCBIZWlkZWxiZXJnLCBWaWN0b3JpYSwgQXVzdHJh

bGlhLiYjeEQ7MV0gTmF0aW9uYWwgQWdlaW5nIFJlc2VhcmNoIEluc3RpdHV0ZSwgUGFya3ZpbGxl

LCBWaWN0b3JpYSwgQXVzdHJhbGlhIFsyXSBDU0lSTywgUGFya3ZpbGxlLCBWaWN0b3JpYSwgQXVz

dHJhbGlhLiYjeEQ7MV0gTWVudGFsIEhlYWx0aCBSZXNlYXJjaCBJbnN0aXR1dGUsIFRoZSBVbml2

ZXJzaXR5IG9mIE1lbGJvdXJuZSwgUGFya3ZpbGxlLCBWaWN0b3JpYSwgQXVzdHJhbGlhIFsyXSBE

ZXBhcnRtZW50IG9mIE51Y2xlYXIgTWVkaWNpbmUgJmFtcDsgQ2VudHJlIGZvciBQRVQsIEF1c3Rp

biBIZWFsdGgsIEhlaWRlbGJlcmcsIFZpY3RvcmlhLCBBdXN0cmFsaWEuPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+QXNzb2NpYXRpb25zIGJldHdlZW4gZ29uYWRvdHJvcGlucywgdGVzdG9z

dGVyb25lIGFuZCBiZXRhIGFteWxvaWQgaW4gbWVuIGF0IHJpc2sgb2YgQWx6aGVpbWVyJmFwb3M7

cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk1vbCBQc3ljaGlhdHJ5PC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjY5LTc1PC9wYWdlcz48dm9sdW1lPjE5PC92b2x1bWU+

PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdv

cmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2Uv

ZGlhZ25vc3RpYyBpbWFnaW5nLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQg

YmV0YS1QZXB0aWRlcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BbmlsaW5lIENvbXBv

dW5kczwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMgRS9nZW5ldGljczwva2V5d29y

ZD48a2V5d29yZD5Db2duaXRpdmUgRHlzZnVuY3Rpb24vZGlhZ25vc3RpYyBpbWFnaW5nL21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q29ob3J0IFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+

R29uYWRvdHJvcGlucy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdv

cmQ+PGtleXdvcmQ+TGluZWFyIE1vZGVsczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3Jk

PjxrZXl3b3JkPk1lbW9yeSBEaXNvcmRlcnMvZGlhZ25vc3RpYyBpbWFnaW5nL21ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9wc3lj

aG9sb2dpY2FsIFRlc3RzPC9rZXl3b3JkPjxrZXl3b3JkPlBlcHRpZGUgRnJhZ21lbnRzLyptZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlBvc2l0cm9uLUVtaXNzaW9uIFRvbW9ncmFwaHk8L2tl

eXdvcmQ+PGtleXdvcmQ+UHN5Y2hpYXRyaWMgU3RhdHVzIFJhdGluZyBTY2FsZXM8L2tleXdvcmQ+

PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlN0YXRpc3RpY3MsIE5vbnBh

cmFtZXRyaWM8L2tleXdvcmQ+PGtleXdvcmQ+VGVzdG9zdGVyb25lLyptZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPlRoaWF6b2xlczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDE0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SmFuPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGlzYm4+MTQ3Ni01NTc4IChFbGVjdHJvbmljKSYjeEQ7MTM1OS00MTg0IChMaW5raW5nKTwvaXNi

bj48YWNjZXNzaW9uLW51bT4yMzA4OTYzMzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11

cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMzA4OTYzMzwvdXJs

PjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9t

cC4yMDEyLjE0NzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5k

Tm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGFvPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVj

TnVtPjEwMDc8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4y

OTAsMzE2PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTAwNzwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyODY1NjQwIj4xMDA3PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5aaGFvLCBMaXFpbjwvYXV0aG9yPjxh

dXRob3I+TWFvLCBaaXN1PC9hdXRob3I+PGF1dGhvcj5Xb29keSwgU2FyYWggSy48L2F1dGhvcj48

YXV0aG9yPkJyaW50b24sIFJvYmVydGEgRC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PHRpdGxlcz48dGl0bGU+U2V4IGRpZmZlcmVuY2VzIGluIG1ldGFib2xpYyBhZ2luZyBvZiB0

aGUgYnJhaW46IGluc2lnaHRzIGludG8gZmVtYWxlIHN1c2NlcHRpYmlsaXR5IHRvIEFsemhlaW1l

ciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb2Jpb2xvZ3kgb2Yg

QWdpbmc8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NjktNzk8L3BhZ2VzPjx2b2x1

bWU+NDI8L3ZvbHVtZT48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIw

MTYvMDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9w

dWJsaXNoZXI+PGlzYm4+MDE5Ny00NTgwPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2oubmV1cm9iaW9sYWdpbmcuMjAxNi4wMi4wMTE8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYv

ai5uZXVyb2Jpb2xhZ2luZy4yMDE2LjAyLjAxMTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9y

ZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+VmVyZGlsZTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1ll

YXI+PFJlY051bT4zNTczPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zNTczPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTQ0OTciPjM1NzM8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlZlcmRpbGUsIEcuPC9hdXRob3I+PGF1dGhv

cj5MYXdzLCBTLiBNLjwvYXV0aG9yPjxhdXRob3I+SGVubGV5LCBELjwvYXV0aG9yPjxhdXRob3I+

QW1lcywgRC48L2F1dGhvcj48YXV0aG9yPkJ1c2gsIEEuIEkuPC9hdXRob3I+PGF1dGhvcj5FbGxp

cywgSy4gQS48L2F1dGhvcj48YXV0aG9yPkZhdXgsIE4uIEcuPC9hdXRob3I+PGF1dGhvcj5HdXB0

YSwgVi4gQi48L2F1dGhvcj48YXV0aG9yPkxpLCBRLiBYLjwvYXV0aG9yPjxhdXRob3I+TWFzdGVy

cywgQy4gTC48L2F1dGhvcj48YXV0aG9yPlBpa2UsIEsuIEUuPC9hdXRob3I+PGF1dGhvcj5Sb3dl

LCBDLiBDLjwvYXV0aG9yPjxhdXRob3I+U3pvZWtlLCBDLjwvYXV0aG9yPjxhdXRob3I+VGFkZGVp

LCBLLjwvYXV0aG9yPjxhdXRob3I+VmlsbGVtYWduZSwgVi4gTC48L2F1dGhvcj48YXV0aG9yPk1h

cnRpbnMsIFIuIE4uPC9hdXRob3I+PGF1dGhvcj5BaWJsIFJlc2VhcmNoIEdyb3VwPC9hdXRob3I+

PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+MV0gQ2VudHJlIG9mIEV4Y2Vs

bGVuY2UgZm9yIEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZSBSZXNlYXJjaCAmYW1wOyBDYXJlLCBT

Y2hvb2wgb2YgTWVkaWNhbCBTY2llbmNlcywgRWRpdGggQ293YW4gVW5pdmVyc2l0eSwgSm9vbmRh

bHVwLCBXZXN0ZXJuIEF1c3RyYWxpYSwgQXVzdHJhbGlhIFsyXSBTaXIgSmFtZXMgTWNDdXNrZXIg

QWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlIFJlc2VhcmNoIFVuaXQgKEhvbGx5d29vZCBQcml2YXRl

IEhvc3BpdGFsKSwgUGVydGgsIFdlc3Rlcm4gQXVzdHJhbGlhLCBBdXN0cmFsaWEuJiN4RDsxXSBD

ZW50cmUgb2YgRXhjZWxsZW5jZSBmb3IgQWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlIFJlc2VhcmNo

ICZhbXA7IENhcmUsIFNjaG9vbCBvZiBNZWRpY2FsIFNjaWVuY2VzLCBFZGl0aCBDb3dhbiBVbml2

ZXJzaXR5LCBKb29uZGFsdXAsIFdlc3Rlcm4gQXVzdHJhbGlhLCBBdXN0cmFsaWEgWzJdIFNpciBK

YW1lcyBNY0N1c2tlciBBbHpoZWltZXImYXBvcztzIERpc2Vhc2UgUmVzZWFyY2ggVW5pdCAoSG9s

bHl3b29kIFByaXZhdGUgSG9zcGl0YWwpLCBQZXJ0aCwgV2VzdGVybiBBdXN0cmFsaWEsIEF1c3Ry

YWxpYSBbM10gQ28tb3BlcmF0aXZlIFJlc2VhcmNoIENlbnRyZSBmb3IgTWVudGFsIEhlYWx0aCwg

aHR0cDovL3d3dy5tZW50YWxoZWFsdGhjcmMuY29tLiYjeEQ7MV0gRGVwYXJ0bWVudCBvZiBFbmRv

Y3Jpbm9sb2d5IGFuZCBEaWFiZXRlcywgU2lyIENoYXJsZXMgR2FpcmRuZXIgSG9zcGl0YWwsIE5l

ZGxhbmRzLCBXZXN0ZXJuIEF1c3RyYWxpYSwgQXVzdHJhbGlhIFsyXSBTY2hvb2wgb2YgTWVkaWNp

bmUgYW5kIFBoYXJtYWNvbG9neSwgVW5pdmVyc2l0eSBvZiBXZXN0ZXJuIEF1c3RyYWxpYSwgQ3Jh

d2xleSwgV2VzdGVybiBBdXN0cmFsaWEsIEF1c3RyYWxpYS4mI3hEOzFdIEFjYWRlbWljIFVuaXQg

Zm9yIFBzeWNoaWF0cnkgb2YgT2xkIEFnZSwgRGVwYXJ0bWVudCBvZiBQc3ljaGlhdHJ5LCBUaGUg

VW5pdmVyc2l0eSBvZiBNZWxib3VybmUsIFN0IFZpbmNlbnQmYXBvcztzIEFnZWQgUHN5Y2hpYXRy

eSBTZXJ2aWNlLCBTdCBHZW9yZ2UmYXBvcztzIEhvc3BpdGFsLCBNZWxib3VybmUsIFZpY3Rvcmlh

LCBBdXN0cmFsaWEgWzJdIE5hdGlvbmFsIEFnZWluZyBSZXNlYXJjaCBJbnN0aXR1dGUsIFBhcmt2

aWxsZSwgVmljdG9yaWEsIEF1c3RyYWxpYS4mI3hEOzFdIENvLW9wZXJhdGl2ZSBSZXNlYXJjaCBD

ZW50cmUgZm9yIE1lbnRhbCBIZWFsdGgsIGh0dHA6Ly93d3cubWVudGFsaGVhbHRoY3JjLmNvbSBb

Ml0gTWVudGFsIEhlYWx0aCBSZXNlYXJjaCBJbnN0aXR1dGUsIFRoZSBVbml2ZXJzaXR5IG9mIE1l

bGJvdXJuZSwgUGFya3ZpbGxlLCBWaWN0b3JpYSwgQXVzdHJhbGlhIFszXSBDZW50cmUgZm9yIE5l

dXJvc2NpZW5jZSwgVGhlIFVuaXZlcnNpdHkgb2YgTWVsYm91cm5lLCBQYXJrdmlsbGUsIFZpY3Rv

cmlhLCBBdXN0cmFsaWEuJiN4RDsxXSBBY2FkZW1pYyBVbml0IGZvciBQc3ljaGlhdHJ5IG9mIE9s

ZCBBZ2UsIERlcGFydG1lbnQgb2YgUHN5Y2hpYXRyeSwgVGhlIFVuaXZlcnNpdHkgb2YgTWVsYm91

cm5lLCBTdCBWaW5jZW50JmFwb3M7cyBBZ2VkIFBzeWNoaWF0cnkgU2VydmljZSwgU3QgR2Vvcmdl

JmFwb3M7cyBIb3NwaXRhbCwgTWVsYm91cm5lLCBWaWN0b3JpYSwgQXVzdHJhbGlhIFsyXSBOYXRp

b25hbCBBZ2VpbmcgUmVzZWFyY2ggSW5zdGl0dXRlLCBQYXJrdmlsbGUsIFZpY3RvcmlhLCBBdXN0

cmFsaWEgWzNdIE1lbnRhbCBIZWFsdGggUmVzZWFyY2ggSW5zdGl0dXRlLCBUaGUgVW5pdmVyc2l0

eSBvZiBNZWxib3VybmUsIFBhcmt2aWxsZSwgVmljdG9yaWEsIEF1c3RyYWxpYS4mI3hEOzFdIE1l

bnRhbCBIZWFsdGggUmVzZWFyY2ggSW5zdGl0dXRlLCBUaGUgVW5pdmVyc2l0eSBvZiBNZWxib3Vy

bmUsIFBhcmt2aWxsZSwgVmljdG9yaWEsIEF1c3RyYWxpYSBbMl0gQ2VudHJlIGZvciBOZXVyb3Nj

aWVuY2UsIFRoZSBVbml2ZXJzaXR5IG9mIE1lbGJvdXJuZSwgUGFya3ZpbGxlLCBWaWN0b3JpYSwg

QXVzdHJhbGlhLiYjeEQ7MV0gTWVudGFsIEhlYWx0aCBSZXNlYXJjaCBJbnN0aXR1dGUsIFRoZSBV

bml2ZXJzaXR5IG9mIE1lbGJvdXJuZSwgUGFya3ZpbGxlLCBWaWN0b3JpYSwgQXVzdHJhbGlhIFsy

XSBEZXBhcnRtZW50IG9mIFBhdGhvbG9neSwgVGhlIFVuaXZlcnNpdHkgb2YgTWVsYm91cm5lLCBQ

YXJrdmlsbGUsIFZpY3RvcmlhLCBBdXN0cmFsaWEuJiN4RDsxXSBNZW50YWwgSGVhbHRoIFJlc2Vh

cmNoIEluc3RpdHV0ZSwgVGhlIFVuaXZlcnNpdHkgb2YgTWVsYm91cm5lLCBQYXJrdmlsbGUsIFZp

Y3RvcmlhLCBBdXN0cmFsaWEgWzJdIENlbnRyZSBmb3IgTmV1cm9zY2llbmNlLCBUaGUgVW5pdmVy

c2l0eSBvZiBNZWxib3VybmUsIFBhcmt2aWxsZSwgVmljdG9yaWEsIEF1c3RyYWxpYSBbM10gRGVw

YXJ0bWVudCBvZiBOdWNsZWFyIE1lZGljaW5lICZhbXA7IENlbnRyZSBmb3IgUEVULCBBdXN0aW4g

SGVhbHRoLCBIZWlkZWxiZXJnLCBWaWN0b3JpYSwgQXVzdHJhbGlhIFs0XSBTY2hvb2wgb2YgUHN5

Y2hvbG9naWNhbCBTY2llbmNlLCBMYSBUcm9iZSBVbml2ZXJzaXR5LCBCdW5kb29yYSwgVmljdG9y

aWEgQXVzdHJhbGlhLiYjeEQ7RGVwYXJ0bWVudCBvZiBOdWNsZWFyIE1lZGljaW5lICZhbXA7IENl

bnRyZSBmb3IgUEVULCBBdXN0aW4gSGVhbHRoLCBIZWlkZWxiZXJnLCBWaWN0b3JpYSwgQXVzdHJh

bGlhLiYjeEQ7MV0gTmF0aW9uYWwgQWdlaW5nIFJlc2VhcmNoIEluc3RpdHV0ZSwgUGFya3ZpbGxl

LCBWaWN0b3JpYSwgQXVzdHJhbGlhIFsyXSBDU0lSTywgUGFya3ZpbGxlLCBWaWN0b3JpYSwgQXVz

dHJhbGlhLiYjeEQ7MV0gTWVudGFsIEhlYWx0aCBSZXNlYXJjaCBJbnN0aXR1dGUsIFRoZSBVbml2

ZXJzaXR5IG9mIE1lbGJvdXJuZSwgUGFya3ZpbGxlLCBWaWN0b3JpYSwgQXVzdHJhbGlhIFsyXSBE

ZXBhcnRtZW50IG9mIE51Y2xlYXIgTWVkaWNpbmUgJmFtcDsgQ2VudHJlIGZvciBQRVQsIEF1c3Rp

biBIZWFsdGgsIEhlaWRlbGJlcmcsIFZpY3RvcmlhLCBBdXN0cmFsaWEuPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+QXNzb2NpYXRpb25zIGJldHdlZW4gZ29uYWRvdHJvcGlucywgdGVzdG9z

dGVyb25lIGFuZCBiZXRhIGFteWxvaWQgaW4gbWVuIGF0IHJpc2sgb2YgQWx6aGVpbWVyJmFwb3M7

cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk1vbCBQc3ljaGlhdHJ5PC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjY5LTc1PC9wYWdlcz48dm9sdW1lPjE5PC92b2x1bWU+

PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdv

cmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2Uv

ZGlhZ25vc3RpYyBpbWFnaW5nLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQg

YmV0YS1QZXB0aWRlcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BbmlsaW5lIENvbXBv

dW5kczwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMgRS9nZW5ldGljczwva2V5d29y

ZD48a2V5d29yZD5Db2duaXRpdmUgRHlzZnVuY3Rpb24vZGlhZ25vc3RpYyBpbWFnaW5nL21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q29ob3J0IFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+

R29uYWRvdHJvcGlucy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdv

cmQ+PGtleXdvcmQ+TGluZWFyIE1vZGVsczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3Jk

PjxrZXl3b3JkPk1lbW9yeSBEaXNvcmRlcnMvZGlhZ25vc3RpYyBpbWFnaW5nL21ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9wc3lj

aG9sb2dpY2FsIFRlc3RzPC9rZXl3b3JkPjxrZXl3b3JkPlBlcHRpZGUgRnJhZ21lbnRzLyptZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlBvc2l0cm9uLUVtaXNzaW9uIFRvbW9ncmFwaHk8L2tl

eXdvcmQ+PGtleXdvcmQ+UHN5Y2hpYXRyaWMgU3RhdHVzIFJhdGluZyBTY2FsZXM8L2tleXdvcmQ+

PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlN0YXRpc3RpY3MsIE5vbnBh

cmFtZXRyaWM8L2tleXdvcmQ+PGtleXdvcmQ+VGVzdG9zdGVyb25lLyptZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPlRoaWF6b2xlczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDE0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SmFuPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGlzYm4+MTQ3Ni01NTc4IChFbGVjdHJvbmljKSYjeEQ7MTM1OS00MTg0IChMaW5raW5nKTwvaXNi

bj48YWNjZXNzaW9uLW51bT4yMzA4OTYzMzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11

cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMzA4OTYzMzwvdXJs

PjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9t

cC4yMDEyLjE0NzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5k

Tm90ZT4A

ADDIN EN.CITE.DATA 290,316 that may further condition the whole discovery/development of successful preventive and therapeutic strategies against the disease.Uncertainties in Drug Development in ADDespite the over 100 human clinical trials on promising therapies in the last decade, AD remains incurable PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjk4MzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI5MCwyOTQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj45ODM8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY0MCI+OTgzPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XaW5ibGFkLCBCZW5ndDwvYXV0aG9y

PjxhdXRob3I+UWl1LCBDaGVuZ3h1YW48L2F1dGhvcj48YXV0aG9yPkJhbGxhcmQsIENsaXZlPC9h

dXRob3I+PGF1dGhvcj5Kb2hhbnNzb24sIEd1bmlsbGE8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+RXZpZGVuY2UtYmFzZWQgcHJldmVudGlvbiBhbmQgdHJl

YXRtZW50IG9mIGRlbWVudGlhIOKAkyBBdXRob3JzJmFwb3M7IHJlcGx5PC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPlRoZSBMYW5jZXQgTmV1cm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBhZ2VzPjEwMDctMTAwODwvcGFnZXM+PHZvbHVtZT4xNTwvdm9sdW1lPjxudW1iZXI+MTA8L251

bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMDk8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+

PGlzYm4+MTQ3NC00NDIyPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHgu

ZG9pLm9yZy8xMC4xMDE2L3MxNDc0LTQ0MjIoMTYpMzAxMjgtNDwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9zMTQ3NC00NDIyKDE2KTMw

MTI4LTQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPlpoYW88L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNOdW0+MTAwNzwvUmVjTnVtPjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTAwNzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0

YW1wPSIxNTMyODY1NjQwIj4xMDA3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5aaGFvLCBMaXFpbjwvYXV0aG9yPjxhdXRob3I+TWFvLCBaaXN1PC9hdXRob3I+PGF1dGhv

cj5Xb29keSwgU2FyYWggSy48L2F1dGhvcj48YXV0aG9yPkJyaW50b24sIFJvYmVydGEgRC48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+U2V4IGRpZmZlcmVu

Y2VzIGluIG1ldGFib2xpYyBhZ2luZyBvZiB0aGUgYnJhaW46IGluc2lnaHRzIGludG8gZmVtYWxl

IHN1c2NlcHRpYmlsaXR5IHRvIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5OZXVyb2Jpb2xvZ3kgb2YgQWdpbmc8L3NlY29uZGFyeS10aXRsZT48L3RpdGxl

cz48cGFnZXM+NjktNzk8L3BhZ2VzPjx2b2x1bWU+NDI8L3ZvbHVtZT48ZGF0ZXM+PHllYXI+MjAx

NjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MDE5Ny00NTgwPC9pc2Ju

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2oubmV1

cm9iaW9sYWdpbmcuMjAxNi4wMi4wMTE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb2Jpb2xhZ2luZy4yMDE2LjAyLjAxMTwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjk4MzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI5MCwyOTQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj45ODM8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY0MCI+OTgzPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XaW5ibGFkLCBCZW5ndDwvYXV0aG9y

PjxhdXRob3I+UWl1LCBDaGVuZ3h1YW48L2F1dGhvcj48YXV0aG9yPkJhbGxhcmQsIENsaXZlPC9h

dXRob3I+PGF1dGhvcj5Kb2hhbnNzb24sIEd1bmlsbGE8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+RXZpZGVuY2UtYmFzZWQgcHJldmVudGlvbiBhbmQgdHJl

YXRtZW50IG9mIGRlbWVudGlhIOKAkyBBdXRob3JzJmFwb3M7IHJlcGx5PC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPlRoZSBMYW5jZXQgTmV1cm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBhZ2VzPjEwMDctMTAwODwvcGFnZXM+PHZvbHVtZT4xNTwvdm9sdW1lPjxudW1iZXI+MTA8L251

bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMDk8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+

PGlzYm4+MTQ3NC00NDIyPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHgu

ZG9pLm9yZy8xMC4xMDE2L3MxNDc0LTQ0MjIoMTYpMzAxMjgtNDwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9zMTQ3NC00NDIyKDE2KTMw

MTI4LTQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPlpoYW88L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNOdW0+MTAwNzwvUmVjTnVtPjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTAwNzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0

YW1wPSIxNTMyODY1NjQwIj4xMDA3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5aaGFvLCBMaXFpbjwvYXV0aG9yPjxhdXRob3I+TWFvLCBaaXN1PC9hdXRob3I+PGF1dGhv

cj5Xb29keSwgU2FyYWggSy48L2F1dGhvcj48YXV0aG9yPkJyaW50b24sIFJvYmVydGEgRC48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+U2V4IGRpZmZlcmVu

Y2VzIGluIG1ldGFib2xpYyBhZ2luZyBvZiB0aGUgYnJhaW46IGluc2lnaHRzIGludG8gZmVtYWxl

IHN1c2NlcHRpYmlsaXR5IHRvIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5OZXVyb2Jpb2xvZ3kgb2YgQWdpbmc8L3NlY29uZGFyeS10aXRsZT48L3RpdGxl

cz48cGFnZXM+NjktNzk8L3BhZ2VzPjx2b2x1bWU+NDI8L3ZvbHVtZT48ZGF0ZXM+PHllYXI+MjAx

NjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MDE5Ny00NTgwPC9pc2Ju

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2oubmV1

cm9iaW9sYWdpbmcuMjAxNi4wMi4wMTE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb2Jpb2xhZ2luZy4yMDE2LjAyLjAxMTwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 290,294. This fact and the increasing prevalence in our aged societies renders AD a socioeconomic burden PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjk4MzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI5MCwyOTQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj45ODM8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY0MCI+OTgzPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XaW5ibGFkLCBCZW5ndDwvYXV0aG9y

PjxhdXRob3I+UWl1LCBDaGVuZ3h1YW48L2F1dGhvcj48YXV0aG9yPkJhbGxhcmQsIENsaXZlPC9h

dXRob3I+PGF1dGhvcj5Kb2hhbnNzb24sIEd1bmlsbGE8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+RXZpZGVuY2UtYmFzZWQgcHJldmVudGlvbiBhbmQgdHJl

YXRtZW50IG9mIGRlbWVudGlhIOKAkyBBdXRob3JzJmFwb3M7IHJlcGx5PC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPlRoZSBMYW5jZXQgTmV1cm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBhZ2VzPjEwMDctMTAwODwvcGFnZXM+PHZvbHVtZT4xNTwvdm9sdW1lPjxudW1iZXI+MTA8L251

bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMDk8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+

PGlzYm4+MTQ3NC00NDIyPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHgu

ZG9pLm9yZy8xMC4xMDE2L3MxNDc0LTQ0MjIoMTYpMzAxMjgtNDwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9zMTQ3NC00NDIyKDE2KTMw

MTI4LTQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPlpoYW88L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNOdW0+MTAwNzwvUmVjTnVtPjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTAwNzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0

YW1wPSIxNTMyODY1NjQwIj4xMDA3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5aaGFvLCBMaXFpbjwvYXV0aG9yPjxhdXRob3I+TWFvLCBaaXN1PC9hdXRob3I+PGF1dGhv

cj5Xb29keSwgU2FyYWggSy48L2F1dGhvcj48YXV0aG9yPkJyaW50b24sIFJvYmVydGEgRC48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+U2V4IGRpZmZlcmVu

Y2VzIGluIG1ldGFib2xpYyBhZ2luZyBvZiB0aGUgYnJhaW46IGluc2lnaHRzIGludG8gZmVtYWxl

IHN1c2NlcHRpYmlsaXR5IHRvIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5OZXVyb2Jpb2xvZ3kgb2YgQWdpbmc8L3NlY29uZGFyeS10aXRsZT48L3RpdGxl

cz48cGFnZXM+NjktNzk8L3BhZ2VzPjx2b2x1bWU+NDI8L3ZvbHVtZT48ZGF0ZXM+PHllYXI+MjAx

NjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MDE5Ny00NTgwPC9pc2Ju

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2oubmV1

cm9iaW9sYWdpbmcuMjAxNi4wMi4wMTE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb2Jpb2xhZ2luZy4yMDE2LjAyLjAxMTwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjk4MzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI5MCwyOTQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj45ODM8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY0MCI+OTgzPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XaW5ibGFkLCBCZW5ndDwvYXV0aG9y

PjxhdXRob3I+UWl1LCBDaGVuZ3h1YW48L2F1dGhvcj48YXV0aG9yPkJhbGxhcmQsIENsaXZlPC9h

dXRob3I+PGF1dGhvcj5Kb2hhbnNzb24sIEd1bmlsbGE8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+RXZpZGVuY2UtYmFzZWQgcHJldmVudGlvbiBhbmQgdHJl

YXRtZW50IG9mIGRlbWVudGlhIOKAkyBBdXRob3JzJmFwb3M7IHJlcGx5PC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPlRoZSBMYW5jZXQgTmV1cm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBhZ2VzPjEwMDctMTAwODwvcGFnZXM+PHZvbHVtZT4xNTwvdm9sdW1lPjxudW1iZXI+MTA8L251

bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMDk8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+

PGlzYm4+MTQ3NC00NDIyPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHgu

ZG9pLm9yZy8xMC4xMDE2L3MxNDc0LTQ0MjIoMTYpMzAxMjgtNDwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9zMTQ3NC00NDIyKDE2KTMw

MTI4LTQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPlpoYW88L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNOdW0+MTAwNzwvUmVjTnVtPjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTAwNzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0

YW1wPSIxNTMyODY1NjQwIj4xMDA3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5aaGFvLCBMaXFpbjwvYXV0aG9yPjxhdXRob3I+TWFvLCBaaXN1PC9hdXRob3I+PGF1dGhv

cj5Xb29keSwgU2FyYWggSy48L2F1dGhvcj48YXV0aG9yPkJyaW50b24sIFJvYmVydGEgRC48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+U2V4IGRpZmZlcmVu

Y2VzIGluIG1ldGFib2xpYyBhZ2luZyBvZiB0aGUgYnJhaW46IGluc2lnaHRzIGludG8gZmVtYWxl

IHN1c2NlcHRpYmlsaXR5IHRvIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5OZXVyb2Jpb2xvZ3kgb2YgQWdpbmc8L3NlY29uZGFyeS10aXRsZT48L3RpdGxl

cz48cGFnZXM+NjktNzk8L3BhZ2VzPjx2b2x1bWU+NDI8L3ZvbHVtZT48ZGF0ZXM+PHllYXI+MjAx

NjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MDE5Ny00NTgwPC9pc2Ju

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2oubmV1

cm9iaW9sYWdpbmcuMjAxNi4wMi4wMTE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb2Jpb2xhZ2luZy4yMDE2LjAyLjAxMTwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 290,294. Thus, there is a need to clearly define its precise pathophysiology, establish accurate biomarkers and more efficient/safer preventive/therapeutic approaches PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjk4MzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI5MCwyOTQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj45ODM8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY0MCI+OTgzPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XaW5ibGFkLCBCZW5ndDwvYXV0aG9y

PjxhdXRob3I+UWl1LCBDaGVuZ3h1YW48L2F1dGhvcj48YXV0aG9yPkJhbGxhcmQsIENsaXZlPC9h

dXRob3I+PGF1dGhvcj5Kb2hhbnNzb24sIEd1bmlsbGE8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+RXZpZGVuY2UtYmFzZWQgcHJldmVudGlvbiBhbmQgdHJl

YXRtZW50IG9mIGRlbWVudGlhIOKAkyBBdXRob3JzJmFwb3M7IHJlcGx5PC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPlRoZSBMYW5jZXQgTmV1cm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBhZ2VzPjEwMDctMTAwODwvcGFnZXM+PHZvbHVtZT4xNTwvdm9sdW1lPjxudW1iZXI+MTA8L251

bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMDk8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+

PGlzYm4+MTQ3NC00NDIyPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHgu

ZG9pLm9yZy8xMC4xMDE2L3MxNDc0LTQ0MjIoMTYpMzAxMjgtNDwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9zMTQ3NC00NDIyKDE2KTMw

MTI4LTQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPlpoYW88L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNOdW0+MTAwNzwvUmVjTnVtPjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTAwNzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0

YW1wPSIxNTMyODY1NjQwIj4xMDA3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5aaGFvLCBMaXFpbjwvYXV0aG9yPjxhdXRob3I+TWFvLCBaaXN1PC9hdXRob3I+PGF1dGhv

cj5Xb29keSwgU2FyYWggSy48L2F1dGhvcj48YXV0aG9yPkJyaW50b24sIFJvYmVydGEgRC48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+U2V4IGRpZmZlcmVu

Y2VzIGluIG1ldGFib2xpYyBhZ2luZyBvZiB0aGUgYnJhaW46IGluc2lnaHRzIGludG8gZmVtYWxl

IHN1c2NlcHRpYmlsaXR5IHRvIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5OZXVyb2Jpb2xvZ3kgb2YgQWdpbmc8L3NlY29uZGFyeS10aXRsZT48L3RpdGxl

cz48cGFnZXM+NjktNzk8L3BhZ2VzPjx2b2x1bWU+NDI8L3ZvbHVtZT48ZGF0ZXM+PHllYXI+MjAx

NjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MDE5Ny00NTgwPC9pc2Ju

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2oubmV1

cm9iaW9sYWdpbmcuMjAxNi4wMi4wMTE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb2Jpb2xhZ2luZy4yMDE2LjAyLjAxMTwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjk4MzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI5MCwyOTQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj45ODM8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY0MCI+OTgzPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XaW5ibGFkLCBCZW5ndDwvYXV0aG9y

PjxhdXRob3I+UWl1LCBDaGVuZ3h1YW48L2F1dGhvcj48YXV0aG9yPkJhbGxhcmQsIENsaXZlPC9h

dXRob3I+PGF1dGhvcj5Kb2hhbnNzb24sIEd1bmlsbGE8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+RXZpZGVuY2UtYmFzZWQgcHJldmVudGlvbiBhbmQgdHJl

YXRtZW50IG9mIGRlbWVudGlhIOKAkyBBdXRob3JzJmFwb3M7IHJlcGx5PC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPlRoZSBMYW5jZXQgTmV1cm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBhZ2VzPjEwMDctMTAwODwvcGFnZXM+PHZvbHVtZT4xNTwvdm9sdW1lPjxudW1iZXI+MTA8L251

bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMDk8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+

PGlzYm4+MTQ3NC00NDIyPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHgu

ZG9pLm9yZy8xMC4xMDE2L3MxNDc0LTQ0MjIoMTYpMzAxMjgtNDwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9zMTQ3NC00NDIyKDE2KTMw

MTI4LTQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPlpoYW88L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNOdW0+MTAwNzwvUmVjTnVtPjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTAwNzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0

YW1wPSIxNTMyODY1NjQwIj4xMDA3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5aaGFvLCBMaXFpbjwvYXV0aG9yPjxhdXRob3I+TWFvLCBaaXN1PC9hdXRob3I+PGF1dGhv

cj5Xb29keSwgU2FyYWggSy48L2F1dGhvcj48YXV0aG9yPkJyaW50b24sIFJvYmVydGEgRC48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+U2V4IGRpZmZlcmVu

Y2VzIGluIG1ldGFib2xpYyBhZ2luZyBvZiB0aGUgYnJhaW46IGluc2lnaHRzIGludG8gZmVtYWxl

IHN1c2NlcHRpYmlsaXR5IHRvIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5OZXVyb2Jpb2xvZ3kgb2YgQWdpbmc8L3NlY29uZGFyeS10aXRsZT48L3RpdGxl

cz48cGFnZXM+NjktNzk8L3BhZ2VzPjx2b2x1bWU+NDI8L3ZvbHVtZT48ZGF0ZXM+PHllYXI+MjAx

NjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MDE5Ny00NTgwPC9pc2Ju

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2oubmV1

cm9iaW9sYWdpbmcuMjAxNi4wMi4wMTE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb2Jpb2xhZ2luZy4yMDE2LjAyLjAxMTwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 290,294.Since the abnormal accumulation of Aβ and hyperphosphorylated Tau are two of the main neuropathological hallmarks of AD, research is mainly focused on the development of Aβ- and Tau-modifying therapies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjk4MzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI2OCwyOTQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj45ODM8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY0MCI+OTgzPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XaW5ibGFkLCBCZW5ndDwvYXV0aG9y

PjxhdXRob3I+UWl1LCBDaGVuZ3h1YW48L2F1dGhvcj48YXV0aG9yPkJhbGxhcmQsIENsaXZlPC9h

dXRob3I+PGF1dGhvcj5Kb2hhbnNzb24sIEd1bmlsbGE8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+RXZpZGVuY2UtYmFzZWQgcHJldmVudGlvbiBhbmQgdHJl

YXRtZW50IG9mIGRlbWVudGlhIOKAkyBBdXRob3JzJmFwb3M7IHJlcGx5PC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPlRoZSBMYW5jZXQgTmV1cm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBhZ2VzPjEwMDctMTAwODwvcGFnZXM+PHZvbHVtZT4xNTwvdm9sdW1lPjxudW1iZXI+MTA8L251

bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMDk8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+

PGlzYm4+MTQ3NC00NDIyPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHgu

ZG9pLm9yZy8xMC4xMDE2L3MxNDc0LTQ0MjIoMTYpMzAxMjgtNDwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9zMTQ3NC00NDIyKDE2KTMw

MTI4LTQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPkphcm9zei1HcmlmZml0aHM8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNOdW0+OTg0

PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj45ODQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5

cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1

YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY0MCI+OTg0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10

eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1

dGhvcnM+PGF1dGhvcj5KYXJvc3otR3JpZmZpdGhzLCBIZWxlZGQgSC48L2F1dGhvcj48YXV0aG9y

Pk5vYmxlLCBFbGl6YWJldGg8L2F1dGhvcj48YXV0aG9yPlJ1c2h3b3J0aCwgSm8gVi48L2F1dGhv

cj48YXV0aG9yPkhvb3BlciwgTmlnZWwgTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PHRpdGxlcz48dGl0bGU+QW15bG9pZC3OsiBSZWNlcHRvcnM6IFRoZSBHb29kLCB0aGUgQmFk

LCBhbmQgdGhlIFByaW9uIFByb3RlaW48L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Sm91cm5hbCBv

ZiBCaW9sb2dpY2FsIENoZW1pc3RyeTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4z

MTc0LTMxODM8L3BhZ2VzPjx2b2x1bWU+MjkxPC92b2x1bWU+PG51bWJlcj43PC9udW1iZXI+PGRh

dGVzPjx5ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDE1LzEyLzMwPC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5BbWVyaWNhbiBTb2NpZXR5IGZvciBCaW9jaGVt

aXN0cnkgJmFtcDsgTW9sZWN1bGFyIEJpb2xvZ3kgKEFTQk1CKTwvcHVibGlzaGVyPjxpc2JuPjAw

MjEtOTI1OCYjeEQ7MTA4My0zNTFYPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRw

Oi8vZHguZG9pLm9yZy8xMC4xMDc0L2piYy5yMTE1LjcwMjcwNDwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA3NC9qYmMucjExNS43MDI3MDQ8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjk4MzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI2OCwyOTQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj45ODM8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY0MCI+OTgzPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XaW5ibGFkLCBCZW5ndDwvYXV0aG9y

PjxhdXRob3I+UWl1LCBDaGVuZ3h1YW48L2F1dGhvcj48YXV0aG9yPkJhbGxhcmQsIENsaXZlPC9h

dXRob3I+PGF1dGhvcj5Kb2hhbnNzb24sIEd1bmlsbGE8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+RXZpZGVuY2UtYmFzZWQgcHJldmVudGlvbiBhbmQgdHJl

YXRtZW50IG9mIGRlbWVudGlhIOKAkyBBdXRob3JzJmFwb3M7IHJlcGx5PC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPlRoZSBMYW5jZXQgTmV1cm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBhZ2VzPjEwMDctMTAwODwvcGFnZXM+PHZvbHVtZT4xNTwvdm9sdW1lPjxudW1iZXI+MTA8L251

bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMDk8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+

PGlzYm4+MTQ3NC00NDIyPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHgu

ZG9pLm9yZy8xMC4xMDE2L3MxNDc0LTQ0MjIoMTYpMzAxMjgtNDwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9zMTQ3NC00NDIyKDE2KTMw

MTI4LTQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPkphcm9zei1HcmlmZml0aHM8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNOdW0+OTg0

PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj45ODQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5

cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1

YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY0MCI+OTg0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10

eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1

dGhvcnM+PGF1dGhvcj5KYXJvc3otR3JpZmZpdGhzLCBIZWxlZGQgSC48L2F1dGhvcj48YXV0aG9y

Pk5vYmxlLCBFbGl6YWJldGg8L2F1dGhvcj48YXV0aG9yPlJ1c2h3b3J0aCwgSm8gVi48L2F1dGhv

cj48YXV0aG9yPkhvb3BlciwgTmlnZWwgTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PHRpdGxlcz48dGl0bGU+QW15bG9pZC3OsiBSZWNlcHRvcnM6IFRoZSBHb29kLCB0aGUgQmFk

LCBhbmQgdGhlIFByaW9uIFByb3RlaW48L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Sm91cm5hbCBv

ZiBCaW9sb2dpY2FsIENoZW1pc3RyeTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4z

MTc0LTMxODM8L3BhZ2VzPjx2b2x1bWU+MjkxPC92b2x1bWU+PG51bWJlcj43PC9udW1iZXI+PGRh

dGVzPjx5ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDE1LzEyLzMwPC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5BbWVyaWNhbiBTb2NpZXR5IGZvciBCaW9jaGVt

aXN0cnkgJmFtcDsgTW9sZWN1bGFyIEJpb2xvZ3kgKEFTQk1CKTwvcHVibGlzaGVyPjxpc2JuPjAw

MjEtOTI1OCYjeEQ7MTA4My0zNTFYPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRw

Oi8vZHguZG9pLm9yZy8xMC4xMDc0L2piYy5yMTE1LjcwMjcwNDwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA3NC9qYmMucjExNS43MDI3MDQ8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 268,294. These have been well succeeded in preclinical studies. However, their translation into clinical trials has been also somehow disappointing ADDIN EN.CITE <EndNote><Cite><Author>Winblad</Author><Year>2016</Year><RecNum>983</RecNum><DisplayText><style face="superscript">294</style></DisplayText><record><rec-number>983</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865640">983</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Winblad, Bengt</author><author>Qiu, Chengxuan</author><author>Ballard, Clive</author><author>Johansson, Gunilla</author></authors></contributors><titles><title>Evidence-based prevention and treatment of dementia – Authors&apos; reply</title><secondary-title>The Lancet Neurology</secondary-title></titles><pages>1007-1008</pages><volume>15</volume><number>10</number><dates><year>2016</year><pub-dates><date>2016/09</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>1474-4422</isbn><urls><related-urls><url>(16)30128-4</url></related-urls></urls><electronic-resource-num>10.1016/s1474-4422(16)30128-4</electronic-resource-num></record></Cite></EndNote>294 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdWFydGU8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxS

ZWNOdW0+Mzc0NjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjMxNzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NDY8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNjkyNSI+Mzc0Njwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RHVhcnRlLCBBLiBJLjwvYXV0aG9yPjxh

dXRob3I+U2FudG9zLCBNLiBTLjwvYXV0aG9yPjxhdXRob3I+T2xpdmVpcmEsIEMuIFIuPC9hdXRo

b3I+PGF1dGhvcj5Nb3JlaXJhLCBQLiBJLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48YXV0aC1hZGRyZXNzPkNOQy0gQ2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5kIENlbGwgQmlv

bG9neSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhLCAzMDA0LTUxNyBDb2ltYnJhLCBQb3J0dWdhbDsg

SW5zdGl0dXRlIGZvciBJbnRlcmRpc2NpcGxpbmFyeSBSZXNlYXJjaCAoSUlJVUMpLCBVbml2ZXJz

aXR5IG9mIENvaW1icmEsIENhc2EgQ29zdGEgQWxlbWFvIC0gUG9sbyBJSSwgUnVhIEQuIEZyYW5j

aXNjbyBkZSBMZW1vcywgMzAzMC03ODkgQ29pbWJyYSwgUG9ydHVnYWwuIEVsZWN0cm9uaWMgYWRk

cmVzczogYW5hLmR1YXJ0ZUBjbmMudWMucHQuJiN4RDtDTkMtIENlbnRlciBmb3IgTmV1cm9zY2ll

bmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgMzAwNC01MTcgQ29p

bWJyYSwgUG9ydHVnYWw7IExpZmUgU2NpZW5jZXMgRGVwYXJ0bWVudCwgVW5pdmVyc2l0eSBvZiBD

b2ltYnJhLCBMYXJnbyBNYXJxdWVzIGRlIFBvbWJhbCwgMzAwNC01MTcgQ29pbWJyYSwgUG9ydHVn

YWwuJiN4RDtDTkMtIENlbnRlciBmb3IgTmV1cm9zY2llbmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVu

aXZlcnNpdHkgb2YgQ29pbWJyYSwgMzAwNC01MTcgQ29pbWJyYSwgUG9ydHVnYWw7IEluc3RpdHV0

ZSBvZiBCaW9jaGVtaXN0cnksIEZhY3VsdHkgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQ29p

bWJyYSwgMzAwNC01MDQgQ29pbWJyYSwgUG9ydHVnYWwuJiN4RDtDTkMtIENlbnRlciBmb3IgTmV1

cm9zY2llbmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgMzAwNC01

MTcgQ29pbWJyYSwgUG9ydHVnYWw7IEluc3RpdHV0ZSBvZiBQaHlzaW9sb2d5LCBGYWN1bHR5IG9m

IE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIENvaW1icmEsIDMwMDQtNTA0IENvaW1icmEsIFBvcnR1

Z2FsLiBFbGVjdHJvbmljIGFkZHJlc3M6IHBpbW9yZWlyYUBmbWVkLnVjLnB0LjwvYXV0aC1hZGRy

ZXNzPjx0aXRsZXM+PHRpdGxlPkJyYWluIGluc3VsaW4gc2lnbmFsbGluZywgZ2x1Y29zZSBtZXRh

Ym9saXNtIGFuZCBmZW1hbGVzJmFwb3M7IHJlcHJvZHVjdGl2ZSBhZ2luZzogQSBkYW5nZXJvdXMg

dHJpYWQgaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

Pk5ldXJvcGhhcm1hY29sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+TmV1cm9waGFybWFjb2xvZ3k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxw

YWdlcz4yMjMtMjQyPC9wYWdlcz48dm9sdW1lPjEzNjwvdm9sdW1lPjxudW1iZXI+UHQgQjwvbnVt

YmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+

PGtleXdvcmQ+QnJhaW4gKG1pdG9jaG9uZHJpYWwpIG1ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+RXN0cm9nZW4gc2lnbmFsbGluZzwva2V5d29yZD48a2V5d29yZD5GZW1hbGUgYWdpbmcvcmVw

cm9kdWN0aXZlIHNlbmVzY2VuY2U8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxpbiBzaWduYWxsaW5n

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5KdWwgMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE4NzMtNzA2NCAoRWxl

Y3Ryb25pYykmI3hEOzAwMjgtMzkwOCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjk0

NzEwNTU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjk0NzEwNTU8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb3BoYXJtLjIwMTguMDEu

MDQ0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdWFydGU8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxS

ZWNOdW0+Mzc0NjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjMxNzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NDY8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNjkyNSI+Mzc0Njwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RHVhcnRlLCBBLiBJLjwvYXV0aG9yPjxh

dXRob3I+U2FudG9zLCBNLiBTLjwvYXV0aG9yPjxhdXRob3I+T2xpdmVpcmEsIEMuIFIuPC9hdXRo

b3I+PGF1dGhvcj5Nb3JlaXJhLCBQLiBJLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48YXV0aC1hZGRyZXNzPkNOQy0gQ2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5kIENlbGwgQmlv

bG9neSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhLCAzMDA0LTUxNyBDb2ltYnJhLCBQb3J0dWdhbDsg

SW5zdGl0dXRlIGZvciBJbnRlcmRpc2NpcGxpbmFyeSBSZXNlYXJjaCAoSUlJVUMpLCBVbml2ZXJz

aXR5IG9mIENvaW1icmEsIENhc2EgQ29zdGEgQWxlbWFvIC0gUG9sbyBJSSwgUnVhIEQuIEZyYW5j

aXNjbyBkZSBMZW1vcywgMzAzMC03ODkgQ29pbWJyYSwgUG9ydHVnYWwuIEVsZWN0cm9uaWMgYWRk

cmVzczogYW5hLmR1YXJ0ZUBjbmMudWMucHQuJiN4RDtDTkMtIENlbnRlciBmb3IgTmV1cm9zY2ll

bmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgMzAwNC01MTcgQ29p

bWJyYSwgUG9ydHVnYWw7IExpZmUgU2NpZW5jZXMgRGVwYXJ0bWVudCwgVW5pdmVyc2l0eSBvZiBD

b2ltYnJhLCBMYXJnbyBNYXJxdWVzIGRlIFBvbWJhbCwgMzAwNC01MTcgQ29pbWJyYSwgUG9ydHVn

YWwuJiN4RDtDTkMtIENlbnRlciBmb3IgTmV1cm9zY2llbmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVu

aXZlcnNpdHkgb2YgQ29pbWJyYSwgMzAwNC01MTcgQ29pbWJyYSwgUG9ydHVnYWw7IEluc3RpdHV0

ZSBvZiBCaW9jaGVtaXN0cnksIEZhY3VsdHkgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQ29p

bWJyYSwgMzAwNC01MDQgQ29pbWJyYSwgUG9ydHVnYWwuJiN4RDtDTkMtIENlbnRlciBmb3IgTmV1

cm9zY2llbmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgMzAwNC01

MTcgQ29pbWJyYSwgUG9ydHVnYWw7IEluc3RpdHV0ZSBvZiBQaHlzaW9sb2d5LCBGYWN1bHR5IG9m

IE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIENvaW1icmEsIDMwMDQtNTA0IENvaW1icmEsIFBvcnR1

Z2FsLiBFbGVjdHJvbmljIGFkZHJlc3M6IHBpbW9yZWlyYUBmbWVkLnVjLnB0LjwvYXV0aC1hZGRy

ZXNzPjx0aXRsZXM+PHRpdGxlPkJyYWluIGluc3VsaW4gc2lnbmFsbGluZywgZ2x1Y29zZSBtZXRh

Ym9saXNtIGFuZCBmZW1hbGVzJmFwb3M7IHJlcHJvZHVjdGl2ZSBhZ2luZzogQSBkYW5nZXJvdXMg

dHJpYWQgaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

Pk5ldXJvcGhhcm1hY29sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+TmV1cm9waGFybWFjb2xvZ3k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxw

YWdlcz4yMjMtMjQyPC9wYWdlcz48dm9sdW1lPjEzNjwvdm9sdW1lPjxudW1iZXI+UHQgQjwvbnVt

YmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+

PGtleXdvcmQ+QnJhaW4gKG1pdG9jaG9uZHJpYWwpIG1ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+RXN0cm9nZW4gc2lnbmFsbGluZzwva2V5d29yZD48a2V5d29yZD5GZW1hbGUgYWdpbmcvcmVw

cm9kdWN0aXZlIHNlbmVzY2VuY2U8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxpbiBzaWduYWxsaW5n

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5KdWwgMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE4NzMtNzA2NCAoRWxl

Y3Ryb25pYykmI3hEOzAwMjgtMzkwOCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjk0

NzEwNTU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjk0NzEwNTU8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb3BoYXJtLjIwMTguMDEu

MDQ0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 317. This may be due to 1) scarcity of good predictive animal models mimicking the multifactorial nature of AD, and of good biomarkers for its progression; 2) delay in broadly transfer the bulk of newly generated “bench knowledge” into clinics; and 3) need to establish better inclusion criteria in clinical trials ADDIN EN.CITE <EndNote><Cite><Author>Winblad</Author><Year>2016</Year><RecNum>983</RecNum><DisplayText><style face="superscript">294</style></DisplayText><record><rec-number>983</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865640">983</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Winblad, Bengt</author><author>Qiu, Chengxuan</author><author>Ballard, Clive</author><author>Johansson, Gunilla</author></authors></contributors><titles><title>Evidence-based prevention and treatment of dementia – Authors&apos; reply</title><secondary-title>The Lancet Neurology</secondary-title></titles><pages>1007-1008</pages><volume>15</volume><number>10</number><dates><year>2016</year><pub-dates><date>2016/09</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>1474-4422</isbn><urls><related-urls><url>(16)30128-4</url></related-urls></urls><electronic-resource-num>10.1016/s1474-4422(16)30128-4</electronic-resource-num></record></Cite></EndNote>294.So far, clinical trials on drugs targeting Aβ production/clearance failed their primary clinical endpoints and some even caused serious side-effects ADDIN EN.CITE <EndNote><Cite><Author>Winblad</Author><Year>2016</Year><RecNum>983</RecNum><DisplayText><style face="superscript">294</style></DisplayText><record><rec-number>983</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865640">983</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Winblad, Bengt</author><author>Qiu, Chengxuan</author><author>Ballard, Clive</author><author>Johansson, Gunilla</author></authors></contributors><titles><title>Evidence-based prevention and treatment of dementia – Authors&apos; reply</title><secondary-title>The Lancet Neurology</secondary-title></titles><pages>1007-1008</pages><volume>15</volume><number>10</number><dates><year>2016</year><pub-dates><date>2016/09</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>1474-4422</isbn><urls><related-urls><url>(16)30128-4</url></related-urls></urls><electronic-resource-num>10.1016/s1474-4422(16)30128-4</electronic-resource-num></record></Cite></EndNote>294 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdWFydGU8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxS

ZWNOdW0+Mzc0NjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjMxNzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NDY8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNjkyNSI+Mzc0Njwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RHVhcnRlLCBBLiBJLjwvYXV0aG9yPjxh

dXRob3I+U2FudG9zLCBNLiBTLjwvYXV0aG9yPjxhdXRob3I+T2xpdmVpcmEsIEMuIFIuPC9hdXRo

b3I+PGF1dGhvcj5Nb3JlaXJhLCBQLiBJLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48YXV0aC1hZGRyZXNzPkNOQy0gQ2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5kIENlbGwgQmlv

bG9neSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhLCAzMDA0LTUxNyBDb2ltYnJhLCBQb3J0dWdhbDsg

SW5zdGl0dXRlIGZvciBJbnRlcmRpc2NpcGxpbmFyeSBSZXNlYXJjaCAoSUlJVUMpLCBVbml2ZXJz

aXR5IG9mIENvaW1icmEsIENhc2EgQ29zdGEgQWxlbWFvIC0gUG9sbyBJSSwgUnVhIEQuIEZyYW5j

aXNjbyBkZSBMZW1vcywgMzAzMC03ODkgQ29pbWJyYSwgUG9ydHVnYWwuIEVsZWN0cm9uaWMgYWRk

cmVzczogYW5hLmR1YXJ0ZUBjbmMudWMucHQuJiN4RDtDTkMtIENlbnRlciBmb3IgTmV1cm9zY2ll

bmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgMzAwNC01MTcgQ29p

bWJyYSwgUG9ydHVnYWw7IExpZmUgU2NpZW5jZXMgRGVwYXJ0bWVudCwgVW5pdmVyc2l0eSBvZiBD

b2ltYnJhLCBMYXJnbyBNYXJxdWVzIGRlIFBvbWJhbCwgMzAwNC01MTcgQ29pbWJyYSwgUG9ydHVn

YWwuJiN4RDtDTkMtIENlbnRlciBmb3IgTmV1cm9zY2llbmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVu

aXZlcnNpdHkgb2YgQ29pbWJyYSwgMzAwNC01MTcgQ29pbWJyYSwgUG9ydHVnYWw7IEluc3RpdHV0

ZSBvZiBCaW9jaGVtaXN0cnksIEZhY3VsdHkgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQ29p

bWJyYSwgMzAwNC01MDQgQ29pbWJyYSwgUG9ydHVnYWwuJiN4RDtDTkMtIENlbnRlciBmb3IgTmV1

cm9zY2llbmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgMzAwNC01

MTcgQ29pbWJyYSwgUG9ydHVnYWw7IEluc3RpdHV0ZSBvZiBQaHlzaW9sb2d5LCBGYWN1bHR5IG9m

IE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIENvaW1icmEsIDMwMDQtNTA0IENvaW1icmEsIFBvcnR1

Z2FsLiBFbGVjdHJvbmljIGFkZHJlc3M6IHBpbW9yZWlyYUBmbWVkLnVjLnB0LjwvYXV0aC1hZGRy

ZXNzPjx0aXRsZXM+PHRpdGxlPkJyYWluIGluc3VsaW4gc2lnbmFsbGluZywgZ2x1Y29zZSBtZXRh

Ym9saXNtIGFuZCBmZW1hbGVzJmFwb3M7IHJlcHJvZHVjdGl2ZSBhZ2luZzogQSBkYW5nZXJvdXMg

dHJpYWQgaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

Pk5ldXJvcGhhcm1hY29sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+TmV1cm9waGFybWFjb2xvZ3k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxw

YWdlcz4yMjMtMjQyPC9wYWdlcz48dm9sdW1lPjEzNjwvdm9sdW1lPjxudW1iZXI+UHQgQjwvbnVt

YmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+

PGtleXdvcmQ+QnJhaW4gKG1pdG9jaG9uZHJpYWwpIG1ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+RXN0cm9nZW4gc2lnbmFsbGluZzwva2V5d29yZD48a2V5d29yZD5GZW1hbGUgYWdpbmcvcmVw

cm9kdWN0aXZlIHNlbmVzY2VuY2U8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxpbiBzaWduYWxsaW5n

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5KdWwgMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE4NzMtNzA2NCAoRWxl

Y3Ryb25pYykmI3hEOzAwMjgtMzkwOCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjk0

NzEwNTU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjk0NzEwNTU8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb3BoYXJtLjIwMTguMDEu

MDQ0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdWFydGU8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxS

ZWNOdW0+Mzc0NjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjMxNzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NDY8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNjkyNSI+Mzc0Njwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RHVhcnRlLCBBLiBJLjwvYXV0aG9yPjxh

dXRob3I+U2FudG9zLCBNLiBTLjwvYXV0aG9yPjxhdXRob3I+T2xpdmVpcmEsIEMuIFIuPC9hdXRo

b3I+PGF1dGhvcj5Nb3JlaXJhLCBQLiBJLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48YXV0aC1hZGRyZXNzPkNOQy0gQ2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5kIENlbGwgQmlv

bG9neSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhLCAzMDA0LTUxNyBDb2ltYnJhLCBQb3J0dWdhbDsg

SW5zdGl0dXRlIGZvciBJbnRlcmRpc2NpcGxpbmFyeSBSZXNlYXJjaCAoSUlJVUMpLCBVbml2ZXJz

aXR5IG9mIENvaW1icmEsIENhc2EgQ29zdGEgQWxlbWFvIC0gUG9sbyBJSSwgUnVhIEQuIEZyYW5j

aXNjbyBkZSBMZW1vcywgMzAzMC03ODkgQ29pbWJyYSwgUG9ydHVnYWwuIEVsZWN0cm9uaWMgYWRk

cmVzczogYW5hLmR1YXJ0ZUBjbmMudWMucHQuJiN4RDtDTkMtIENlbnRlciBmb3IgTmV1cm9zY2ll

bmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgMzAwNC01MTcgQ29p

bWJyYSwgUG9ydHVnYWw7IExpZmUgU2NpZW5jZXMgRGVwYXJ0bWVudCwgVW5pdmVyc2l0eSBvZiBD

b2ltYnJhLCBMYXJnbyBNYXJxdWVzIGRlIFBvbWJhbCwgMzAwNC01MTcgQ29pbWJyYSwgUG9ydHVn

YWwuJiN4RDtDTkMtIENlbnRlciBmb3IgTmV1cm9zY2llbmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVu

aXZlcnNpdHkgb2YgQ29pbWJyYSwgMzAwNC01MTcgQ29pbWJyYSwgUG9ydHVnYWw7IEluc3RpdHV0

ZSBvZiBCaW9jaGVtaXN0cnksIEZhY3VsdHkgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQ29p

bWJyYSwgMzAwNC01MDQgQ29pbWJyYSwgUG9ydHVnYWwuJiN4RDtDTkMtIENlbnRlciBmb3IgTmV1

cm9zY2llbmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgMzAwNC01

MTcgQ29pbWJyYSwgUG9ydHVnYWw7IEluc3RpdHV0ZSBvZiBQaHlzaW9sb2d5LCBGYWN1bHR5IG9m

IE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIENvaW1icmEsIDMwMDQtNTA0IENvaW1icmEsIFBvcnR1

Z2FsLiBFbGVjdHJvbmljIGFkZHJlc3M6IHBpbW9yZWlyYUBmbWVkLnVjLnB0LjwvYXV0aC1hZGRy

ZXNzPjx0aXRsZXM+PHRpdGxlPkJyYWluIGluc3VsaW4gc2lnbmFsbGluZywgZ2x1Y29zZSBtZXRh

Ym9saXNtIGFuZCBmZW1hbGVzJmFwb3M7IHJlcHJvZHVjdGl2ZSBhZ2luZzogQSBkYW5nZXJvdXMg

dHJpYWQgaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

Pk5ldXJvcGhhcm1hY29sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+TmV1cm9waGFybWFjb2xvZ3k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxw

YWdlcz4yMjMtMjQyPC9wYWdlcz48dm9sdW1lPjEzNjwvdm9sdW1lPjxudW1iZXI+UHQgQjwvbnVt

YmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+

PGtleXdvcmQ+QnJhaW4gKG1pdG9jaG9uZHJpYWwpIG1ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+RXN0cm9nZW4gc2lnbmFsbGluZzwva2V5d29yZD48a2V5d29yZD5GZW1hbGUgYWdpbmcvcmVw

cm9kdWN0aXZlIHNlbmVzY2VuY2U8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxpbiBzaWduYWxsaW5n

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5KdWwgMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE4NzMtNzA2NCAoRWxl

Y3Ryb25pYykmI3hEOzAwMjgtMzkwOCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjk0

NzEwNTU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjk0NzEwNTU8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb3BoYXJtLjIwMTguMDEu

MDQ0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 317. Disappointing results were also obtained for clinical studies on anti-Aβ immunotherapy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjk4MzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI5NCwzMTg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj45ODM8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY0MCI+OTgzPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XaW5ibGFkLCBCZW5ndDwvYXV0aG9y

PjxhdXRob3I+UWl1LCBDaGVuZ3h1YW48L2F1dGhvcj48YXV0aG9yPkJhbGxhcmQsIENsaXZlPC9h

dXRob3I+PGF1dGhvcj5Kb2hhbnNzb24sIEd1bmlsbGE8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+RXZpZGVuY2UtYmFzZWQgcHJldmVudGlvbiBhbmQgdHJl

YXRtZW50IG9mIGRlbWVudGlhIOKAkyBBdXRob3JzJmFwb3M7IHJlcGx5PC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPlRoZSBMYW5jZXQgTmV1cm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBhZ2VzPjEwMDctMTAwODwvcGFnZXM+PHZvbHVtZT4xNTwvdm9sdW1lPjxudW1iZXI+MTA8L251

bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMDk8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+

PGlzYm4+MTQ3NC00NDIyPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHgu

ZG9pLm9yZy8xMC4xMDE2L3MxNDc0LTQ0MjIoMTYpMzAxMjgtNDwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9zMTQ3NC00NDIyKDE2KTMw

MTI4LTQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPkFua2FyY3JvbmE8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNOdW0+MzU5NDwvUmVj

TnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MzU5NDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxr

ZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIg

dGltZXN0YW1wPSIxNTM1OTE2MDcxIj4zNTk0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5BbmthcmNyb25hLCBNLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1

dGhvcj48YXV0aG9yPk1vbnRlaXJvLCBDLjwvYXV0aG9yPjxhdXRob3I+RmVhcm5zLCBDLjwvYXV0

aG9yPjxhdXRob3I+UG93ZXJzLCBFLiBULjwvYXV0aG9yPjxhdXRob3I+Sm9oYW5zc29uLCBKLjwv

YXV0aG9yPjxhdXRob3I+V2VzdGVybWFyaywgRy4gVC48L2F1dGhvcj48YXV0aG9yPlByZXN0bywg

Si48L2F1dGhvcj48YXV0aG9yPkVyaWN6b24sIEIuIEcuPC9hdXRob3I+PGF1dGhvcj5LZWxseSwg

Si4gVy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBh

cnRtZW50IG9mIE5ldXJvYmlvbG9neSBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBEaXZpc2lv

biBvZiBOZXVyb2dlcmlhdHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBLYXJv

bGluc2thIEluc3RpdHV0ZXQsIEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIENo

ZW1pc3RyeSwgVGhlIFNrYWdncyBJbnN0aXR1dGUgZm9yIENoZW1pY2FsIEJpb2xvZ3ksIExhIEpv

bGxhLCBDQSwgVVNBLiYjeEQ7RGVwYXJ0bWVudCBvZiBNb2xlY3VsYXIgYW5kIEV4cGVyaW1lbnRh

bCBNZWRpY2luZSwgVGhlIFNjcmlwcHMgUmVzZWFyY2ggSW5zdGl0dXRlLCBMYSBKb2xsYSwgQ0Es

IFVTQS4mI3hEO0RlcGFydG1lbnQgb2YgTWVkaWNhbCBDZWxsIEJpb2xvZ3ksIFVwcHNhbGEgVW5p

dmVyc2l0eSwgVXBwc2FsYSwgU3dlZGVuLiYjeEQ7RGl2aXNpb24gb2YgVHJhbnNwbGFudGF0aW9u

IFN1cmdlcnksIEthcm9saW5za2EgVW5pdmVyc2l0eSBIb3NwaXRhbCwgU3RvY2tob2xtLCBTd2Vk

ZW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Q3VycmVudCBhbmQgZnV0dXJlIHRyZWF0

bWVudCBvZiBhbXlsb2lkIGRpc2Vhc2VzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogSW50ZXJu

IE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkog

SW50ZXJuIE1lZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjE3Ny0yMDI8L3BhZ2Vz

Pjx2b2x1bWU+MjgwPC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3Jk

PkFsemhlaW1lciBEaXNlYXNlL3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZC9waHlz

aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWRvc2lzL3BoeXNpb3BhdGhvbG9neS8qdGhl

cmFweTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkRpYWJldGVz

IE1lbGxpdHVzLCBUeXBlIDIvdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdv

cmQ+PGtleXdvcmQ+TGl2ZXIgVHJhbnNwbGFudGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlByZWFs

YnVtaW4vcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD4qQWx6aGVpbWVyJmFwb3M7cyBkaXNl

YXNlPC9rZXl3b3JkPjxrZXl3b3JkPiphbXlsb2lkb3Npczwva2V5d29yZD48a2V5d29yZD4qdHJh

bnN0aHlyZXRpbjwva2V5d29yZD48a2V5d29yZD4qdHJlYXRtZW50PC9rZXl3b3JkPjxrZXl3b3Jk

Pip0eXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNjwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPkF1ZzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju

PjEzNjUtMjc5NiAoRWxlY3Ryb25pYykmI3hEOzA5NTQtNjgyMCAoTGlua2luZyk8L2lzYm4+PGFj

Y2Vzc2lvbi1udW0+MjcxNjU1MTc8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48

dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjcxNjU1MTc8L3VybD48L3Jl

bGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNDk1NjU1MzwvY3VzdG9tMj48ZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+MTAuMTExMS9qb2ltLjEyNTA2PC9lbGVjdHJvbmljLXJlc291cmNlLW51

bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjk4MzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI5NCwzMTg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj45ODM8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY0MCI+OTgzPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XaW5ibGFkLCBCZW5ndDwvYXV0aG9y

PjxhdXRob3I+UWl1LCBDaGVuZ3h1YW48L2F1dGhvcj48YXV0aG9yPkJhbGxhcmQsIENsaXZlPC9h

dXRob3I+PGF1dGhvcj5Kb2hhbnNzb24sIEd1bmlsbGE8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+RXZpZGVuY2UtYmFzZWQgcHJldmVudGlvbiBhbmQgdHJl

YXRtZW50IG9mIGRlbWVudGlhIOKAkyBBdXRob3JzJmFwb3M7IHJlcGx5PC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPlRoZSBMYW5jZXQgTmV1cm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBhZ2VzPjEwMDctMTAwODwvcGFnZXM+PHZvbHVtZT4xNTwvdm9sdW1lPjxudW1iZXI+MTA8L251

bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMDk8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+

PGlzYm4+MTQ3NC00NDIyPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHgu

ZG9pLm9yZy8xMC4xMDE2L3MxNDc0LTQ0MjIoMTYpMzAxMjgtNDwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9zMTQ3NC00NDIyKDE2KTMw

MTI4LTQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPkFua2FyY3JvbmE8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNOdW0+MzU5NDwvUmVj

TnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MzU5NDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxr

ZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIg

dGltZXN0YW1wPSIxNTM1OTE2MDcxIj4zNTk0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5BbmthcmNyb25hLCBNLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1

dGhvcj48YXV0aG9yPk1vbnRlaXJvLCBDLjwvYXV0aG9yPjxhdXRob3I+RmVhcm5zLCBDLjwvYXV0

aG9yPjxhdXRob3I+UG93ZXJzLCBFLiBULjwvYXV0aG9yPjxhdXRob3I+Sm9oYW5zc29uLCBKLjwv

YXV0aG9yPjxhdXRob3I+V2VzdGVybWFyaywgRy4gVC48L2F1dGhvcj48YXV0aG9yPlByZXN0bywg

Si48L2F1dGhvcj48YXV0aG9yPkVyaWN6b24sIEIuIEcuPC9hdXRob3I+PGF1dGhvcj5LZWxseSwg

Si4gVy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBh

cnRtZW50IG9mIE5ldXJvYmlvbG9neSBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBEaXZpc2lv

biBvZiBOZXVyb2dlcmlhdHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBLYXJv

bGluc2thIEluc3RpdHV0ZXQsIEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIENo

ZW1pc3RyeSwgVGhlIFNrYWdncyBJbnN0aXR1dGUgZm9yIENoZW1pY2FsIEJpb2xvZ3ksIExhIEpv

bGxhLCBDQSwgVVNBLiYjeEQ7RGVwYXJ0bWVudCBvZiBNb2xlY3VsYXIgYW5kIEV4cGVyaW1lbnRh

bCBNZWRpY2luZSwgVGhlIFNjcmlwcHMgUmVzZWFyY2ggSW5zdGl0dXRlLCBMYSBKb2xsYSwgQ0Es

IFVTQS4mI3hEO0RlcGFydG1lbnQgb2YgTWVkaWNhbCBDZWxsIEJpb2xvZ3ksIFVwcHNhbGEgVW5p

dmVyc2l0eSwgVXBwc2FsYSwgU3dlZGVuLiYjeEQ7RGl2aXNpb24gb2YgVHJhbnNwbGFudGF0aW9u

IFN1cmdlcnksIEthcm9saW5za2EgVW5pdmVyc2l0eSBIb3NwaXRhbCwgU3RvY2tob2xtLCBTd2Vk

ZW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Q3VycmVudCBhbmQgZnV0dXJlIHRyZWF0

bWVudCBvZiBhbXlsb2lkIGRpc2Vhc2VzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogSW50ZXJu

IE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkog

SW50ZXJuIE1lZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjE3Ny0yMDI8L3BhZ2Vz

Pjx2b2x1bWU+MjgwPC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3Jk

PkFsemhlaW1lciBEaXNlYXNlL3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZC9waHlz

aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWRvc2lzL3BoeXNpb3BhdGhvbG9neS8qdGhl

cmFweTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkRpYWJldGVz

IE1lbGxpdHVzLCBUeXBlIDIvdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdv

cmQ+PGtleXdvcmQ+TGl2ZXIgVHJhbnNwbGFudGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlByZWFs

YnVtaW4vcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD4qQWx6aGVpbWVyJmFwb3M7cyBkaXNl

YXNlPC9rZXl3b3JkPjxrZXl3b3JkPiphbXlsb2lkb3Npczwva2V5d29yZD48a2V5d29yZD4qdHJh

bnN0aHlyZXRpbjwva2V5d29yZD48a2V5d29yZD4qdHJlYXRtZW50PC9rZXl3b3JkPjxrZXl3b3Jk

Pip0eXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNjwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPkF1ZzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju

PjEzNjUtMjc5NiAoRWxlY3Ryb25pYykmI3hEOzA5NTQtNjgyMCAoTGlua2luZyk8L2lzYm4+PGFj

Y2Vzc2lvbi1udW0+MjcxNjU1MTc8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48

dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjcxNjU1MTc8L3VybD48L3Jl

bGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNDk1NjU1MzwvY3VzdG9tMj48ZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+MTAuMTExMS9qb2ltLjEyNTA2PC9lbGVjdHJvbmljLXJlc291cmNlLW51

bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 294,318 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdWFydGU8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxS

ZWNOdW0+Mzc0NjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjMxNzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NDY8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNjkyNSI+Mzc0Njwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RHVhcnRlLCBBLiBJLjwvYXV0aG9yPjxh

dXRob3I+U2FudG9zLCBNLiBTLjwvYXV0aG9yPjxhdXRob3I+T2xpdmVpcmEsIEMuIFIuPC9hdXRo

b3I+PGF1dGhvcj5Nb3JlaXJhLCBQLiBJLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48YXV0aC1hZGRyZXNzPkNOQy0gQ2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5kIENlbGwgQmlv

bG9neSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhLCAzMDA0LTUxNyBDb2ltYnJhLCBQb3J0dWdhbDsg

SW5zdGl0dXRlIGZvciBJbnRlcmRpc2NpcGxpbmFyeSBSZXNlYXJjaCAoSUlJVUMpLCBVbml2ZXJz

aXR5IG9mIENvaW1icmEsIENhc2EgQ29zdGEgQWxlbWFvIC0gUG9sbyBJSSwgUnVhIEQuIEZyYW5j

aXNjbyBkZSBMZW1vcywgMzAzMC03ODkgQ29pbWJyYSwgUG9ydHVnYWwuIEVsZWN0cm9uaWMgYWRk

cmVzczogYW5hLmR1YXJ0ZUBjbmMudWMucHQuJiN4RDtDTkMtIENlbnRlciBmb3IgTmV1cm9zY2ll

bmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgMzAwNC01MTcgQ29p

bWJyYSwgUG9ydHVnYWw7IExpZmUgU2NpZW5jZXMgRGVwYXJ0bWVudCwgVW5pdmVyc2l0eSBvZiBD

b2ltYnJhLCBMYXJnbyBNYXJxdWVzIGRlIFBvbWJhbCwgMzAwNC01MTcgQ29pbWJyYSwgUG9ydHVn

YWwuJiN4RDtDTkMtIENlbnRlciBmb3IgTmV1cm9zY2llbmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVu

aXZlcnNpdHkgb2YgQ29pbWJyYSwgMzAwNC01MTcgQ29pbWJyYSwgUG9ydHVnYWw7IEluc3RpdHV0

ZSBvZiBCaW9jaGVtaXN0cnksIEZhY3VsdHkgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQ29p

bWJyYSwgMzAwNC01MDQgQ29pbWJyYSwgUG9ydHVnYWwuJiN4RDtDTkMtIENlbnRlciBmb3IgTmV1

cm9zY2llbmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgMzAwNC01

MTcgQ29pbWJyYSwgUG9ydHVnYWw7IEluc3RpdHV0ZSBvZiBQaHlzaW9sb2d5LCBGYWN1bHR5IG9m

IE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIENvaW1icmEsIDMwMDQtNTA0IENvaW1icmEsIFBvcnR1

Z2FsLiBFbGVjdHJvbmljIGFkZHJlc3M6IHBpbW9yZWlyYUBmbWVkLnVjLnB0LjwvYXV0aC1hZGRy

ZXNzPjx0aXRsZXM+PHRpdGxlPkJyYWluIGluc3VsaW4gc2lnbmFsbGluZywgZ2x1Y29zZSBtZXRh

Ym9saXNtIGFuZCBmZW1hbGVzJmFwb3M7IHJlcHJvZHVjdGl2ZSBhZ2luZzogQSBkYW5nZXJvdXMg

dHJpYWQgaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

Pk5ldXJvcGhhcm1hY29sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+TmV1cm9waGFybWFjb2xvZ3k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxw

YWdlcz4yMjMtMjQyPC9wYWdlcz48dm9sdW1lPjEzNjwvdm9sdW1lPjxudW1iZXI+UHQgQjwvbnVt

YmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+

PGtleXdvcmQ+QnJhaW4gKG1pdG9jaG9uZHJpYWwpIG1ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+RXN0cm9nZW4gc2lnbmFsbGluZzwva2V5d29yZD48a2V5d29yZD5GZW1hbGUgYWdpbmcvcmVw

cm9kdWN0aXZlIHNlbmVzY2VuY2U8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxpbiBzaWduYWxsaW5n

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5KdWwgMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE4NzMtNzA2NCAoRWxl

Y3Ryb25pYykmI3hEOzAwMjgtMzkwOCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjk0

NzEwNTU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjk0NzEwNTU8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb3BoYXJtLjIwMTguMDEu

MDQ0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdWFydGU8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxS

ZWNOdW0+Mzc0NjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjMxNzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NDY8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNjkyNSI+Mzc0Njwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RHVhcnRlLCBBLiBJLjwvYXV0aG9yPjxh

dXRob3I+U2FudG9zLCBNLiBTLjwvYXV0aG9yPjxhdXRob3I+T2xpdmVpcmEsIEMuIFIuPC9hdXRo

b3I+PGF1dGhvcj5Nb3JlaXJhLCBQLiBJLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48YXV0aC1hZGRyZXNzPkNOQy0gQ2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5kIENlbGwgQmlv

bG9neSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhLCAzMDA0LTUxNyBDb2ltYnJhLCBQb3J0dWdhbDsg

SW5zdGl0dXRlIGZvciBJbnRlcmRpc2NpcGxpbmFyeSBSZXNlYXJjaCAoSUlJVUMpLCBVbml2ZXJz

aXR5IG9mIENvaW1icmEsIENhc2EgQ29zdGEgQWxlbWFvIC0gUG9sbyBJSSwgUnVhIEQuIEZyYW5j

aXNjbyBkZSBMZW1vcywgMzAzMC03ODkgQ29pbWJyYSwgUG9ydHVnYWwuIEVsZWN0cm9uaWMgYWRk

cmVzczogYW5hLmR1YXJ0ZUBjbmMudWMucHQuJiN4RDtDTkMtIENlbnRlciBmb3IgTmV1cm9zY2ll

bmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgMzAwNC01MTcgQ29p

bWJyYSwgUG9ydHVnYWw7IExpZmUgU2NpZW5jZXMgRGVwYXJ0bWVudCwgVW5pdmVyc2l0eSBvZiBD

b2ltYnJhLCBMYXJnbyBNYXJxdWVzIGRlIFBvbWJhbCwgMzAwNC01MTcgQ29pbWJyYSwgUG9ydHVn

YWwuJiN4RDtDTkMtIENlbnRlciBmb3IgTmV1cm9zY2llbmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVu

aXZlcnNpdHkgb2YgQ29pbWJyYSwgMzAwNC01MTcgQ29pbWJyYSwgUG9ydHVnYWw7IEluc3RpdHV0

ZSBvZiBCaW9jaGVtaXN0cnksIEZhY3VsdHkgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQ29p

bWJyYSwgMzAwNC01MDQgQ29pbWJyYSwgUG9ydHVnYWwuJiN4RDtDTkMtIENlbnRlciBmb3IgTmV1

cm9zY2llbmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgMzAwNC01

MTcgQ29pbWJyYSwgUG9ydHVnYWw7IEluc3RpdHV0ZSBvZiBQaHlzaW9sb2d5LCBGYWN1bHR5IG9m

IE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIENvaW1icmEsIDMwMDQtNTA0IENvaW1icmEsIFBvcnR1

Z2FsLiBFbGVjdHJvbmljIGFkZHJlc3M6IHBpbW9yZWlyYUBmbWVkLnVjLnB0LjwvYXV0aC1hZGRy

ZXNzPjx0aXRsZXM+PHRpdGxlPkJyYWluIGluc3VsaW4gc2lnbmFsbGluZywgZ2x1Y29zZSBtZXRh

Ym9saXNtIGFuZCBmZW1hbGVzJmFwb3M7IHJlcHJvZHVjdGl2ZSBhZ2luZzogQSBkYW5nZXJvdXMg

dHJpYWQgaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

Pk5ldXJvcGhhcm1hY29sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+TmV1cm9waGFybWFjb2xvZ3k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxw

YWdlcz4yMjMtMjQyPC9wYWdlcz48dm9sdW1lPjEzNjwvdm9sdW1lPjxudW1iZXI+UHQgQjwvbnVt

YmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+

PGtleXdvcmQ+QnJhaW4gKG1pdG9jaG9uZHJpYWwpIG1ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+RXN0cm9nZW4gc2lnbmFsbGluZzwva2V5d29yZD48a2V5d29yZD5GZW1hbGUgYWdpbmcvcmVw

cm9kdWN0aXZlIHNlbmVzY2VuY2U8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxpbiBzaWduYWxsaW5n

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5KdWwgMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE4NzMtNzA2NCAoRWxl

Y3Ryb25pYykmI3hEOzAwMjgtMzkwOCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjk0

NzEwNTU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjk0NzEwNTU8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb3BoYXJtLjIwMTguMDEu

MDQ0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 317. On the other hand, Tau kinase inhibitors (e.g. against GSK3β) were beneficial in vivo PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaXNuaWV3c2tpPC9BdXRob3I+PFllYXI+MjAxNTwvWWVh

cj48UmVjTnVtPjM3NDI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2Ny

aXB0Ij4zMTk8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zNzQyPC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTYyMjAiPjM3NDI8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPldpc25pZXdza2ksIFQuPC9hdXRo

b3I+PGF1dGhvcj5Hb25pLCBGLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0

aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBDZW50ZXIgZm9yIENvZ25pdGl2ZSBO

ZXVyb2xvZ3ksIE5ldyBZb3JrIFVuaXZlcnNpdHkgU2Nob29sIG9mIE1lZGljaW5lLCBBbGV4YW5k

cmlhIEVSU1AsIDQ1MCBFYXN0IDI5KHRoKSBTdHJlZXQsIE5ldyBZb3JrLCBOWSAxMDAxNiwgVVNB

OyBEZXBhcnRtZW50IG9mIFBhdGhvbG9neSwgTmV3IFlvcmsgVW5pdmVyc2l0eSBTY2hvb2wgb2Yg

TWVkaWNpbmUsIEFsZXhhbmRyaWEgRVJTUCwgNDUwIEVhc3QgMjkodGgpIFN0cmVldCwgTmV3IFlv

cmssIE5ZIDEwMDE2LCBVU0E7IERlcGFydG1lbnQgb2YgUHN5Y2hpYXRyeSwgTmV3IFlvcmsgVW5p

dmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUsIEFsZXhhbmRyaWEgRVJTUCwgNDUwIEVhc3QgMjko

dGgpIFN0cmVldCwgTmV3IFlvcmssIE5ZIDEwMDE2LCBVU0EuIEVsZWN0cm9uaWMgYWRkcmVzczog

dGhvbWFzLndpc25pZXdza2lAbnl1bWMub3JnLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ks

IENlbnRlciBmb3IgQ29nbml0aXZlIE5ldXJvbG9neSwgTmV3IFlvcmsgVW5pdmVyc2l0eSBTY2hv

b2wgb2YgTWVkaWNpbmUsIEFsZXhhbmRyaWEgRVJTUCwgNDUwIEVhc3QgMjkodGgpIFN0cmVldCwg

TmV3IFlvcmssIE5ZIDEwMDE2LCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+SW1t

dW5vdGhlcmFwZXV0aWMgYXBwcm9hY2hlcyBmb3IgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5ldXJvbjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxw

ZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvbjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBh

Z2VzPjExNjItNzY8L3BhZ2VzPjx2b2x1bWU+ODU8L3ZvbHVtZT48bnVtYmVyPjY8L251bWJlcj48

a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvZHJ1ZyB0aGVyYXB5LyppbW11bm9s

b2d5L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvKmlt

bXVub2xvZ3kvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxr

ZXl3b3JkPkFudGlib2RpZXMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkRpc2Vh

c2UgTW9kZWxzLCBBbmltYWw8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3

b3JkPipJbW11bm90aGVyYXB5L21ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5z

LyppbW11bm9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+

MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1hciAxODwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxpc2JuPjEwOTctNDE5OSAoRWxlY3Ryb25pYykmI3hEOzA4OTYtNjI3MyAoTGlua2luZyk8

L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjU3ODk3NTM8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0

ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjU3ODk3NTM8

L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNDM2NjYxODwvY3VzdG9tMj48

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLm5ldXJvbi4yMDE0LjEyLjA2NDwvZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaXNuaWV3c2tpPC9BdXRob3I+PFllYXI+MjAxNTwvWWVh

cj48UmVjTnVtPjM3NDI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2Ny

aXB0Ij4zMTk8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zNzQyPC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTYyMjAiPjM3NDI8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPldpc25pZXdza2ksIFQuPC9hdXRo

b3I+PGF1dGhvcj5Hb25pLCBGLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0

aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBDZW50ZXIgZm9yIENvZ25pdGl2ZSBO

ZXVyb2xvZ3ksIE5ldyBZb3JrIFVuaXZlcnNpdHkgU2Nob29sIG9mIE1lZGljaW5lLCBBbGV4YW5k

cmlhIEVSU1AsIDQ1MCBFYXN0IDI5KHRoKSBTdHJlZXQsIE5ldyBZb3JrLCBOWSAxMDAxNiwgVVNB

OyBEZXBhcnRtZW50IG9mIFBhdGhvbG9neSwgTmV3IFlvcmsgVW5pdmVyc2l0eSBTY2hvb2wgb2Yg

TWVkaWNpbmUsIEFsZXhhbmRyaWEgRVJTUCwgNDUwIEVhc3QgMjkodGgpIFN0cmVldCwgTmV3IFlv

cmssIE5ZIDEwMDE2LCBVU0E7IERlcGFydG1lbnQgb2YgUHN5Y2hpYXRyeSwgTmV3IFlvcmsgVW5p

dmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUsIEFsZXhhbmRyaWEgRVJTUCwgNDUwIEVhc3QgMjko

dGgpIFN0cmVldCwgTmV3IFlvcmssIE5ZIDEwMDE2LCBVU0EuIEVsZWN0cm9uaWMgYWRkcmVzczog

dGhvbWFzLndpc25pZXdza2lAbnl1bWMub3JnLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ks

IENlbnRlciBmb3IgQ29nbml0aXZlIE5ldXJvbG9neSwgTmV3IFlvcmsgVW5pdmVyc2l0eSBTY2hv

b2wgb2YgTWVkaWNpbmUsIEFsZXhhbmRyaWEgRVJTUCwgNDUwIEVhc3QgMjkodGgpIFN0cmVldCwg

TmV3IFlvcmssIE5ZIDEwMDE2LCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+SW1t

dW5vdGhlcmFwZXV0aWMgYXBwcm9hY2hlcyBmb3IgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5ldXJvbjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxw

ZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvbjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBh

Z2VzPjExNjItNzY8L3BhZ2VzPjx2b2x1bWU+ODU8L3ZvbHVtZT48bnVtYmVyPjY8L251bWJlcj48

a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvZHJ1ZyB0aGVyYXB5LyppbW11bm9s

b2d5L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvKmlt

bXVub2xvZ3kvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxr

ZXl3b3JkPkFudGlib2RpZXMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkRpc2Vh

c2UgTW9kZWxzLCBBbmltYWw8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3

b3JkPipJbW11bm90aGVyYXB5L21ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5z

LyppbW11bm9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+

MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1hciAxODwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxpc2JuPjEwOTctNDE5OSAoRWxlY3Ryb25pYykmI3hEOzA4OTYtNjI3MyAoTGlua2luZyk8

L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjU3ODk3NTM8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0

ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjU3ODk3NTM8

L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNDM2NjYxODwvY3VzdG9tMj48

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLm5ldXJvbi4yMDE0LjEyLjA2NDwvZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 319, but in a Phase IIb trial with mild to moderate AD patients Tideglusib (a GSK3β inhibitor) did not reach its primary cognitive endpoint ADDIN EN.CITE <EndNote><Cite><Author>Medina</Author><Year>2010</Year><RecNum>3745</RecNum><DisplayText><style face="superscript">320</style></DisplayText><record><rec-number>3745</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535916304">3745</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Medina, M.</author><author>Avila, J.</author></authors></contributors><auth-address>Noscira S.A, Avenida de Industria 52, 28760 Tres Cantos (Madrid), Spain.</auth-address><titles><title>Glycogen synthase kinase-3 (GSK-3) inhibitors for the treatment of Alzheimer&apos;s disease</title><secondary-title>Curr Pharm Des</secondary-title></titles><pages>2790-8</pages><volume>16</volume><number>25</number><keywords><keyword>Alzheimer Disease/*drug therapy/enzymology/*pathology</keyword><keyword>Animals</keyword><keyword>Drug Delivery Systems/methods</keyword><keyword>Glycogen Synthase Kinase 3/*antagonists &amp; inhibitors/metabolism</keyword><keyword>Humans</keyword><keyword>Lithium Compounds/pharmacology</keyword><keyword>Models, Biological</keyword><keyword>Nerve Degeneration/*drug therapy/enzymology</keyword><keyword>Protein Kinase Inhibitors/pharmacology/*therapeutic use</keyword></keywords><dates><year>2010</year></dates><isbn>1873-4286 (Electronic)&#xD;1381-6128 (Linking)</isbn><accession-num>20698823</accession-num><urls><related-urls><url>. Hopefully ongoing or future clinical trials on immunotherapy against P-Tau or Aβ drugs show better outcomes.Opportunities in Drug Development in ADThe “charm” of repurposing efficient anti-T2D drugs to recover brain insulin signaling and glucose metabolism in AD.The failures described above point to the urgent need to unveil the precise etiology and pathophysiological mechanisms of AD, as these will be also crucial to discover more accurate diagnostic and efficient therapeutic tools PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjk4MzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI5NCwzMTc8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj45ODM8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY0MCI+OTgzPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XaW5ibGFkLCBCZW5ndDwvYXV0aG9y

PjxhdXRob3I+UWl1LCBDaGVuZ3h1YW48L2F1dGhvcj48YXV0aG9yPkJhbGxhcmQsIENsaXZlPC9h

dXRob3I+PGF1dGhvcj5Kb2hhbnNzb24sIEd1bmlsbGE8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+RXZpZGVuY2UtYmFzZWQgcHJldmVudGlvbiBhbmQgdHJl

YXRtZW50IG9mIGRlbWVudGlhIOKAkyBBdXRob3JzJmFwb3M7IHJlcGx5PC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPlRoZSBMYW5jZXQgTmV1cm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBhZ2VzPjEwMDctMTAwODwvcGFnZXM+PHZvbHVtZT4xNTwvdm9sdW1lPjxudW1iZXI+MTA8L251

bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMDk8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+

PGlzYm4+MTQ3NC00NDIyPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHgu

ZG9pLm9yZy8xMC4xMDE2L3MxNDc0LTQ0MjIoMTYpMzAxMjgtNDwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9zMTQ3NC00NDIyKDE2KTMw

MTI4LTQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPkR1YXJ0ZTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJlY051bT4zNzQ2PC9SZWNOdW0+

PHJlY29yZD48cmVjLW51bWJlcj4zNzQ2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBh

cHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1l

c3RhbXA9IjE1MzU5MTY5MjUiPjM3NDY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt

ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48

YXV0aG9yPkR1YXJ0ZSwgQS4gSS48L2F1dGhvcj48YXV0aG9yPlNhbnRvcywgTS4gUy48L2F1dGhv

cj48YXV0aG9yPk9saXZlaXJhLCBDLiBSLjwvYXV0aG9yPjxhdXRob3I+TW9yZWlyYSwgUC4gSS48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DTkMtIENlbnRl

ciBmb3IgTmV1cm9zY2llbmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJy

YSwgMzAwNC01MTcgQ29pbWJyYSwgUG9ydHVnYWw7IEluc3RpdHV0ZSBmb3IgSW50ZXJkaXNjaXBs

aW5hcnkgUmVzZWFyY2ggKElJSVVDKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhLCBDYXNhIENvc3Rh

IEFsZW1hbyAtIFBvbG8gSUksIFJ1YSBELiBGcmFuY2lzY28gZGUgTGVtb3MsIDMwMzAtNzg5IENv

aW1icmEsIFBvcnR1Z2FsLiBFbGVjdHJvbmljIGFkZHJlc3M6IGFuYS5kdWFydGVAY25jLnVjLnB0

LiYjeEQ7Q05DLSBDZW50ZXIgZm9yIE5ldXJvc2NpZW5jZSBhbmQgQ2VsbCBCaW9sb2d5LCBVbml2

ZXJzaXR5IG9mIENvaW1icmEsIDMwMDQtNTE3IENvaW1icmEsIFBvcnR1Z2FsOyBMaWZlIFNjaWVu

Y2VzIERlcGFydG1lbnQsIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgTGFyZ28gTWFycXVlcyBkZSBQ

b21iYWwsIDMwMDQtNTE3IENvaW1icmEsIFBvcnR1Z2FsLiYjeEQ7Q05DLSBDZW50ZXIgZm9yIE5l

dXJvc2NpZW5jZSBhbmQgQ2VsbCBCaW9sb2d5LCBVbml2ZXJzaXR5IG9mIENvaW1icmEsIDMwMDQt

NTE3IENvaW1icmEsIFBvcnR1Z2FsOyBJbnN0aXR1dGUgb2YgQmlvY2hlbWlzdHJ5LCBGYWN1bHR5

IG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIENvaW1icmEsIDMwMDQtNTA0IENvaW1icmEsIFBv

cnR1Z2FsLiYjeEQ7Q05DLSBDZW50ZXIgZm9yIE5ldXJvc2NpZW5jZSBhbmQgQ2VsbCBCaW9sb2d5

LCBVbml2ZXJzaXR5IG9mIENvaW1icmEsIDMwMDQtNTE3IENvaW1icmEsIFBvcnR1Z2FsOyBJbnN0

aXR1dGUgb2YgUGh5c2lvbG9neSwgRmFjdWx0eSBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBD

b2ltYnJhLCAzMDA0LTUwNCBDb2ltYnJhLCBQb3J0dWdhbC4gRWxlY3Ryb25pYyBhZGRyZXNzOiBw

aW1vcmVpcmFAZm1lZC51Yy5wdC48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5CcmFpbiBp

bnN1bGluIHNpZ25hbGxpbmcsIGdsdWNvc2UgbWV0YWJvbGlzbSBhbmQgZmVtYWxlcyZhcG9zOyBy

ZXByb2R1Y3RpdmUgYWdpbmc6IEEgZGFuZ2Vyb3VzIHRyaWFkIGluIEFsemhlaW1lciZhcG9zO3Mg

ZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb3BoYXJtYWNvbG9neTwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvcGhhcm1hY29s

b2d5PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjIzLTI0MjwvcGFnZXM+PHZvbHVt

ZT4xMzY8L3ZvbHVtZT48bnVtYmVyPlB0IEI8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6

aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluIChtaXRvY2hvbmRy

aWFsKSBtZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkVzdHJvZ2VuIHNpZ25hbGxpbmc8L2tl

eXdvcmQ+PGtleXdvcmQ+RmVtYWxlIGFnaW5nL3JlcHJvZHVjdGl2ZSBzZW5lc2NlbmNlPC9rZXl3

b3JkPjxrZXl3b3JkPkluc3VsaW4gc2lnbmFsbGluZzwva2V5d29yZD48L2tleXdvcmRzPjxkYXRl

cz48eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVsIDE8L2RhdGU+PC9wdWItZGF0

ZXM+PC9kYXRlcz48aXNibj4xODczLTcwNjQgKEVsZWN0cm9uaWMpJiN4RDswMDI4LTM5MDggKExp

bmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5NDcxMDU1PC9hY2Nlc3Npb24tbnVtPjx1cmxz

PjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI5

NDcxMDU1PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4xMDE2L2oubmV1cm9waGFybS4yMDE4LjAxLjA0NDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjk4MzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI5NCwzMTc8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj45ODM8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjg2NTY0MCI+OTgzPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XaW5ibGFkLCBCZW5ndDwvYXV0aG9y

PjxhdXRob3I+UWl1LCBDaGVuZ3h1YW48L2F1dGhvcj48YXV0aG9yPkJhbGxhcmQsIENsaXZlPC9h

dXRob3I+PGF1dGhvcj5Kb2hhbnNzb24sIEd1bmlsbGE8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+RXZpZGVuY2UtYmFzZWQgcHJldmVudGlvbiBhbmQgdHJl

YXRtZW50IG9mIGRlbWVudGlhIOKAkyBBdXRob3JzJmFwb3M7IHJlcGx5PC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPlRoZSBMYW5jZXQgTmV1cm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBhZ2VzPjEwMDctMTAwODwvcGFnZXM+PHZvbHVtZT4xNTwvdm9sdW1lPjxudW1iZXI+MTA8L251

bWJlcj48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTYvMDk8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+

PGlzYm4+MTQ3NC00NDIyPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHgu

ZG9pLm9yZy8xMC4xMDE2L3MxNDc0LTQ0MjIoMTYpMzAxMjgtNDwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9zMTQ3NC00NDIyKDE2KTMw

MTI4LTQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPkR1YXJ0ZTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJlY051bT4zNzQ2PC9SZWNOdW0+

PHJlY29yZD48cmVjLW51bWJlcj4zNzQ2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBh

cHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1l

c3RhbXA9IjE1MzU5MTY5MjUiPjM3NDY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt

ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48

YXV0aG9yPkR1YXJ0ZSwgQS4gSS48L2F1dGhvcj48YXV0aG9yPlNhbnRvcywgTS4gUy48L2F1dGhv

cj48YXV0aG9yPk9saXZlaXJhLCBDLiBSLjwvYXV0aG9yPjxhdXRob3I+TW9yZWlyYSwgUC4gSS48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DTkMtIENlbnRl

ciBmb3IgTmV1cm9zY2llbmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJy

YSwgMzAwNC01MTcgQ29pbWJyYSwgUG9ydHVnYWw7IEluc3RpdHV0ZSBmb3IgSW50ZXJkaXNjaXBs

aW5hcnkgUmVzZWFyY2ggKElJSVVDKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhLCBDYXNhIENvc3Rh

IEFsZW1hbyAtIFBvbG8gSUksIFJ1YSBELiBGcmFuY2lzY28gZGUgTGVtb3MsIDMwMzAtNzg5IENv

aW1icmEsIFBvcnR1Z2FsLiBFbGVjdHJvbmljIGFkZHJlc3M6IGFuYS5kdWFydGVAY25jLnVjLnB0

LiYjeEQ7Q05DLSBDZW50ZXIgZm9yIE5ldXJvc2NpZW5jZSBhbmQgQ2VsbCBCaW9sb2d5LCBVbml2

ZXJzaXR5IG9mIENvaW1icmEsIDMwMDQtNTE3IENvaW1icmEsIFBvcnR1Z2FsOyBMaWZlIFNjaWVu

Y2VzIERlcGFydG1lbnQsIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgTGFyZ28gTWFycXVlcyBkZSBQ

b21iYWwsIDMwMDQtNTE3IENvaW1icmEsIFBvcnR1Z2FsLiYjeEQ7Q05DLSBDZW50ZXIgZm9yIE5l

dXJvc2NpZW5jZSBhbmQgQ2VsbCBCaW9sb2d5LCBVbml2ZXJzaXR5IG9mIENvaW1icmEsIDMwMDQt

NTE3IENvaW1icmEsIFBvcnR1Z2FsOyBJbnN0aXR1dGUgb2YgQmlvY2hlbWlzdHJ5LCBGYWN1bHR5

IG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIENvaW1icmEsIDMwMDQtNTA0IENvaW1icmEsIFBv

cnR1Z2FsLiYjeEQ7Q05DLSBDZW50ZXIgZm9yIE5ldXJvc2NpZW5jZSBhbmQgQ2VsbCBCaW9sb2d5

LCBVbml2ZXJzaXR5IG9mIENvaW1icmEsIDMwMDQtNTE3IENvaW1icmEsIFBvcnR1Z2FsOyBJbnN0

aXR1dGUgb2YgUGh5c2lvbG9neSwgRmFjdWx0eSBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBD

b2ltYnJhLCAzMDA0LTUwNCBDb2ltYnJhLCBQb3J0dWdhbC4gRWxlY3Ryb25pYyBhZGRyZXNzOiBw

aW1vcmVpcmFAZm1lZC51Yy5wdC48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5CcmFpbiBp

bnN1bGluIHNpZ25hbGxpbmcsIGdsdWNvc2UgbWV0YWJvbGlzbSBhbmQgZmVtYWxlcyZhcG9zOyBy

ZXByb2R1Y3RpdmUgYWdpbmc6IEEgZGFuZ2Vyb3VzIHRyaWFkIGluIEFsemhlaW1lciZhcG9zO3Mg

ZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb3BoYXJtYWNvbG9neTwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvcGhhcm1hY29s

b2d5PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjIzLTI0MjwvcGFnZXM+PHZvbHVt

ZT4xMzY8L3ZvbHVtZT48bnVtYmVyPlB0IEI8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6

aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluIChtaXRvY2hvbmRy

aWFsKSBtZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkVzdHJvZ2VuIHNpZ25hbGxpbmc8L2tl

eXdvcmQ+PGtleXdvcmQ+RmVtYWxlIGFnaW5nL3JlcHJvZHVjdGl2ZSBzZW5lc2NlbmNlPC9rZXl3

b3JkPjxrZXl3b3JkPkluc3VsaW4gc2lnbmFsbGluZzwva2V5d29yZD48L2tleXdvcmRzPjxkYXRl

cz48eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVsIDE8L2RhdGU+PC9wdWItZGF0

ZXM+PC9kYXRlcz48aXNibj4xODczLTcwNjQgKEVsZWN0cm9uaWMpJiN4RDswMDI4LTM5MDggKExp

bmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5NDcxMDU1PC9hY2Nlc3Npb24tbnVtPjx1cmxz

PjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI5

NDcxMDU1PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4xMDE2L2oubmV1cm9waGFybS4yMDE4LjAxLjA0NDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 294,317. They also emphasize the need of supporting Phase III clinical trials on strong and accurate preclinical data and to tackle multiple therapeutic targets ADDIN EN.CITE <EndNote><Cite><Author>Winblad</Author><Year>2016</Year><RecNum>983</RecNum><DisplayText><style face="superscript">294</style></DisplayText><record><rec-number>983</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865640">983</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Winblad, Bengt</author><author>Qiu, Chengxuan</author><author>Ballard, Clive</author><author>Johansson, Gunilla</author></authors></contributors><titles><title>Evidence-based prevention and treatment of dementia – Authors&apos; reply</title><secondary-title>The Lancet Neurology</secondary-title></titles><pages>1007-1008</pages><volume>15</volume><number>10</number><dates><year>2016</year><pub-dates><date>2016/09</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>1474-4422</isbn><urls><related-urls><url>(16)30128-4</url></related-urls></urls><electronic-resource-num>10.1016/s1474-4422(16)30128-4</electronic-resource-num></record></Cite></EndNote>294. Moreover, the refocus on preventive strategies and/or drugs targeting the prodromal or very early stages of AD (before the onset of dementia) will hopefully maintain a longer quality of life ADDIN EN.CITE <EndNote><Cite><Author>Winblad</Author><Year>2016</Year><RecNum>983</RecNum><DisplayText><style face="superscript">294</style></DisplayText><record><rec-number>983</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865640">983</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Winblad, Bengt</author><author>Qiu, Chengxuan</author><author>Ballard, Clive</author><author>Johansson, Gunilla</author></authors></contributors><titles><title>Evidence-based prevention and treatment of dementia – Authors&apos; reply</title><secondary-title>The Lancet Neurology</secondary-title></titles><pages>1007-1008</pages><volume>15</volume><number>10</number><dates><year>2016</year><pub-dates><date>2016/09</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>1474-4422</isbn><urls><related-urls><url>(16)30128-4</url></related-urls></urls><electronic-resource-num>10.1016/s1474-4422(16)30128-4</electronic-resource-num></record></Cite></EndNote>294.Among such promising therapeutic (and preventive?) strategies in AD, one tempting target is the rescue of brain insulin signaling and glucose metabolism ADDIN EN.CITE <EndNote><Cite><Author>Winblad</Author><Year>2016</Year><RecNum>983</RecNum><DisplayText><style face="superscript">294</style></DisplayText><record><rec-number>983</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1532865640">983</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Winblad, Bengt</author><author>Qiu, Chengxuan</author><author>Ballard, Clive</author><author>Johansson, Gunilla</author></authors></contributors><titles><title>Evidence-based prevention and treatment of dementia – Authors&apos; reply</title><secondary-title>The Lancet Neurology</secondary-title></titles><pages>1007-1008</pages><volume>15</volume><number>10</number><dates><year>2016</year><pub-dates><date>2016/09</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>1474-4422</isbn><urls><related-urls><url>(16)30128-4</url></related-urls></urls><electronic-resource-num>10.1016/s1474-4422(16)30128-4</electronic-resource-num></record></Cite></EndNote>294. Accordingly, an increasing attention has been given to the potential benefits of repositioning efficient, commercialized anti-T2D drugs to treat AD ADDIN EN.CITE <EndNote><Cite><Author>Medina</Author><Year>2014</Year><RecNum>3747</RecNum><DisplayText><style face="superscript">321</style></DisplayText><record><rec-number>3747</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535917266">3747</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Medina, M.</author><author>Avila, J.</author></authors></contributors><auth-address>Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas (CIBERNED), Valderrebollo 5, 28041 Madrid, Spain.&#xD;Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas (CIBERNED), Valderrebollo 5, 28041 Madrid, Spain; Centro de Biologia Molecular &quot;Severo Ochoa&quot; CSIC-UAM, Nicolas Cabrera 1, 28049 Madrid, Spain. Electronic address: javila@cbm.uam.es.</auth-address><titles><title>New perspectives on the role of tau in Alzheimer&apos;s disease. Implications for therapy</title><secondary-title>Biochem Pharmacol</secondary-title></titles><pages>540-7</pages><volume>88</volume><number>4</number><keywords><keyword>Alzheimer Disease/*physiopathology/therapy</keyword><keyword>Humans</keyword><keyword>Immunotherapy</keyword><keyword>Microtubules/metabolism</keyword><keyword>Phosphorylation</keyword><keyword>tau Proteins/metabolism/*physiology</keyword><keyword>Alzheimer</keyword><keyword>Dementia</keyword><keyword>Tau</keyword><keyword>Tauopathies</keyword><keyword>Therapy</keyword></keywords><dates><year>2014</year><pub-dates><date>Apr 15</date></pub-dates></dates><isbn>1873-2968 (Electronic)&#xD;0006-2952 (Linking)</isbn><accession-num>24462919</accession-num><urls><related-urls><url> PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGFpa2g8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

ZWNOdW0+Mzc0ODwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjMyMi0zMjQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zNzQ4PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTczOTYiPjM3NDg8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNoYWlraCwgUy48L2F1dGhvcj48

YXV0aG9yPlJpenZpLCBTLiBNLjwvYXV0aG9yPjxhdXRob3I+U2hha2lsLCBTLjwvYXV0aG9yPjxh

dXRob3I+Uml5YXosIFMuPC9hdXRob3I+PGF1dGhvcj5CaXN3YXMsIEQuPC9hdXRob3I+PGF1dGhv

cj5KYWhhbiwgUi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVz

cz5EZXBhcnRtZW50IG9mIEJpb3NjaWVuY2VzLCBJbnRlZ3JhbCBVbml2ZXJzaXR5LCBMdWNrbm93

LCBJbmRpYS4mI3hEO0RlcGFydG1lbnQgb2YgQmlvZW5naW5lZXJpbmcsIEludGVncmFsIFVuaXZl

cnNpdHksIEx1Y2tub3csIEluZGlhLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkZvcnhp

Z2EgKGRhcGFnbGlmbG96aW4pOiBQbGF1c2libGUgcm9sZSBpbiB0aGUgdHJlYXRtZW50IG9mIGRp

YWJldGVzLWFzc29jaWF0ZWQgbmV1cm9sb2dpY2FsIGRpc29yZGVyczwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5CaW90ZWNobm9sIEFwcGwgQmlvY2hlbTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwYWdlcz4xNDUtNTA8L3BhZ2VzPjx2b2x1bWU+NjM8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJl

cj48a2V5d29yZHM+PGtleXdvcmQ+QWNldHlsY2hvbGluZXN0ZXJhc2UvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9jb21wbGljYXRpb25zL2RydWcgdGhlcmFw

eS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkJlbnpoeWRyeWwgQ29tcG91bmRzLypwaGFy

bWFjb2xvZ3kvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNob2xpbmVzdGVyYXNl

IEluaGliaXRvcnMvKnBoYXJtYWNvbG9neS90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdv

cmQ+RGlhYmV0ZXMgTWVsbGl0dXMsIFR5cGUgMi9jb21wbGljYXRpb25zLypkcnVnIHRoZXJhcHkv

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5HbHVjb3NpZGVzLypwaGFybWFjb2xvZ3kvdGhl

cmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5I

eXBvZ2x5Y2VtaWMgQWdlbnRzLypwaGFybWFjb2xvZ3kvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3Jk

PjxrZXl3b3JkPk1vbGVjdWxhciBEb2NraW5nIFNpbXVsYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+

TmVydm91cyBTeXN0ZW0gRGlzZWFzZXMvY29tcGxpY2F0aW9ucy8qZHJ1ZyB0aGVyYXB5L21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+U29kaXVtLUdsdWNvc2UgVHJhbnNwb3J0ZXIgMi8qYW50

YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9ycy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFs

emhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5hY2V0eWxjaG9saW5lc3Rl

cmFzZTwva2V5d29yZD48a2V5d29yZD5kYXBhZ2xpZmxvemluPC9rZXl3b3JkPjxrZXl3b3JkPnNv

ZGl1bSBnbHVjb3NlIGNvLXRyYW5zcG9ydGVyIDI8L2tleXdvcmQ+PGtleXdvcmQ+dHlwZSAyIGRp

YWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1k

YXRlcz48ZGF0ZT5KYW4tRmViPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ3MC04

NzQ0IChFbGVjdHJvbmljKSYjeEQ7MDg4NS00NTEzIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNTQwMjYyNDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNTQwMjYyNDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwMi9iYWIuMTMxOTwvZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Q29yYmV0

dDwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJlY051bT4zNzQ5PC9SZWNOdW0+PHJlY29yZD48

cmVjLW51bWJlcj4zNzQ5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk

Yi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1

MzU5MTc1MDciPjM3NDk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h

bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkNv

cmJldHQsIEEuPC9hdXRob3I+PGF1dGhvcj5CYWxsYXJkLCBDLjwvYXV0aG9yPjwvYXV0aG9ycz48

L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5JcyBhIHBvdGVudGlhbCBBbHpoZWltZXImYXBv

cztzIHRoZXJhcHkgYWxyZWFkeSBpbiB1c2UgZm9yIG90aGVyIGNvbmRpdGlvbnM/IENhbiBtZWRp

Y2F0aW9ucyBmb3IgaHlwZXJ0ZW5zaW9uLCBkaWFiZXRlcyBhbmQgYWNuZSBoZWxwIHdpdGggdGhl

IHN5bXB0b21zPzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5FeHBlcnQgT3BpbiBJbnZlc3RpZyBE

cnVnczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz45NDEtMzwvcGFnZXM+PHZvbHVt

ZT4yMjwvdm9sdW1lPjxudW1iZXI+ODwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWlt

ZXIgRGlzZWFzZS8qZHJ1ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkFuZ2lvdGVuc2luIFJl

Y2VwdG9yIEFudGFnb25pc3RzL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5BbnRp

LUJhY3RlcmlhbCBBZ2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNhbGNp

dW0gQ2hhbm5lbCBCbG9ja2Vycy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+KkRy

dWcgUmVwb3NpdGlvbmluZzwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdv

cmQ+SHlwb2dseWNlbWljIEFnZW50cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkF1ZzwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE3NDQtNzY1OCAoRWxlY3Ryb25pYykmI3hEOzEzNTQtMzc4

NCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjM4MDg3MDg8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMjM4MDg3MDg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjE1MTcvMTM1NDM3ODQuMjAxMy44MTU3MjM8L2VsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlNhbmRoaXI8L0F1dGhvcj48WWVhcj4y

MDE1PC9ZZWFyPjxSZWNOdW0+Mzc1MDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc1MDwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTY1Ij4zNzUwPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TYW5kaGlyLCBSLjwvYXV0aG9y

PjxhdXRob3I+R3VwdGEsIFMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo

LWFkZHJlc3M+UmFqYXQgU2FuZGhpciwgU21yaXRpIEd1cHRhLCBEZXBhcnRtZW50IG9mIEJpb2No

ZW1pc3RyeSwgUGFuamFiIFVuaXZlcnNpdHksIENoYW5kaWdhcmggMTYwMDE0LCBJbmRpYS48L2F1

dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Nb2xlY3VsYXIgYW5kIGJpb2NoZW1pY2FsIHRyYWpl

Y3RvcmllcyBmcm9tIGRpYWJldGVzIHRvIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogQSBjcml0

aWNhbCBhcHByYWlzYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+V29ybGQgSiBEaWFiZXRlczwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMjIzLTQyPC9wYWdlcz48dm9sdW1lPjY8

L3ZvbHVtZT48bnVtYmVyPjEyPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciZh

cG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBtZWxsaXR1czwva2V5d29y

ZD48a2V5d29yZD5JbnN1bGluPC9rZXl3b3JkPjxrZXl3b3JkPlR5cGUgMiBkaWFiZXRlczwva2V5

d29yZD48a2V5d29yZD5UeXBlIDMgZGlhYmV0ZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPlNlcCAyNTwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxpc2JuPjE5NDgtOTM1OCAoUHJpbnQpJiN4RDsxOTQ4LTkzNTggKExpbmtpbmcp

PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2NDY0NzYwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh

dGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI2NDY0NzYw

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQ1OTg2MDU8L2N1c3RvbTI+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjQyMzkvd2pkLnY2LmkxMi4xMjIzPC9lbGVjdHJv

bmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGFpa2g8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

ZWNOdW0+Mzc0ODwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjMyMi0zMjQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zNzQ4PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTczOTYiPjM3NDg8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNoYWlraCwgUy48L2F1dGhvcj48

YXV0aG9yPlJpenZpLCBTLiBNLjwvYXV0aG9yPjxhdXRob3I+U2hha2lsLCBTLjwvYXV0aG9yPjxh

dXRob3I+Uml5YXosIFMuPC9hdXRob3I+PGF1dGhvcj5CaXN3YXMsIEQuPC9hdXRob3I+PGF1dGhv

cj5KYWhhbiwgUi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVz

cz5EZXBhcnRtZW50IG9mIEJpb3NjaWVuY2VzLCBJbnRlZ3JhbCBVbml2ZXJzaXR5LCBMdWNrbm93

LCBJbmRpYS4mI3hEO0RlcGFydG1lbnQgb2YgQmlvZW5naW5lZXJpbmcsIEludGVncmFsIFVuaXZl

cnNpdHksIEx1Y2tub3csIEluZGlhLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkZvcnhp

Z2EgKGRhcGFnbGlmbG96aW4pOiBQbGF1c2libGUgcm9sZSBpbiB0aGUgdHJlYXRtZW50IG9mIGRp

YWJldGVzLWFzc29jaWF0ZWQgbmV1cm9sb2dpY2FsIGRpc29yZGVyczwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5CaW90ZWNobm9sIEFwcGwgQmlvY2hlbTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwYWdlcz4xNDUtNTA8L3BhZ2VzPjx2b2x1bWU+NjM8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJl

cj48a2V5d29yZHM+PGtleXdvcmQ+QWNldHlsY2hvbGluZXN0ZXJhc2UvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9jb21wbGljYXRpb25zL2RydWcgdGhlcmFw

eS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkJlbnpoeWRyeWwgQ29tcG91bmRzLypwaGFy

bWFjb2xvZ3kvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNob2xpbmVzdGVyYXNl

IEluaGliaXRvcnMvKnBoYXJtYWNvbG9neS90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdv

cmQ+RGlhYmV0ZXMgTWVsbGl0dXMsIFR5cGUgMi9jb21wbGljYXRpb25zLypkcnVnIHRoZXJhcHkv

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5HbHVjb3NpZGVzLypwaGFybWFjb2xvZ3kvdGhl

cmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5I

eXBvZ2x5Y2VtaWMgQWdlbnRzLypwaGFybWFjb2xvZ3kvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3Jk

PjxrZXl3b3JkPk1vbGVjdWxhciBEb2NraW5nIFNpbXVsYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+

TmVydm91cyBTeXN0ZW0gRGlzZWFzZXMvY29tcGxpY2F0aW9ucy8qZHJ1ZyB0aGVyYXB5L21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+U29kaXVtLUdsdWNvc2UgVHJhbnNwb3J0ZXIgMi8qYW50

YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9ycy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFs

emhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5hY2V0eWxjaG9saW5lc3Rl

cmFzZTwva2V5d29yZD48a2V5d29yZD5kYXBhZ2xpZmxvemluPC9rZXl3b3JkPjxrZXl3b3JkPnNv

ZGl1bSBnbHVjb3NlIGNvLXRyYW5zcG9ydGVyIDI8L2tleXdvcmQ+PGtleXdvcmQ+dHlwZSAyIGRp

YWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1k

YXRlcz48ZGF0ZT5KYW4tRmViPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ3MC04

NzQ0IChFbGVjdHJvbmljKSYjeEQ7MDg4NS00NTEzIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNTQwMjYyNDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNTQwMjYyNDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwMi9iYWIuMTMxOTwvZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Q29yYmV0

dDwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJlY051bT4zNzQ5PC9SZWNOdW0+PHJlY29yZD48

cmVjLW51bWJlcj4zNzQ5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk

Yi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1

MzU5MTc1MDciPjM3NDk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h

bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkNv

cmJldHQsIEEuPC9hdXRob3I+PGF1dGhvcj5CYWxsYXJkLCBDLjwvYXV0aG9yPjwvYXV0aG9ycz48

L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5JcyBhIHBvdGVudGlhbCBBbHpoZWltZXImYXBv

cztzIHRoZXJhcHkgYWxyZWFkeSBpbiB1c2UgZm9yIG90aGVyIGNvbmRpdGlvbnM/IENhbiBtZWRp

Y2F0aW9ucyBmb3IgaHlwZXJ0ZW5zaW9uLCBkaWFiZXRlcyBhbmQgYWNuZSBoZWxwIHdpdGggdGhl

IHN5bXB0b21zPzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5FeHBlcnQgT3BpbiBJbnZlc3RpZyBE

cnVnczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz45NDEtMzwvcGFnZXM+PHZvbHVt

ZT4yMjwvdm9sdW1lPjxudW1iZXI+ODwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWlt

ZXIgRGlzZWFzZS8qZHJ1ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkFuZ2lvdGVuc2luIFJl

Y2VwdG9yIEFudGFnb25pc3RzL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5BbnRp

LUJhY3RlcmlhbCBBZ2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNhbGNp

dW0gQ2hhbm5lbCBCbG9ja2Vycy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+KkRy

dWcgUmVwb3NpdGlvbmluZzwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdv

cmQ+SHlwb2dseWNlbWljIEFnZW50cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkF1ZzwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE3NDQtNzY1OCAoRWxlY3Ryb25pYykmI3hEOzEzNTQtMzc4

NCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjM4MDg3MDg8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMjM4MDg3MDg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjE1MTcvMTM1NDM3ODQuMjAxMy44MTU3MjM8L2VsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlNhbmRoaXI8L0F1dGhvcj48WWVhcj4y

MDE1PC9ZZWFyPjxSZWNOdW0+Mzc1MDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc1MDwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTY1Ij4zNzUwPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TYW5kaGlyLCBSLjwvYXV0aG9y

PjxhdXRob3I+R3VwdGEsIFMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo

LWFkZHJlc3M+UmFqYXQgU2FuZGhpciwgU21yaXRpIEd1cHRhLCBEZXBhcnRtZW50IG9mIEJpb2No

ZW1pc3RyeSwgUGFuamFiIFVuaXZlcnNpdHksIENoYW5kaWdhcmggMTYwMDE0LCBJbmRpYS48L2F1

dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Nb2xlY3VsYXIgYW5kIGJpb2NoZW1pY2FsIHRyYWpl

Y3RvcmllcyBmcm9tIGRpYWJldGVzIHRvIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogQSBjcml0

aWNhbCBhcHByYWlzYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+V29ybGQgSiBEaWFiZXRlczwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMjIzLTQyPC9wYWdlcz48dm9sdW1lPjY8

L3ZvbHVtZT48bnVtYmVyPjEyPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciZh

cG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBtZWxsaXR1czwva2V5d29y

ZD48a2V5d29yZD5JbnN1bGluPC9rZXl3b3JkPjxrZXl3b3JkPlR5cGUgMiBkaWFiZXRlczwva2V5

d29yZD48a2V5d29yZD5UeXBlIDMgZGlhYmV0ZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPlNlcCAyNTwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxpc2JuPjE5NDgtOTM1OCAoUHJpbnQpJiN4RDsxOTQ4LTkzNTggKExpbmtpbmcp

PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2NDY0NzYwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh

dGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI2NDY0NzYw

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQ1OTg2MDU8L2N1c3RvbTI+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjQyMzkvd2pkLnY2LmkxMi4xMjIzPC9lbGVjdHJv

bmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 322-324. This hypothesis is supported by the molecular mechanisms shared by T2D and AD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMsMzI0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMsMzI0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 323,324. This is also tempting due to the potential targeting of preclinical/prodromal AD, mild cognitive impairment (MCI), or at-risk conditions (prevention), rather than just its later stages PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjk4MzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI5NCwzMjMsMzI0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+OTgz

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU2NDAiPjk4Mzwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+V2luYmxhZCwgQmVuZ3Q8L2F1

dGhvcj48YXV0aG9yPlFpdSwgQ2hlbmd4dWFuPC9hdXRob3I+PGF1dGhvcj5CYWxsYXJkLCBDbGl2

ZTwvYXV0aG9yPjxhdXRob3I+Sm9oYW5zc29uLCBHdW5pbGxhPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkV2aWRlbmNlLWJhc2VkIHByZXZlbnRpb24gYW5k

IHRyZWF0bWVudCBvZiBkZW1lbnRpYSDigJMgQXV0aG9ycyZhcG9zOyByZXBseTwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5UaGUgTGFuY2V0IE5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0

bGVzPjxwYWdlcz4xMDA3LTEwMDg8L3BhZ2VzPjx2b2x1bWU+MTU8L3ZvbHVtZT48bnVtYmVyPjEw

PC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDE2LzA5

PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5FbHNldmllciBCVjwvcHVibGlz

aGVyPjxpc2JuPjE0NzQtNDQyMjwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDov

L2R4LmRvaS5vcmcvMTAuMTAxNi9zMTQ3NC00NDIyKDE2KTMwMTI4LTQ8L3VybD48L3JlbGF0ZWQt

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvczE0NzQtNDQyMigx

NikzMDEyOC00PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+

PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVtPjM3NDk8L1Jl

Y051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NDk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48

a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYi

IHRpbWVzdGFtcD0iMTUzNTkxNzUwNyI+Mzc0OTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlw

ZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRo

b3JzPjxhdXRob3I+Q29yYmV0dCwgQS48L2F1dGhvcj48YXV0aG9yPkJhbGxhcmQsIEMuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPklzIGEgcG90ZW50aWFs

IEFsemhlaW1lciZhcG9zO3MgdGhlcmFweSBhbHJlYWR5IGluIHVzZSBmb3Igb3RoZXIgY29uZGl0

aW9ucz8gQ2FuIG1lZGljYXRpb25zIGZvciBoeXBlcnRlbnNpb24sIGRpYWJldGVzIGFuZCBhY25l

IGhlbHAgd2l0aCB0aGUgc3ltcHRvbXM/PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkV4cGVydCBP

cGluIEludmVzdGlnIERydWdzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjk0MS0z

PC9wYWdlcz48dm9sdW1lPjIyPC92b2x1bWU+PG51bWJlcj44PC9udW1iZXI+PGtleXdvcmRzPjxr

ZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypkcnVnIHRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+

QW5naW90ZW5zaW4gUmVjZXB0b3IgQW50YWdvbmlzdHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3Jk

PjxrZXl3b3JkPkFudGktQmFjdGVyaWFsIEFnZW50cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+

PGtleXdvcmQ+Q2FsY2l1bSBDaGFubmVsIEJsb2NrZXJzL3RoZXJhcGV1dGljIHVzZTwva2V5d29y

ZD48a2V5d29yZD4qRHJ1ZyBSZXBvc2l0aW9uaW5nPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwv

a2V5d29yZD48a2V5d29yZD5IeXBvZ2x5Y2VtaWMgQWdlbnRzL3RoZXJhcGV1dGljIHVzZTwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

QXVnPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTc0NC03NjU4IChFbGVjdHJvbmlj

KSYjeEQ7MTM1NC0zNzg0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzgwODcwODwv

YWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5s

bS5uaWguZ292L3B1Ym1lZC8yMzgwODcwODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTUxNy8xMzU0Mzc4NC4yMDEzLjgxNTcyMzwvZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+U2FuZGhpcjwv

QXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJlY051bT4zNzUwPC9SZWNOdW0+PHJlY29yZD48cmVj

LW51bWJlcj4zNzUwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1p

ZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5

MTc1NjUiPjM3NTA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBB

cnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNhbmRo

aXIsIFIuPC9hdXRob3I+PGF1dGhvcj5HdXB0YSwgUy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5SYWphdCBTYW5kaGlyLCBTbXJpdGkgR3VwdGEsIERlcGFy

dG1lbnQgb2YgQmlvY2hlbWlzdHJ5LCBQYW5qYWIgVW5pdmVyc2l0eSwgQ2hhbmRpZ2FyaCAxNjAw

MTQsIEluZGlhLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPk1vbGVjdWxhciBhbmQgYmlv

Y2hlbWljYWwgdHJhamVjdG9yaWVzIGZyb20gZGlhYmV0ZXMgdG8gQWx6aGVpbWVyJmFwb3M7cyBk

aXNlYXNlOiBBIGNyaXRpY2FsIGFwcHJhaXNhbDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Xb3Js

ZCBKIERpYWJldGVzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEyMjMtNDI8L3Bh

Z2VzPjx2b2x1bWU+Njwvdm9sdW1lPjxudW1iZXI+MTI8L251bWJlcj48a2V5d29yZHM+PGtleXdv

cmQ+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkRpYWJldGVzIG1l

bGxpdHVzPC9rZXl3b3JkPjxrZXl3b3JkPkluc3VsaW48L2tleXdvcmQ+PGtleXdvcmQ+VHlwZSAy

IGRpYWJldGVzPC9rZXl3b3JkPjxrZXl3b3JkPlR5cGUgMyBkaWFiZXRlczwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDE1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwIDI1PC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTk0OC05MzU4IChQcmludCkmI3hEOzE5NDgt

OTM1OCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjY0NjQ3NjA8L2FjY2Vzc2lvbi1u

dW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9w

dWJtZWQvMjY0NjQ3NjA8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNDU5

ODYwNTwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuNDIzOS93amQudjYuaTEy

LjEyMjM8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjk4MzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjI5NCwzMjMsMzI0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+OTgz

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI4NjU2NDAiPjk4Mzwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+V2luYmxhZCwgQmVuZ3Q8L2F1

dGhvcj48YXV0aG9yPlFpdSwgQ2hlbmd4dWFuPC9hdXRob3I+PGF1dGhvcj5CYWxsYXJkLCBDbGl2

ZTwvYXV0aG9yPjxhdXRob3I+Sm9oYW5zc29uLCBHdW5pbGxhPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkV2aWRlbmNlLWJhc2VkIHByZXZlbnRpb24gYW5k

IHRyZWF0bWVudCBvZiBkZW1lbnRpYSDigJMgQXV0aG9ycyZhcG9zOyByZXBseTwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5UaGUgTGFuY2V0IE5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0

bGVzPjxwYWdlcz4xMDA3LTEwMDg8L3BhZ2VzPjx2b2x1bWU+MTU8L3ZvbHVtZT48bnVtYmVyPjEw

PC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDE2LzA5

PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5FbHNldmllciBCVjwvcHVibGlz

aGVyPjxpc2JuPjE0NzQtNDQyMjwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDov

L2R4LmRvaS5vcmcvMTAuMTAxNi9zMTQ3NC00NDIyKDE2KTMwMTI4LTQ8L3VybD48L3JlbGF0ZWQt

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvczE0NzQtNDQyMigx

NikzMDEyOC00PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+

PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVtPjM3NDk8L1Jl

Y051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NDk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48

a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYi

IHRpbWVzdGFtcD0iMTUzNTkxNzUwNyI+Mzc0OTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlw

ZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRo

b3JzPjxhdXRob3I+Q29yYmV0dCwgQS48L2F1dGhvcj48YXV0aG9yPkJhbGxhcmQsIEMuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPklzIGEgcG90ZW50aWFs

IEFsemhlaW1lciZhcG9zO3MgdGhlcmFweSBhbHJlYWR5IGluIHVzZSBmb3Igb3RoZXIgY29uZGl0

aW9ucz8gQ2FuIG1lZGljYXRpb25zIGZvciBoeXBlcnRlbnNpb24sIGRpYWJldGVzIGFuZCBhY25l

IGhlbHAgd2l0aCB0aGUgc3ltcHRvbXM/PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkV4cGVydCBP

cGluIEludmVzdGlnIERydWdzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjk0MS0z

PC9wYWdlcz48dm9sdW1lPjIyPC92b2x1bWU+PG51bWJlcj44PC9udW1iZXI+PGtleXdvcmRzPjxr

ZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypkcnVnIHRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+

QW5naW90ZW5zaW4gUmVjZXB0b3IgQW50YWdvbmlzdHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3Jk

PjxrZXl3b3JkPkFudGktQmFjdGVyaWFsIEFnZW50cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+

PGtleXdvcmQ+Q2FsY2l1bSBDaGFubmVsIEJsb2NrZXJzL3RoZXJhcGV1dGljIHVzZTwva2V5d29y

ZD48a2V5d29yZD4qRHJ1ZyBSZXBvc2l0aW9uaW5nPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwv

a2V5d29yZD48a2V5d29yZD5IeXBvZ2x5Y2VtaWMgQWdlbnRzL3RoZXJhcGV1dGljIHVzZTwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

QXVnPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTc0NC03NjU4IChFbGVjdHJvbmlj

KSYjeEQ7MTM1NC0zNzg0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzgwODcwODwv

YWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5s

bS5uaWguZ292L3B1Ym1lZC8yMzgwODcwODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTUxNy8xMzU0Mzc4NC4yMDEzLjgxNTcyMzwvZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+U2FuZGhpcjwv

QXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJlY051bT4zNzUwPC9SZWNOdW0+PHJlY29yZD48cmVj

LW51bWJlcj4zNzUwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1p

ZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5

MTc1NjUiPjM3NTA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBB

cnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNhbmRo

aXIsIFIuPC9hdXRob3I+PGF1dGhvcj5HdXB0YSwgUy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5SYWphdCBTYW5kaGlyLCBTbXJpdGkgR3VwdGEsIERlcGFy

dG1lbnQgb2YgQmlvY2hlbWlzdHJ5LCBQYW5qYWIgVW5pdmVyc2l0eSwgQ2hhbmRpZ2FyaCAxNjAw

MTQsIEluZGlhLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPk1vbGVjdWxhciBhbmQgYmlv

Y2hlbWljYWwgdHJhamVjdG9yaWVzIGZyb20gZGlhYmV0ZXMgdG8gQWx6aGVpbWVyJmFwb3M7cyBk

aXNlYXNlOiBBIGNyaXRpY2FsIGFwcHJhaXNhbDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Xb3Js

ZCBKIERpYWJldGVzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEyMjMtNDI8L3Bh

Z2VzPjx2b2x1bWU+Njwvdm9sdW1lPjxudW1iZXI+MTI8L251bWJlcj48a2V5d29yZHM+PGtleXdv

cmQ+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkRpYWJldGVzIG1l

bGxpdHVzPC9rZXl3b3JkPjxrZXl3b3JkPkluc3VsaW48L2tleXdvcmQ+PGtleXdvcmQ+VHlwZSAy

IGRpYWJldGVzPC9rZXl3b3JkPjxrZXl3b3JkPlR5cGUgMyBkaWFiZXRlczwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDE1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwIDI1PC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTk0OC05MzU4IChQcmludCkmI3hEOzE5NDgt

OTM1OCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjY0NjQ3NjA8L2FjY2Vzc2lvbi1u

dW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9w

dWJtZWQvMjY0NjQ3NjA8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNDU5

ODYwNTwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuNDIzOS93amQudjYuaTEy

LjEyMjM8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

AG==

ADDIN EN.CITE.DATA 294,323,324.The temptation of using biguanides (metformin) against AD: a friend or foe?Metformin is the most efficient anti-T2D biguanide PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMtMzI1PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+U2ViYXN0aWFvPC9BdXRob3I+PFllYXI+MjAx

NDwvWWVhcj48UmVjTnVtPjM3NTE8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTE8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzczNiI+Mzc1MTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U2ViYXN0aWFvLCBJLjwvYXV0aG9y

PjxhdXRob3I+Q2FuZGVpYXMsIEUuPC9hdXRob3I+PGF1dGhvcj5TYW50b3MsIE0uIFMuPC9hdXRo

b3I+PGF1dGhvcj5kZSBPbGl2ZWlyYSwgQy4gUi48L2F1dGhvcj48YXV0aG9yPk1vcmVpcmEsIFAu

IEkuPC9hdXRob3I+PGF1dGhvcj5EdWFydGUsIEEuIEkuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+Q2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5kIENlbGwg

QmlvbG9neSAoQ05DKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwgQ29pbWJyYSAsIFBvcnR1Z2Fs

IDsgRGVwYXJ0bWVudCBvZiBMaWZlIFNjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIENvaW1icmEgLCBD

b2ltYnJhICwgUG9ydHVnYWwgOyBJbnN0aXR1dGUgZm9yIEludGVyZGlzY2lwbGluYXJ5IFJlc2Vh

cmNoIChJSUlVQyksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSAsIENvaW1icmEgLCBQb3J0dWdhbC4m

I3hEO0NlbnRlciBmb3IgTmV1cm9zY2llbmNlIGFuZCBDZWxsIEJpb2xvZ3kgKENOQyksIFVuaXZl

cnNpdHkgb2YgQ29pbWJyYSAsIENvaW1icmEgLCBQb3J0dWdhbCA7IEluc3RpdHV0ZSBmb3IgSW50

ZXJkaXNjaXBsaW5hcnkgUmVzZWFyY2ggKElJSVVDKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwg

Q29pbWJyYSAsIFBvcnR1Z2FsLiYjeEQ7Q2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5kIENlbGwg

QmlvbG9neSAoQ05DKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwgQ29pbWJyYSAsIFBvcnR1Z2Fs

IDsgSW5zdGl0dXRlIG9mIEJpb2NoZW1pc3RyeSwgRmFjdWx0eSBvZiBNZWRpY2luZSwgVW5pdmVy

c2l0eSBvZiBDb2ltYnJhICwgQ29pbWJyYSAsIFBvcnR1Z2FsLiYjeEQ7Q2VudGVyIGZvciBOZXVy

b3NjaWVuY2UgYW5kIENlbGwgQmlvbG9neSAoQ05DKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwg

Q29pbWJyYSAsIFBvcnR1Z2FsIDsgSW5zdGl0dXRlIG9mIFBoeXNpb2xvZ3ksIEZhY3VsdHkgb2Yg

TWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSAsIENvaW1icmEgLCBQb3J0dWdhbC48L2F1

dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5JbnN1bGluIGFzIGEgQnJpZGdlIGJldHdlZW4gVHlw

ZSAyIERpYWJldGVzIGFuZCBBbHpoZWltZXIgRGlzZWFzZSAtIEhvdyBBbnRpLURpYWJldGljcyBD

b3VsZCBiZSBhIFNvbHV0aW9uIGZvciBEZW1lbnRpYTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5G

cm9udCBFbmRvY3Jpbm9sIChMYXVzYW5uZSk8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFn

ZXM+MTEwPC9wYWdlcz48dm9sdW1lPjU8L3ZvbHVtZT48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVp

bWVyIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+YW50aS10eXBlIDIgZGlhYmV0ZXMgY29tcG91

bmRzPC9rZXl3b3JkPjxrZXl3b3JkPmJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPmV4ZW5kaW4tNDwv

a2V5d29yZD48a2V5d29yZD5pbmNyZXRpbnMvZ2x1Y2Fnb24tbGlrZSBwZXB0aWRlLTEvZ2x1Y2Fn

b24tbGlrZSBwZXB0aWRlLTEgcmVjZXB0b3I8L2tleXdvcmQ+PGtleXdvcmQ+aW5zdWxpbi9pbnN1

bGluIHJlY2VwdG9yIHNpZ25hbGluZzwva2V5d29yZD48a2V5d29yZD50eXBlIDIgZGlhYmV0ZXM8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48L2RhdGVzPjxpc2Ju

PjE2NjQtMjM5MiAoUHJpbnQpJiN4RDsxNjY0LTIzOTIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI1MDcxNzI1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI1MDcxNzI1PC91cmw+PC9yZWxhdGVk

LXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQwODYwMjU8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjEwLjMzODkvZmVuZG8uMjAxNC4wMDExMDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMtMzI1PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+U2ViYXN0aWFvPC9BdXRob3I+PFllYXI+MjAx

NDwvWWVhcj48UmVjTnVtPjM3NTE8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTE8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzczNiI+Mzc1MTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U2ViYXN0aWFvLCBJLjwvYXV0aG9y

PjxhdXRob3I+Q2FuZGVpYXMsIEUuPC9hdXRob3I+PGF1dGhvcj5TYW50b3MsIE0uIFMuPC9hdXRo

b3I+PGF1dGhvcj5kZSBPbGl2ZWlyYSwgQy4gUi48L2F1dGhvcj48YXV0aG9yPk1vcmVpcmEsIFAu

IEkuPC9hdXRob3I+PGF1dGhvcj5EdWFydGUsIEEuIEkuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+Q2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5kIENlbGwg

QmlvbG9neSAoQ05DKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwgQ29pbWJyYSAsIFBvcnR1Z2Fs

IDsgRGVwYXJ0bWVudCBvZiBMaWZlIFNjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIENvaW1icmEgLCBD

b2ltYnJhICwgUG9ydHVnYWwgOyBJbnN0aXR1dGUgZm9yIEludGVyZGlzY2lwbGluYXJ5IFJlc2Vh

cmNoIChJSUlVQyksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSAsIENvaW1icmEgLCBQb3J0dWdhbC4m

I3hEO0NlbnRlciBmb3IgTmV1cm9zY2llbmNlIGFuZCBDZWxsIEJpb2xvZ3kgKENOQyksIFVuaXZl

cnNpdHkgb2YgQ29pbWJyYSAsIENvaW1icmEgLCBQb3J0dWdhbCA7IEluc3RpdHV0ZSBmb3IgSW50

ZXJkaXNjaXBsaW5hcnkgUmVzZWFyY2ggKElJSVVDKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwg

Q29pbWJyYSAsIFBvcnR1Z2FsLiYjeEQ7Q2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5kIENlbGwg

QmlvbG9neSAoQ05DKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwgQ29pbWJyYSAsIFBvcnR1Z2Fs

IDsgSW5zdGl0dXRlIG9mIEJpb2NoZW1pc3RyeSwgRmFjdWx0eSBvZiBNZWRpY2luZSwgVW5pdmVy

c2l0eSBvZiBDb2ltYnJhICwgQ29pbWJyYSAsIFBvcnR1Z2FsLiYjeEQ7Q2VudGVyIGZvciBOZXVy

b3NjaWVuY2UgYW5kIENlbGwgQmlvbG9neSAoQ05DKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwg

Q29pbWJyYSAsIFBvcnR1Z2FsIDsgSW5zdGl0dXRlIG9mIFBoeXNpb2xvZ3ksIEZhY3VsdHkgb2Yg

TWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSAsIENvaW1icmEgLCBQb3J0dWdhbC48L2F1

dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5JbnN1bGluIGFzIGEgQnJpZGdlIGJldHdlZW4gVHlw

ZSAyIERpYWJldGVzIGFuZCBBbHpoZWltZXIgRGlzZWFzZSAtIEhvdyBBbnRpLURpYWJldGljcyBD

b3VsZCBiZSBhIFNvbHV0aW9uIGZvciBEZW1lbnRpYTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5G

cm9udCBFbmRvY3Jpbm9sIChMYXVzYW5uZSk8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFn

ZXM+MTEwPC9wYWdlcz48dm9sdW1lPjU8L3ZvbHVtZT48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVp

bWVyIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+YW50aS10eXBlIDIgZGlhYmV0ZXMgY29tcG91

bmRzPC9rZXl3b3JkPjxrZXl3b3JkPmJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPmV4ZW5kaW4tNDwv

a2V5d29yZD48a2V5d29yZD5pbmNyZXRpbnMvZ2x1Y2Fnb24tbGlrZSBwZXB0aWRlLTEvZ2x1Y2Fn

b24tbGlrZSBwZXB0aWRlLTEgcmVjZXB0b3I8L2tleXdvcmQ+PGtleXdvcmQ+aW5zdWxpbi9pbnN1

bGluIHJlY2VwdG9yIHNpZ25hbGluZzwva2V5d29yZD48a2V5d29yZD50eXBlIDIgZGlhYmV0ZXM8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48L2RhdGVzPjxpc2Ju

PjE2NjQtMjM5MiAoUHJpbnQpJiN4RDsxNjY0LTIzOTIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI1MDcxNzI1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI1MDcxNzI1PC91cmw+PC9yZWxhdGVk

LXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQwODYwMjU8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjEwLjMzODkvZmVuZG8uMjAxNC4wMDExMDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 323-325. It is relatively inexpensive and with a low risk of hypoglycemia ADDIN EN.CITE <EndNote><Cite><Author>Corbett</Author><Year>2013</Year><RecNum>3749</RecNum><DisplayText><style face="superscript">323</style></DisplayText><record><rec-number>3749</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535917507">3749</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Corbett, A.</author><author>Ballard, C.</author></authors></contributors><titles><title>Is a potential Alzheimer&apos;s therapy already in use for other conditions? Can medications for hypertension, diabetes and acne help with the symptoms?</title><secondary-title>Expert Opin Investig Drugs</secondary-title></titles><pages>941-3</pages><volume>22</volume><number>8</number><keywords><keyword>Alzheimer Disease/*drug therapy</keyword><keyword>Angiotensin Receptor Antagonists/therapeutic use</keyword><keyword>Anti-Bacterial Agents/therapeutic use</keyword><keyword>Calcium Channel Blockers/therapeutic use</keyword><keyword>*Drug Repositioning</keyword><keyword>Humans</keyword><keyword>Hypoglycemic Agents/therapeutic use</keyword></keywords><dates><year>2013</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1744-7658 (Electronic)&#xD;1354-3784 (Linking)</isbn><accession-num>23808708</accession-num><urls><related-urls><url>. Metformin inhibits insulin-mediated hepatic glucose production and promotes peripheral glucose disposal by activating liver and skeletal muscle AMPK signaling PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMsMzI0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMsMzI0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 323,324. Some controversy persists on its effect in body weight, since some studies showed no effect, while others reported a weight loss PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMsMzI0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMsMzI0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 323,324. Given its good tolerability, metformin can be used as mono- or multi-therapy at all stages of T2D ADDIN EN.CITE <EndNote><Cite><Author>Corbett</Author><Year>2013</Year><RecNum>3749</RecNum><DisplayText><style face="superscript">323</style></DisplayText><record><rec-number>3749</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535917507">3749</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Corbett, A.</author><author>Ballard, C.</author></authors></contributors><titles><title>Is a potential Alzheimer&apos;s therapy already in use for other conditions? Can medications for hypertension, diabetes and acne help with the symptoms?</title><secondary-title>Expert Opin Investig Drugs</secondary-title></titles><pages>941-3</pages><volume>22</volume><number>8</number><keywords><keyword>Alzheimer Disease/*drug therapy</keyword><keyword>Angiotensin Receptor Antagonists/therapeutic use</keyword><keyword>Anti-Bacterial Agents/therapeutic use</keyword><keyword>Calcium Channel Blockers/therapeutic use</keyword><keyword>*Drug Repositioning</keyword><keyword>Humans</keyword><keyword>Hypoglycemic Agents/therapeutic use</keyword></keywords><dates><year>2013</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1744-7658 (Electronic)&#xD;1354-3784 (Linking)</isbn><accession-num>23808708</accession-num><urls><related-urls><url>. Among its adverse effects are gastrointestinal distress, hepatic dysfunction, congestive heart failure, dehydration, and alcoholism PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMsMzI0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMsMzI0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 323,324. Therefore, metformin must be used with caution in elderly patients.Preclinical data suggest that metformin may be neuroprotective, probably by recovering brain insulin action and energy metabolism PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMtMzI1PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+U2ViYXN0aWFvPC9BdXRob3I+PFllYXI+MjAx

NDwvWWVhcj48UmVjTnVtPjM3NTE8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTE8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzczNiI+Mzc1MTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U2ViYXN0aWFvLCBJLjwvYXV0aG9y

PjxhdXRob3I+Q2FuZGVpYXMsIEUuPC9hdXRob3I+PGF1dGhvcj5TYW50b3MsIE0uIFMuPC9hdXRo

b3I+PGF1dGhvcj5kZSBPbGl2ZWlyYSwgQy4gUi48L2F1dGhvcj48YXV0aG9yPk1vcmVpcmEsIFAu

IEkuPC9hdXRob3I+PGF1dGhvcj5EdWFydGUsIEEuIEkuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+Q2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5kIENlbGwg

QmlvbG9neSAoQ05DKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwgQ29pbWJyYSAsIFBvcnR1Z2Fs

IDsgRGVwYXJ0bWVudCBvZiBMaWZlIFNjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIENvaW1icmEgLCBD

b2ltYnJhICwgUG9ydHVnYWwgOyBJbnN0aXR1dGUgZm9yIEludGVyZGlzY2lwbGluYXJ5IFJlc2Vh

cmNoIChJSUlVQyksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSAsIENvaW1icmEgLCBQb3J0dWdhbC4m

I3hEO0NlbnRlciBmb3IgTmV1cm9zY2llbmNlIGFuZCBDZWxsIEJpb2xvZ3kgKENOQyksIFVuaXZl

cnNpdHkgb2YgQ29pbWJyYSAsIENvaW1icmEgLCBQb3J0dWdhbCA7IEluc3RpdHV0ZSBmb3IgSW50

ZXJkaXNjaXBsaW5hcnkgUmVzZWFyY2ggKElJSVVDKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwg

Q29pbWJyYSAsIFBvcnR1Z2FsLiYjeEQ7Q2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5kIENlbGwg

QmlvbG9neSAoQ05DKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwgQ29pbWJyYSAsIFBvcnR1Z2Fs

IDsgSW5zdGl0dXRlIG9mIEJpb2NoZW1pc3RyeSwgRmFjdWx0eSBvZiBNZWRpY2luZSwgVW5pdmVy

c2l0eSBvZiBDb2ltYnJhICwgQ29pbWJyYSAsIFBvcnR1Z2FsLiYjeEQ7Q2VudGVyIGZvciBOZXVy

b3NjaWVuY2UgYW5kIENlbGwgQmlvbG9neSAoQ05DKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwg

Q29pbWJyYSAsIFBvcnR1Z2FsIDsgSW5zdGl0dXRlIG9mIFBoeXNpb2xvZ3ksIEZhY3VsdHkgb2Yg

TWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSAsIENvaW1icmEgLCBQb3J0dWdhbC48L2F1

dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5JbnN1bGluIGFzIGEgQnJpZGdlIGJldHdlZW4gVHlw

ZSAyIERpYWJldGVzIGFuZCBBbHpoZWltZXIgRGlzZWFzZSAtIEhvdyBBbnRpLURpYWJldGljcyBD

b3VsZCBiZSBhIFNvbHV0aW9uIGZvciBEZW1lbnRpYTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5G

cm9udCBFbmRvY3Jpbm9sIChMYXVzYW5uZSk8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFn

ZXM+MTEwPC9wYWdlcz48dm9sdW1lPjU8L3ZvbHVtZT48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVp

bWVyIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+YW50aS10eXBlIDIgZGlhYmV0ZXMgY29tcG91

bmRzPC9rZXl3b3JkPjxrZXl3b3JkPmJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPmV4ZW5kaW4tNDwv

a2V5d29yZD48a2V5d29yZD5pbmNyZXRpbnMvZ2x1Y2Fnb24tbGlrZSBwZXB0aWRlLTEvZ2x1Y2Fn

b24tbGlrZSBwZXB0aWRlLTEgcmVjZXB0b3I8L2tleXdvcmQ+PGtleXdvcmQ+aW5zdWxpbi9pbnN1

bGluIHJlY2VwdG9yIHNpZ25hbGluZzwva2V5d29yZD48a2V5d29yZD50eXBlIDIgZGlhYmV0ZXM8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48L2RhdGVzPjxpc2Ju

PjE2NjQtMjM5MiAoUHJpbnQpJiN4RDsxNjY0LTIzOTIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI1MDcxNzI1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI1MDcxNzI1PC91cmw+PC9yZWxhdGVk

LXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQwODYwMjU8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjEwLjMzODkvZmVuZG8uMjAxNC4wMDExMDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMtMzI1PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+U2ViYXN0aWFvPC9BdXRob3I+PFllYXI+MjAx

NDwvWWVhcj48UmVjTnVtPjM3NTE8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTE8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzczNiI+Mzc1MTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U2ViYXN0aWFvLCBJLjwvYXV0aG9y

PjxhdXRob3I+Q2FuZGVpYXMsIEUuPC9hdXRob3I+PGF1dGhvcj5TYW50b3MsIE0uIFMuPC9hdXRo

b3I+PGF1dGhvcj5kZSBPbGl2ZWlyYSwgQy4gUi48L2F1dGhvcj48YXV0aG9yPk1vcmVpcmEsIFAu

IEkuPC9hdXRob3I+PGF1dGhvcj5EdWFydGUsIEEuIEkuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+Q2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5kIENlbGwg

QmlvbG9neSAoQ05DKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwgQ29pbWJyYSAsIFBvcnR1Z2Fs

IDsgRGVwYXJ0bWVudCBvZiBMaWZlIFNjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIENvaW1icmEgLCBD

b2ltYnJhICwgUG9ydHVnYWwgOyBJbnN0aXR1dGUgZm9yIEludGVyZGlzY2lwbGluYXJ5IFJlc2Vh

cmNoIChJSUlVQyksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSAsIENvaW1icmEgLCBQb3J0dWdhbC4m

I3hEO0NlbnRlciBmb3IgTmV1cm9zY2llbmNlIGFuZCBDZWxsIEJpb2xvZ3kgKENOQyksIFVuaXZl

cnNpdHkgb2YgQ29pbWJyYSAsIENvaW1icmEgLCBQb3J0dWdhbCA7IEluc3RpdHV0ZSBmb3IgSW50

ZXJkaXNjaXBsaW5hcnkgUmVzZWFyY2ggKElJSVVDKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwg

Q29pbWJyYSAsIFBvcnR1Z2FsLiYjeEQ7Q2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5kIENlbGwg

QmlvbG9neSAoQ05DKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwgQ29pbWJyYSAsIFBvcnR1Z2Fs

IDsgSW5zdGl0dXRlIG9mIEJpb2NoZW1pc3RyeSwgRmFjdWx0eSBvZiBNZWRpY2luZSwgVW5pdmVy

c2l0eSBvZiBDb2ltYnJhICwgQ29pbWJyYSAsIFBvcnR1Z2FsLiYjeEQ7Q2VudGVyIGZvciBOZXVy

b3NjaWVuY2UgYW5kIENlbGwgQmlvbG9neSAoQ05DKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwg

Q29pbWJyYSAsIFBvcnR1Z2FsIDsgSW5zdGl0dXRlIG9mIFBoeXNpb2xvZ3ksIEZhY3VsdHkgb2Yg

TWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSAsIENvaW1icmEgLCBQb3J0dWdhbC48L2F1

dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5JbnN1bGluIGFzIGEgQnJpZGdlIGJldHdlZW4gVHlw

ZSAyIERpYWJldGVzIGFuZCBBbHpoZWltZXIgRGlzZWFzZSAtIEhvdyBBbnRpLURpYWJldGljcyBD

b3VsZCBiZSBhIFNvbHV0aW9uIGZvciBEZW1lbnRpYTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5G

cm9udCBFbmRvY3Jpbm9sIChMYXVzYW5uZSk8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFn

ZXM+MTEwPC9wYWdlcz48dm9sdW1lPjU8L3ZvbHVtZT48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVp

bWVyIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+YW50aS10eXBlIDIgZGlhYmV0ZXMgY29tcG91

bmRzPC9rZXl3b3JkPjxrZXl3b3JkPmJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPmV4ZW5kaW4tNDwv

a2V5d29yZD48a2V5d29yZD5pbmNyZXRpbnMvZ2x1Y2Fnb24tbGlrZSBwZXB0aWRlLTEvZ2x1Y2Fn

b24tbGlrZSBwZXB0aWRlLTEgcmVjZXB0b3I8L2tleXdvcmQ+PGtleXdvcmQ+aW5zdWxpbi9pbnN1

bGluIHJlY2VwdG9yIHNpZ25hbGluZzwva2V5d29yZD48a2V5d29yZD50eXBlIDIgZGlhYmV0ZXM8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48L2RhdGVzPjxpc2Ju

PjE2NjQtMjM5MiAoUHJpbnQpJiN4RDsxNjY0LTIzOTIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI1MDcxNzI1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI1MDcxNzI1PC91cmw+PC9yZWxhdGVk

LXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQwODYwMjU8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjEwLjMzODkvZmVuZG8uMjAxNC4wMDExMDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 323-325. Metformin also increased markers for mitochondrial biogenesis and fusion (e.g. Mfn2 and OPA1), attenuated mitochondrial transition pore opening and oxidative stress, protecting against apoptosis and cognitive deficits PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMtMzI1PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+U2ViYXN0aWFvPC9BdXRob3I+PFllYXI+MjAx

NDwvWWVhcj48UmVjTnVtPjM3NTE8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTE8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzczNiI+Mzc1MTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U2ViYXN0aWFvLCBJLjwvYXV0aG9y

PjxhdXRob3I+Q2FuZGVpYXMsIEUuPC9hdXRob3I+PGF1dGhvcj5TYW50b3MsIE0uIFMuPC9hdXRo

b3I+PGF1dGhvcj5kZSBPbGl2ZWlyYSwgQy4gUi48L2F1dGhvcj48YXV0aG9yPk1vcmVpcmEsIFAu

IEkuPC9hdXRob3I+PGF1dGhvcj5EdWFydGUsIEEuIEkuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+Q2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5kIENlbGwg

QmlvbG9neSAoQ05DKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwgQ29pbWJyYSAsIFBvcnR1Z2Fs

IDsgRGVwYXJ0bWVudCBvZiBMaWZlIFNjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIENvaW1icmEgLCBD

b2ltYnJhICwgUG9ydHVnYWwgOyBJbnN0aXR1dGUgZm9yIEludGVyZGlzY2lwbGluYXJ5IFJlc2Vh

cmNoIChJSUlVQyksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSAsIENvaW1icmEgLCBQb3J0dWdhbC4m

I3hEO0NlbnRlciBmb3IgTmV1cm9zY2llbmNlIGFuZCBDZWxsIEJpb2xvZ3kgKENOQyksIFVuaXZl

cnNpdHkgb2YgQ29pbWJyYSAsIENvaW1icmEgLCBQb3J0dWdhbCA7IEluc3RpdHV0ZSBmb3IgSW50

ZXJkaXNjaXBsaW5hcnkgUmVzZWFyY2ggKElJSVVDKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwg

Q29pbWJyYSAsIFBvcnR1Z2FsLiYjeEQ7Q2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5kIENlbGwg

QmlvbG9neSAoQ05DKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwgQ29pbWJyYSAsIFBvcnR1Z2Fs

IDsgSW5zdGl0dXRlIG9mIEJpb2NoZW1pc3RyeSwgRmFjdWx0eSBvZiBNZWRpY2luZSwgVW5pdmVy

c2l0eSBvZiBDb2ltYnJhICwgQ29pbWJyYSAsIFBvcnR1Z2FsLiYjeEQ7Q2VudGVyIGZvciBOZXVy

b3NjaWVuY2UgYW5kIENlbGwgQmlvbG9neSAoQ05DKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwg

Q29pbWJyYSAsIFBvcnR1Z2FsIDsgSW5zdGl0dXRlIG9mIFBoeXNpb2xvZ3ksIEZhY3VsdHkgb2Yg

TWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSAsIENvaW1icmEgLCBQb3J0dWdhbC48L2F1

dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5JbnN1bGluIGFzIGEgQnJpZGdlIGJldHdlZW4gVHlw

ZSAyIERpYWJldGVzIGFuZCBBbHpoZWltZXIgRGlzZWFzZSAtIEhvdyBBbnRpLURpYWJldGljcyBD

b3VsZCBiZSBhIFNvbHV0aW9uIGZvciBEZW1lbnRpYTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5G

cm9udCBFbmRvY3Jpbm9sIChMYXVzYW5uZSk8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFn

ZXM+MTEwPC9wYWdlcz48dm9sdW1lPjU8L3ZvbHVtZT48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVp

bWVyIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+YW50aS10eXBlIDIgZGlhYmV0ZXMgY29tcG91

bmRzPC9rZXl3b3JkPjxrZXl3b3JkPmJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPmV4ZW5kaW4tNDwv

a2V5d29yZD48a2V5d29yZD5pbmNyZXRpbnMvZ2x1Y2Fnb24tbGlrZSBwZXB0aWRlLTEvZ2x1Y2Fn

b24tbGlrZSBwZXB0aWRlLTEgcmVjZXB0b3I8L2tleXdvcmQ+PGtleXdvcmQ+aW5zdWxpbi9pbnN1

bGluIHJlY2VwdG9yIHNpZ25hbGluZzwva2V5d29yZD48a2V5d29yZD50eXBlIDIgZGlhYmV0ZXM8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48L2RhdGVzPjxpc2Ju

PjE2NjQtMjM5MiAoUHJpbnQpJiN4RDsxNjY0LTIzOTIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI1MDcxNzI1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI1MDcxNzI1PC91cmw+PC9yZWxhdGVk

LXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQwODYwMjU8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjEwLjMzODkvZmVuZG8uMjAxNC4wMDExMDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMtMzI1PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+U2ViYXN0aWFvPC9BdXRob3I+PFllYXI+MjAx

NDwvWWVhcj48UmVjTnVtPjM3NTE8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTE8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzczNiI+Mzc1MTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U2ViYXN0aWFvLCBJLjwvYXV0aG9y

PjxhdXRob3I+Q2FuZGVpYXMsIEUuPC9hdXRob3I+PGF1dGhvcj5TYW50b3MsIE0uIFMuPC9hdXRo

b3I+PGF1dGhvcj5kZSBPbGl2ZWlyYSwgQy4gUi48L2F1dGhvcj48YXV0aG9yPk1vcmVpcmEsIFAu

IEkuPC9hdXRob3I+PGF1dGhvcj5EdWFydGUsIEEuIEkuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+Q2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5kIENlbGwg

QmlvbG9neSAoQ05DKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwgQ29pbWJyYSAsIFBvcnR1Z2Fs

IDsgRGVwYXJ0bWVudCBvZiBMaWZlIFNjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIENvaW1icmEgLCBD

b2ltYnJhICwgUG9ydHVnYWwgOyBJbnN0aXR1dGUgZm9yIEludGVyZGlzY2lwbGluYXJ5IFJlc2Vh

cmNoIChJSUlVQyksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSAsIENvaW1icmEgLCBQb3J0dWdhbC4m

I3hEO0NlbnRlciBmb3IgTmV1cm9zY2llbmNlIGFuZCBDZWxsIEJpb2xvZ3kgKENOQyksIFVuaXZl

cnNpdHkgb2YgQ29pbWJyYSAsIENvaW1icmEgLCBQb3J0dWdhbCA7IEluc3RpdHV0ZSBmb3IgSW50

ZXJkaXNjaXBsaW5hcnkgUmVzZWFyY2ggKElJSVVDKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwg

Q29pbWJyYSAsIFBvcnR1Z2FsLiYjeEQ7Q2VudGVyIGZvciBOZXVyb3NjaWVuY2UgYW5kIENlbGwg

QmlvbG9neSAoQ05DKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwgQ29pbWJyYSAsIFBvcnR1Z2Fs

IDsgSW5zdGl0dXRlIG9mIEJpb2NoZW1pc3RyeSwgRmFjdWx0eSBvZiBNZWRpY2luZSwgVW5pdmVy

c2l0eSBvZiBDb2ltYnJhICwgQ29pbWJyYSAsIFBvcnR1Z2FsLiYjeEQ7Q2VudGVyIGZvciBOZXVy

b3NjaWVuY2UgYW5kIENlbGwgQmlvbG9neSAoQ05DKSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhICwg

Q29pbWJyYSAsIFBvcnR1Z2FsIDsgSW5zdGl0dXRlIG9mIFBoeXNpb2xvZ3ksIEZhY3VsdHkgb2Yg

TWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSAsIENvaW1icmEgLCBQb3J0dWdhbC48L2F1

dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5JbnN1bGluIGFzIGEgQnJpZGdlIGJldHdlZW4gVHlw

ZSAyIERpYWJldGVzIGFuZCBBbHpoZWltZXIgRGlzZWFzZSAtIEhvdyBBbnRpLURpYWJldGljcyBD

b3VsZCBiZSBhIFNvbHV0aW9uIGZvciBEZW1lbnRpYTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5G

cm9udCBFbmRvY3Jpbm9sIChMYXVzYW5uZSk8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFn

ZXM+MTEwPC9wYWdlcz48dm9sdW1lPjU8L3ZvbHVtZT48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVp

bWVyIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+YW50aS10eXBlIDIgZGlhYmV0ZXMgY29tcG91

bmRzPC9rZXl3b3JkPjxrZXl3b3JkPmJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPmV4ZW5kaW4tNDwv

a2V5d29yZD48a2V5d29yZD5pbmNyZXRpbnMvZ2x1Y2Fnb24tbGlrZSBwZXB0aWRlLTEvZ2x1Y2Fn

b24tbGlrZSBwZXB0aWRlLTEgcmVjZXB0b3I8L2tleXdvcmQ+PGtleXdvcmQ+aW5zdWxpbi9pbnN1

bGluIHJlY2VwdG9yIHNpZ25hbGluZzwva2V5d29yZD48a2V5d29yZD50eXBlIDIgZGlhYmV0ZXM8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48L2RhdGVzPjxpc2Ju

PjE2NjQtMjM5MiAoUHJpbnQpJiN4RDsxNjY0LTIzOTIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI1MDcxNzI1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI1MDcxNzI1PC91cmw+PC9yZWxhdGVk

LXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQwODYwMjU8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjEwLjMzODkvZmVuZG8uMjAxNC4wMDExMDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 323-325. It also modulated lipid and protein synthesis, fatty acid oxidation and promoted neurogenesis ADDIN EN.CITE <EndNote><Cite><Author>Corbett</Author><Year>2013</Year><RecNum>3749</RecNum><DisplayText><style face="superscript">323</style></DisplayText><record><rec-number>3749</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535917507">3749</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Corbett, A.</author><author>Ballard, C.</author></authors></contributors><titles><title>Is a potential Alzheimer&apos;s therapy already in use for other conditions? Can medications for hypertension, diabetes and acne help with the symptoms?</title><secondary-title>Expert Opin Investig Drugs</secondary-title></titles><pages>941-3</pages><volume>22</volume><number>8</number><keywords><keyword>Alzheimer Disease/*drug therapy</keyword><keyword>Angiotensin Receptor Antagonists/therapeutic use</keyword><keyword>Anti-Bacterial Agents/therapeutic use</keyword><keyword>Calcium Channel Blockers/therapeutic use</keyword><keyword>*Drug Repositioning</keyword><keyword>Humans</keyword><keyword>Hypoglycemic Agents/therapeutic use</keyword></keywords><dates><year>2013</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1744-7658 (Electronic)&#xD;1354-3784 (Linking)</isbn><accession-num>23808708</accession-num><urls><related-urls><url>. However, the rescue in hippocampal JNK signaling and synaptic markers achieved by metformin did not improve cognitive function in obese T2D mice ADDIN EN.CITE <EndNote><Cite><Author>Ahmed</Author><Year>2017</Year><RecNum>3754</RecNum><DisplayText><style face="superscript">326</style></DisplayText><record><rec-number>3754</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535918283">3754</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ahmed, Sara</author><author>Mahmood, Zahra</author><author>Javed, Aneela</author><author>Hashmi, Shoaib Naiyer</author><author>Zerr, Inga</author><author>Zafar, Saima</author><author>Zahid, Saadia</author></authors></contributors><titles><title>Effect of Metformin on Adult Hippocampal Neurogenesis: Comparison with Donepezil and Links to Cognition</title><secondary-title>Journal of Molecular Neuroscience</secondary-title></titles><periodical><full-title>Journal of Molecular Neuroscience</full-title></periodical><pages>88-98</pages><volume>62</volume><number>1</number><dates><year>2017</year><pub-dates><date>2017/04/04</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>0895-8696&#xD;1559-1166</isbn><urls><related-urls><url> and even promoted hepatic mitochondrial dysfunction and cell death ADDIN EN.CITE <EndNote><Cite><Author>Li</Author><Year>2012</Year><RecNum>3755</RecNum><DisplayText><style face="superscript">327</style></DisplayText><record><rec-number>3755</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535918283">3755</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Li, Jiejie</author><author>Deng, Jiao</author><author>Sheng, Wenli</author><author>Zuo, Zhiyi</author></authors></contributors><titles><title>Metformin attenuates Alzheimer&apos;s disease-like neuropathology in obese, leptin-resistant mice</title><secondary-title>Pharmacology Biochemistry and Behavior</secondary-title></titles><periodical><full-title>Pharmacology Biochemistry and Behavior</full-title></periodical><pages>564-574</pages><volume>101</volume><number>4</number><dates><year>2012</year><pub-dates><date>2012/06</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>0091-3057</isbn><urls><related-urls><url> its role in aging and AD, metformin decreased the risk for dementia in aged individuals and improved cognition in AD patients ADDIN EN.CITE <EndNote><Cite><Author>Carvalho</Author><Year>2007</Year><RecNum>3756</RecNum><DisplayText><style face="superscript">328</style></DisplayText><record><rec-number>3756</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535918283">3756</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Carvalho, Cristina</author><author>Correia, Sónia</author><author>Santos, Maria S.</author><author>Sei?a, Raquel</author><author>Oliveira, Catarina R.</author><author>Moreira, Paula I.</author></authors></contributors><titles><title>Metformin promotes isolated rat liver mitochondria impairment</title><secondary-title>Molecular and Cellular Biochemistry</secondary-title></titles><periodical><full-title>Molecular and Cellular Biochemistry</full-title></periodical><pages>75-83</pages><volume>308</volume><number>1-2</number><dates><year>2007</year><pub-dates><date>2007/10/02</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>0300-8177&#xD;1573-4919</isbn><urls><related-urls><url> PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ic3U8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxSZWNO

dW0+Mzc3MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjMy

OTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NzA8L3JlYy1udW1i

ZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBo

cGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxODU2MiI+Mzc3MDwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SHN1LCBDLiBDLjwvYXV0aG9yPjxhdXRob3I+

V2FobHF2aXN0LCBNLiBMLjwvYXV0aG9yPjxhdXRob3I+TGVlLCBNLiBTLjwvYXV0aG9yPjxhdXRo

b3I+VHNhaSwgSC4gTi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk

cmVzcz5EaXZpc2lvbiBvZiBIZWFsdGggUG9saWN5IFJlc2VhcmNoIGFuZCBEZXZlbG9wbWVudCwg

SW5zdGl0dXRlIG9mIFBvcHVsYXRpb24gSGVhbHRoIFNjaWVuY2VzLCBOYXRpb25hbCBIZWFsdGgg

UmVzZWFyY2ggSW5zdGl0dXRlcywgWmh1bmFuLCBNaWFvbGkgQ291bnR5LCBUYWl3YW4sIFJPQy4g

Y2NoQG5ocmkub3JnLnR3PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+SW5jaWRlbmNlIG9m

IGRlbWVudGlhIGlzIGluY3JlYXNlZCBpbiB0eXBlIDIgZGlhYmV0ZXMgYW5kIHJlZHVjZWQgYnkg

dGhlIHVzZSBvZiBzdWxmb255bHVyZWFzIGFuZCBtZXRmb3JtaW48L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+SiBBbHpoZWltZXJzIERpczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2Rp

Y2FsPjxmdWxsLXRpdGxlPkogQWx6aGVpbWVycyBEaXM8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz40ODUtOTM8L3BhZ2VzPjx2b2x1bWU+MjQ8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJl

cj48a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQg

b3Zlcjwva2V5d29yZD48a2V5d29yZD5BbmFseXNpcyBvZiBWYXJpYW5jZTwva2V5d29yZD48a2V5

d29yZD5Db2hvcnQgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5EZW1lbnRpYS8qZXBpZGVtaW9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkRpYWJldGVzIE1lbGxpdHVzLCBUeXBlIDIvKmRydWcgdGhl

cmFweS8qZXBpZGVtaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5

d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlwb2dseWNlbWljIEFnZW50cy8qdGhlcmFw

ZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkluY2lkZW5jZTwva2V5d29yZD48a2V5d29yZD5J

bnN1cmFuY2UsIEhlYWx0aC9zdGF0aXN0aWNzICZhbXA7IG51bWVyaWNhbCBkYXRhPC9rZXl3b3Jk

PjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWV0Zm9ybWluLyp0aGVyYXBldXRpYyB1

c2U8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UHJldmFs

ZW5jZTwva2V5d29yZD48a2V5d29yZD5SZXRyb3NwZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtl

eXdvcmQ+U3VsZm9ueWx1cmVhIENvbXBvdW5kcy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxr

ZXl3b3JkPlRhaXdhbi9lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAxMTwveWVhcj48L2RhdGVzPjxpc2JuPjE4NzUtODkwOCAoRWxlY3Ryb25pYykmI3hEOzEz

ODctMjg3NyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjEyOTcyNzY8L2FjY2Vzc2lv

bi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdv

di9wdWJtZWQvMjEyOTcyNzY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjEwLjMyMzMvSkFELTIwMTEtMTAxNTI0PC9lbGVjdHJvbmljLXJlc291cmNl

LW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ic3U8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxSZWNO

dW0+Mzc3MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjMy

OTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NzA8L3JlYy1udW1i

ZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBo

cGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxODU2MiI+Mzc3MDwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SHN1LCBDLiBDLjwvYXV0aG9yPjxhdXRob3I+

V2FobHF2aXN0LCBNLiBMLjwvYXV0aG9yPjxhdXRob3I+TGVlLCBNLiBTLjwvYXV0aG9yPjxhdXRo

b3I+VHNhaSwgSC4gTi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk

cmVzcz5EaXZpc2lvbiBvZiBIZWFsdGggUG9saWN5IFJlc2VhcmNoIGFuZCBEZXZlbG9wbWVudCwg

SW5zdGl0dXRlIG9mIFBvcHVsYXRpb24gSGVhbHRoIFNjaWVuY2VzLCBOYXRpb25hbCBIZWFsdGgg

UmVzZWFyY2ggSW5zdGl0dXRlcywgWmh1bmFuLCBNaWFvbGkgQ291bnR5LCBUYWl3YW4sIFJPQy4g

Y2NoQG5ocmkub3JnLnR3PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+SW5jaWRlbmNlIG9m

IGRlbWVudGlhIGlzIGluY3JlYXNlZCBpbiB0eXBlIDIgZGlhYmV0ZXMgYW5kIHJlZHVjZWQgYnkg

dGhlIHVzZSBvZiBzdWxmb255bHVyZWFzIGFuZCBtZXRmb3JtaW48L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+SiBBbHpoZWltZXJzIERpczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2Rp

Y2FsPjxmdWxsLXRpdGxlPkogQWx6aGVpbWVycyBEaXM8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz40ODUtOTM8L3BhZ2VzPjx2b2x1bWU+MjQ8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJl

cj48a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQg

b3Zlcjwva2V5d29yZD48a2V5d29yZD5BbmFseXNpcyBvZiBWYXJpYW5jZTwva2V5d29yZD48a2V5

d29yZD5Db2hvcnQgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5EZW1lbnRpYS8qZXBpZGVtaW9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkRpYWJldGVzIE1lbGxpdHVzLCBUeXBlIDIvKmRydWcgdGhl

cmFweS8qZXBpZGVtaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5

d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlwb2dseWNlbWljIEFnZW50cy8qdGhlcmFw

ZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkluY2lkZW5jZTwva2V5d29yZD48a2V5d29yZD5J

bnN1cmFuY2UsIEhlYWx0aC9zdGF0aXN0aWNzICZhbXA7IG51bWVyaWNhbCBkYXRhPC9rZXl3b3Jk

PjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWV0Zm9ybWluLyp0aGVyYXBldXRpYyB1

c2U8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UHJldmFs

ZW5jZTwva2V5d29yZD48a2V5d29yZD5SZXRyb3NwZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtl

eXdvcmQ+U3VsZm9ueWx1cmVhIENvbXBvdW5kcy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxr

ZXl3b3JkPlRhaXdhbi9lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAxMTwveWVhcj48L2RhdGVzPjxpc2JuPjE4NzUtODkwOCAoRWxlY3Ryb25pYykmI3hEOzEz

ODctMjg3NyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjEyOTcyNzY8L2FjY2Vzc2lv

bi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdv

di9wdWJtZWQvMjEyOTcyNzY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjEwLjMyMzMvSkFELTIwMTEtMTAxNTI0PC9lbGVjdHJvbmljLXJlc291cmNl

LW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 329. This may involve the attenuation in neuronal insulin resistance and AD-like neuropathology, most likely via AMPK-related regulation of APP amyloidogenic processing; inhibition of mTOR and subsequent autophagic/lysosomal removal of Aβ; and/or the stimulation of PP2A activity and decreased Tau hyperphosphorylation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYWk8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxSZWNO

dW0+Mzc1OTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjMz

MCwzMzE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zNzU5PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTgyODMiPjM3NTk8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkNhaSwgWmhpeW91PC9hdXRob3I+PGF1

dGhvcj5SYXRrYSwgQW5uYTwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVz

Pjx0aXRsZT5PcGlvaWQgU3lzdGVtIGFuZCBBbHpoZWltZXLigJlzIERpc2Vhc2U8L3RpdGxlPjxz

ZWNvbmRhcnktdGl0bGU+TmV1cm9Nb2xlY3VsYXIgTWVkaWNpbmU8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb01vbGVjdWxhciBNZWRpY2luZTwv

ZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjkxLTExMTwvcGFnZXM+PHZvbHVtZT4xNDwv

dm9sdW1lPjxudW1iZXI+MjwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDEyPC95ZWFyPjxwdWItZGF0

ZXM+PGRhdGU+MjAxMi8wNC8yMjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxwdWJsaXNoZXI+

U3ByaW5nZXIgTmF0dXJlPC9wdWJsaXNoZXI+PGlzYm4+MTUzNS0xMDg0JiN4RDsxNTU5LTExNzQ8

L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjEwMDcv

czEyMDE3LTAxMi04MTgwLTM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjEwLjEwMDcvczEyMDE3LTAxMi04MTgwLTM8L2VsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk1vb3JlPC9BdXRob3I+PFllYXI+

MjAxMzwvWWVhcj48UmVjTnVtPjM3NzE8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NzE8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxODY3MSI+Mzc3MTwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TW9vcmUsIEUuIE0uPC9hdXRo

b3I+PGF1dGhvcj5NYW5kZXIsIEEuIEcuPC9hdXRob3I+PGF1dGhvcj5BbWVzLCBELjwvYXV0aG9y

PjxhdXRob3I+S290b3dpY3osIE0uIEEuPC9hdXRob3I+PGF1dGhvcj5DYXJuZSwgUi4gUC48L2F1

dGhvcj48YXV0aG9yPkJyb2RhdHksIEguPC9hdXRob3I+PGF1dGhvcj5Xb29kd2FyZCwgTS48L2F1

dGhvcj48YXV0aG9yPkJvdW5keSwgSy48L2F1dGhvcj48YXV0aG9yPkVsbGlzLCBLLiBBLjwvYXV0

aG9yPjxhdXRob3I+QnVzaCwgQS4gSS48L2F1dGhvcj48YXV0aG9yPkZhdXgsIE4uIEcuPC9hdXRo

b3I+PGF1dGhvcj5NYXJ0aW5zLCBSLjwvYXV0aG9yPjxhdXRob3I+U3pvZWtlLCBDLjwvYXV0aG9y

PjxhdXRob3I+Um93ZSwgQy48L2F1dGhvcj48YXV0aG9yPldhdHRlcnMsIEQuIEEuPC9hdXRob3I+

PGF1dGhvcj5BaWJsIEludmVzdGlnYXRvcnM8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5Db3JyZXNwb25kaW5nIGF1dGhvcjogRWlsZWVuIE0uIE1vb3JlLCBl

aWxlZW4ubW9vcmVAYmFyd29uaGVhbHRoLm9yZy5hdS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0

aXRsZT5JbmNyZWFzZWQgcmlzayBvZiBjb2duaXRpdmUgaW1wYWlybWVudCBpbiBwYXRpZW50cyB3

aXRoIGRpYWJldGVzIGlzIGFzc29jaWF0ZWQgd2l0aCBtZXRmb3JtaW48L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+RGlhYmV0ZXMgQ2FyZTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4y

OTgxLTc8L3BhZ2VzPjx2b2x1bWU+MzY8L3ZvbHVtZT48bnVtYmVyPjEwPC9udW1iZXI+PGtleXdv

cmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tl

eXdvcmQ+PGtleXdvcmQ+Q2FsY2l1bS90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+

Q29nbml0aW9uIERpc29yZGVycy8qZXBpZGVtaW9sb2d5LypldGlvbG9neTwva2V5d29yZD48a2V5

d29yZD5EaWFiZXRlcyBNZWxsaXR1cy9ibG9vZC8qZHJ1ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3

b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TG9n

aXN0aWMgTW9kZWxzPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWV0

Zm9ybWluLyphZHZlcnNlIGVmZmVjdHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlByb3NwZWN0aXZlIFN0dWRpZXM8L2tleXdv

cmQ+PGtleXdvcmQ+Vml0YW1pbiBCIDEyL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29y

ZD5WaXRhbWluIEIgMTIgRGVmaWNpZW5jeS9kcnVnIHRoZXJhcHk8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPk9jdDwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE5MzUtNTU0OCAoRWxlY3Ryb25pYykmI3hEOzAxNDktNTk5

MiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjQwMDkzMDE8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMjQwMDkzMDE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMzc4MTU2

ODwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMjMzNy9kYzEzLTAyMjk8L2Vs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYWk8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxSZWNO

dW0+Mzc1OTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjMz

MCwzMzE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zNzU5PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTgyODMiPjM3NTk8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkNhaSwgWmhpeW91PC9hdXRob3I+PGF1

dGhvcj5SYXRrYSwgQW5uYTwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVz

Pjx0aXRsZT5PcGlvaWQgU3lzdGVtIGFuZCBBbHpoZWltZXLigJlzIERpc2Vhc2U8L3RpdGxlPjxz

ZWNvbmRhcnktdGl0bGU+TmV1cm9Nb2xlY3VsYXIgTWVkaWNpbmU8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb01vbGVjdWxhciBNZWRpY2luZTwv

ZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjkxLTExMTwvcGFnZXM+PHZvbHVtZT4xNDwv

dm9sdW1lPjxudW1iZXI+MjwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDEyPC95ZWFyPjxwdWItZGF0

ZXM+PGRhdGU+MjAxMi8wNC8yMjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxwdWJsaXNoZXI+

U3ByaW5nZXIgTmF0dXJlPC9wdWJsaXNoZXI+PGlzYm4+MTUzNS0xMDg0JiN4RDsxNTU5LTExNzQ8

L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjEwMDcv

czEyMDE3LTAxMi04MTgwLTM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjEwLjEwMDcvczEyMDE3LTAxMi04MTgwLTM8L2VsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk1vb3JlPC9BdXRob3I+PFllYXI+

MjAxMzwvWWVhcj48UmVjTnVtPjM3NzE8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NzE8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxODY3MSI+Mzc3MTwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TW9vcmUsIEUuIE0uPC9hdXRo

b3I+PGF1dGhvcj5NYW5kZXIsIEEuIEcuPC9hdXRob3I+PGF1dGhvcj5BbWVzLCBELjwvYXV0aG9y

PjxhdXRob3I+S290b3dpY3osIE0uIEEuPC9hdXRob3I+PGF1dGhvcj5DYXJuZSwgUi4gUC48L2F1

dGhvcj48YXV0aG9yPkJyb2RhdHksIEguPC9hdXRob3I+PGF1dGhvcj5Xb29kd2FyZCwgTS48L2F1

dGhvcj48YXV0aG9yPkJvdW5keSwgSy48L2F1dGhvcj48YXV0aG9yPkVsbGlzLCBLLiBBLjwvYXV0

aG9yPjxhdXRob3I+QnVzaCwgQS4gSS48L2F1dGhvcj48YXV0aG9yPkZhdXgsIE4uIEcuPC9hdXRo

b3I+PGF1dGhvcj5NYXJ0aW5zLCBSLjwvYXV0aG9yPjxhdXRob3I+U3pvZWtlLCBDLjwvYXV0aG9y

PjxhdXRob3I+Um93ZSwgQy48L2F1dGhvcj48YXV0aG9yPldhdHRlcnMsIEQuIEEuPC9hdXRob3I+

PGF1dGhvcj5BaWJsIEludmVzdGlnYXRvcnM8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5Db3JyZXNwb25kaW5nIGF1dGhvcjogRWlsZWVuIE0uIE1vb3JlLCBl

aWxlZW4ubW9vcmVAYmFyd29uaGVhbHRoLm9yZy5hdS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0

aXRsZT5JbmNyZWFzZWQgcmlzayBvZiBjb2duaXRpdmUgaW1wYWlybWVudCBpbiBwYXRpZW50cyB3

aXRoIGRpYWJldGVzIGlzIGFzc29jaWF0ZWQgd2l0aCBtZXRmb3JtaW48L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+RGlhYmV0ZXMgQ2FyZTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4y

OTgxLTc8L3BhZ2VzPjx2b2x1bWU+MzY8L3ZvbHVtZT48bnVtYmVyPjEwPC9udW1iZXI+PGtleXdv

cmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tl

eXdvcmQ+PGtleXdvcmQ+Q2FsY2l1bS90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+

Q29nbml0aW9uIERpc29yZGVycy8qZXBpZGVtaW9sb2d5LypldGlvbG9neTwva2V5d29yZD48a2V5

d29yZD5EaWFiZXRlcyBNZWxsaXR1cy9ibG9vZC8qZHJ1ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3

b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TG9n

aXN0aWMgTW9kZWxzPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWV0

Zm9ybWluLyphZHZlcnNlIGVmZmVjdHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlByb3NwZWN0aXZlIFN0dWRpZXM8L2tleXdv

cmQ+PGtleXdvcmQ+Vml0YW1pbiBCIDEyL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29y

ZD5WaXRhbWluIEIgMTIgRGVmaWNpZW5jeS9kcnVnIHRoZXJhcHk8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPk9jdDwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE5MzUtNTU0OCAoRWxlY3Ryb25pYykmI3hEOzAxNDktNTk5

MiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjQwMDkzMDE8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMjQwMDkzMDE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMzc4MTU2

ODwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMjMzNy9kYzEzLTAyMjk8L2Vs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 330,331. Given such promising data, according to , two Phase II clinical trials on the effects of metformin administration in middle-aged and aged obese patients with amnestic MCI (NCT00620191), or in MCI and early AD patients (NCT01965756) were recently completed and results are awaited soon.The possible limitations of using sulfonylureas to treat ADGlipizide and Glyburide (Glibenclamide) are the most used sulfonylureas of second generation, being relatively inexpensive and quite efficient ADDIN EN.CITE <EndNote><Cite><Author>Corbett</Author><Year>2013</Year><RecNum>3749</RecNum><DisplayText><style face="superscript">323</style></DisplayText><record><rec-number>3749</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535917507">3749</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Corbett, A.</author><author>Ballard, C.</author></authors></contributors><titles><title>Is a potential Alzheimer&apos;s therapy already in use for other conditions? Can medications for hypertension, diabetes and acne help with the symptoms?</title><secondary-title>Expert Opin Investig Drugs</secondary-title></titles><pages>941-3</pages><volume>22</volume><number>8</number><keywords><keyword>Alzheimer Disease/*drug therapy</keyword><keyword>Angiotensin Receptor Antagonists/therapeutic use</keyword><keyword>Anti-Bacterial Agents/therapeutic use</keyword><keyword>Calcium Channel Blockers/therapeutic use</keyword><keyword>*Drug Repositioning</keyword><keyword>Humans</keyword><keyword>Hypoglycemic Agents/therapeutic use</keyword></keywords><dates><year>2013</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1744-7658 (Electronic)&#xD;1354-3784 (Linking)</isbn><accession-num>23808708</accession-num><urls><related-urls><url>. Sulfonylureas promote glucose-independent insulin secretion mainly via activation of specific receptors. These promote the closure of ATP-sensitive K+ channels and plasma membrane depolarization, allowing Ca2+ influx through voltage-gated, L-type Ca2+ channels and exocytosis of insulin-containing vesicles PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWNrc3RlaW48L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFy

PjxSZWNOdW0+MzgxODwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjMzMjwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM4MTg8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxOTI4OSI+MzgxODwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+S2lja3N0ZWluLCBFLjwvYXV0aG9y

PjxhdXRob3I+S3JhdXNzLCBTLjwvYXV0aG9yPjxhdXRob3I+VGhvcm5oaWxsLCBQLjwvYXV0aG9y

PjxhdXRob3I+UnV0c2Nob3csIEQuPC9hdXRob3I+PGF1dGhvcj5aZWxsZXIsIFIuPC9hdXRob3I+

PGF1dGhvcj5TaGFya2V5LCBKLjwvYXV0aG9yPjxhdXRob3I+V2lsbGlhbXNvbiwgUi48L2F1dGhv

cj48YXV0aG9yPkZ1Y2hzLCBNLjwvYXV0aG9yPjxhdXRob3I+S29obGVyLCBBLjwvYXV0aG9yPjxh

dXRob3I+R2xvc3NtYW5uLCBILjwvYXV0aG9yPjxhdXRob3I+U2NobmVpZGVyLCBSLjwvYXV0aG9y

PjxhdXRob3I+U3V0aGVybGFuZCwgQy48L2F1dGhvcj48YXV0aG9yPlNjaHdlaWdlciwgUy48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5NYXgtUGxhbmNrIElu

c3RpdHV0ZSBmb3IgTW9sZWN1bGFyIEdlbmV0aWNzLDE0MTk1IEJlcmxpbiwgR2VybWFueS48L2F1

dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5CaWd1YW5pZGUgbWV0Zm9ybWluIGFjdHMgb24gdGF1

IHBob3NwaG9yeWxhdGlvbiB2aWEgbVRPUi9wcm90ZWluIHBob3NwaGF0YXNlIDJBIChQUDJBKSBz

aWduYWxpbmc8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2NpIFUgUyBB

PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UHJvYyBO

YXRsIEFjYWQgU2NpIFUgUyBBPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjE4MzAt

NTwvcGFnZXM+PHZvbHVtZT4xMDc8L3ZvbHVtZT48bnVtYmVyPjUwPC9udW1iZXI+PGtleXdvcmRz

PjxrZXl3b3JkPkFkZW55bGF0ZSBLaW5hc2UvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5B

bHpoZWltZXIgRGlzZWFzZS9tZXRhYm9saXNtL3BhdGhvbG9neS9waHlzaW9wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5DZWxscywgQ3VsdHVyZWQ8

L2tleXdvcmQ+PGtleXdvcmQ+RW56eW1lIEluaGliaXRvcnMvcGhhcm1hY29sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkVwaXRvcGVzPC9rZXl3b3JkPjxrZXl3b3JkPkhlTGEgQ2VsbHM8L2tleXdvcmQ+

PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBBZ2VudHMvcGhh

cm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1lY2hhbmlzdGljIFRhcmdldCBvZiBSYXBhbXlj

aW4gQ29tcGxleCAxPC9rZXl3b3JkPjxrZXl3b3JkPk1ldGZvcm1pbi8qcGhhcm1hY29sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgVHJhbnNnZW5pYzwv

a2V5d29yZD48a2V5d29yZD5NdWx0aXByb3RlaW4gQ29tcGxleGVzPC9rZXl3b3JkPjxrZXl3b3Jk

Pk5ldXJvZmlicmlsbGFyeSBUYW5nbGVzLyptZXRhYm9saXNtL3BhdGhvbG9neTwva2V5d29yZD48

a2V5d29yZD5OZXVyb25zL2N5dG9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+T2th

ZGFpYyBBY2lkL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5QaG9zcGhvcnlsYXRpb248

L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVpbiBQaG9zcGhhdGFzZSAyL2dlbmV0aWNzLyptZXRhYm9s

aXNtPC9rZXl3b3JkPjxrZXl3b3JkPlByb3RlaW5zL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+U2lnbmFsIFRyYW5zZHVjdGlvbi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+VE9S

IFNlcmluZS1UaHJlb25pbmUgS2luYXNlcy9nZW5ldGljcy8qbWV0YWJvbGlzbTwva2V5d29yZD48

a2V5d29yZD50YXUgUHJvdGVpbnMvZ2VuZXRpY3MvKm1ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3

b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMDwveWVhcj48cHViLWRhdGVzPjxkYXRlPkRlYyAxNDwvZGF0

ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjEwOTEtNjQ5MCAoRWxlY3Ryb25pYykmI3hEOzAw

MjctODQyNCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjEwOTgyODc8L2FjY2Vzc2lv

bi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdv

di9wdWJtZWQvMjEwOTgyODc8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1D

MzAwMzA3MjwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA3My9wbmFzLjA5

MTI3OTMxMDc8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5v

dGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWNrc3RlaW48L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFy

PjxSZWNOdW0+MzgxODwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjMzMjwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM4MTg8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxOTI4OSI+MzgxODwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+S2lja3N0ZWluLCBFLjwvYXV0aG9y

PjxhdXRob3I+S3JhdXNzLCBTLjwvYXV0aG9yPjxhdXRob3I+VGhvcm5oaWxsLCBQLjwvYXV0aG9y

PjxhdXRob3I+UnV0c2Nob3csIEQuPC9hdXRob3I+PGF1dGhvcj5aZWxsZXIsIFIuPC9hdXRob3I+

PGF1dGhvcj5TaGFya2V5LCBKLjwvYXV0aG9yPjxhdXRob3I+V2lsbGlhbXNvbiwgUi48L2F1dGhv

cj48YXV0aG9yPkZ1Y2hzLCBNLjwvYXV0aG9yPjxhdXRob3I+S29obGVyLCBBLjwvYXV0aG9yPjxh

dXRob3I+R2xvc3NtYW5uLCBILjwvYXV0aG9yPjxhdXRob3I+U2NobmVpZGVyLCBSLjwvYXV0aG9y

PjxhdXRob3I+U3V0aGVybGFuZCwgQy48L2F1dGhvcj48YXV0aG9yPlNjaHdlaWdlciwgUy48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5NYXgtUGxhbmNrIElu

c3RpdHV0ZSBmb3IgTW9sZWN1bGFyIEdlbmV0aWNzLDE0MTk1IEJlcmxpbiwgR2VybWFueS48L2F1

dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5CaWd1YW5pZGUgbWV0Zm9ybWluIGFjdHMgb24gdGF1

IHBob3NwaG9yeWxhdGlvbiB2aWEgbVRPUi9wcm90ZWluIHBob3NwaGF0YXNlIDJBIChQUDJBKSBz

aWduYWxpbmc8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2NpIFUgUyBB

PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UHJvYyBO

YXRsIEFjYWQgU2NpIFUgUyBBPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjE4MzAt

NTwvcGFnZXM+PHZvbHVtZT4xMDc8L3ZvbHVtZT48bnVtYmVyPjUwPC9udW1iZXI+PGtleXdvcmRz

PjxrZXl3b3JkPkFkZW55bGF0ZSBLaW5hc2UvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5B

bHpoZWltZXIgRGlzZWFzZS9tZXRhYm9saXNtL3BhdGhvbG9neS9waHlzaW9wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5DZWxscywgQ3VsdHVyZWQ8

L2tleXdvcmQ+PGtleXdvcmQ+RW56eW1lIEluaGliaXRvcnMvcGhhcm1hY29sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkVwaXRvcGVzPC9rZXl3b3JkPjxrZXl3b3JkPkhlTGEgQ2VsbHM8L2tleXdvcmQ+

PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBBZ2VudHMvcGhh

cm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1lY2hhbmlzdGljIFRhcmdldCBvZiBSYXBhbXlj

aW4gQ29tcGxleCAxPC9rZXl3b3JkPjxrZXl3b3JkPk1ldGZvcm1pbi8qcGhhcm1hY29sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgVHJhbnNnZW5pYzwv

a2V5d29yZD48a2V5d29yZD5NdWx0aXByb3RlaW4gQ29tcGxleGVzPC9rZXl3b3JkPjxrZXl3b3Jk

Pk5ldXJvZmlicmlsbGFyeSBUYW5nbGVzLyptZXRhYm9saXNtL3BhdGhvbG9neTwva2V5d29yZD48

a2V5d29yZD5OZXVyb25zL2N5dG9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+T2th

ZGFpYyBBY2lkL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5QaG9zcGhvcnlsYXRpb248

L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVpbiBQaG9zcGhhdGFzZSAyL2dlbmV0aWNzLyptZXRhYm9s

aXNtPC9rZXl3b3JkPjxrZXl3b3JkPlByb3RlaW5zL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+U2lnbmFsIFRyYW5zZHVjdGlvbi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+VE9S

IFNlcmluZS1UaHJlb25pbmUgS2luYXNlcy9nZW5ldGljcy8qbWV0YWJvbGlzbTwva2V5d29yZD48

a2V5d29yZD50YXUgUHJvdGVpbnMvZ2VuZXRpY3MvKm1ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3

b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMDwveWVhcj48cHViLWRhdGVzPjxkYXRlPkRlYyAxNDwvZGF0

ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjEwOTEtNjQ5MCAoRWxlY3Ryb25pYykmI3hEOzAw

MjctODQyNCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjEwOTgyODc8L2FjY2Vzc2lv

bi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdv

di9wdWJtZWQvMjEwOTgyODc8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1D

MzAwMzA3MjwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA3My9wbmFzLjA5

MTI3OTMxMDc8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5v

dGU+AG==

ADDIN EN.CITE.DATA 332. However, sulfonylureas may be also agonists of PPARγ ADDIN EN.CITE <EndNote><Cite><Author>Tahrani</Author><Year>2016</Year><RecNum>3823</RecNum><DisplayText><style face="superscript">333</style></DisplayText><record><rec-number>3823</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535919353">3823</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tahrani, A. A.</author><author>Barnett, A. H.</author><author>Bailey, C. J.</author></authors></contributors><auth-address>Centre of Endocrinology, Diabetes and Metabolism, 2nd Floor, Institute of Biomedical Research, University of Birmingham, Birmingham, B15 2TT, UK.&#xD;Department of Diabetes and Endocrinology, Heart of England NHS Foundation Trust, Birmingham, B9 5SS, UK.&#xD;School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK.</auth-address><titles><title>Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus</title><secondary-title>Nat Rev Endocrinol</secondary-title></titles><pages>566-92</pages><volume>12</volume><number>10</number><dates><year>2016</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1759-5037 (Electronic)&#xD;1759-5029 (Linking)</isbn><accession-num>27339889</accession-num><urls><related-urls><url>, and/or inhibit hepatic glucose production and insulin clearance ADDIN EN.CITE <EndNote><Cite><Author>Corbett</Author><Year>2013</Year><RecNum>3749</RecNum><DisplayText><style face="superscript">323</style></DisplayText><record><rec-number>3749</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535917507">3749</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Corbett, A.</author><author>Ballard, C.</author></authors></contributors><titles><title>Is a potential Alzheimer&apos;s therapy already in use for other conditions? Can medications for hypertension, diabetes and acne help with the symptoms?</title><secondary-title>Expert Opin Investig Drugs</secondary-title></titles><pages>941-3</pages><volume>22</volume><number>8</number><keywords><keyword>Alzheimer Disease/*drug therapy</keyword><keyword>Angiotensin Receptor Antagonists/therapeutic use</keyword><keyword>Anti-Bacterial Agents/therapeutic use</keyword><keyword>Calcium Channel Blockers/therapeutic use</keyword><keyword>*Drug Repositioning</keyword><keyword>Humans</keyword><keyword>Hypoglycemic Agents/therapeutic use</keyword></keywords><dates><year>2013</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1744-7658 (Electronic)&#xD;1354-3784 (Linking)</isbn><accession-num>23808708</accession-num><urls><related-urls><url>. Given their good tolerability, sulfonylureas can be used as mono- or multi-therapy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMsMzI0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMsMzI0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 323,324.The increased risk for hypoglycemia (particularly among elderly patients), and the higher cardiovascular mortality and weight gain associated with sulfonylureas may somehow limit their use against AD ADDIN EN.CITE <EndNote><Cite><Author>Sandhir</Author><Year>2015</Year><RecNum>3750</RecNum><DisplayText><style face="superscript">324</style></DisplayText><record><rec-number>3750</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535917565">3750</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sandhir, R.</author><author>Gupta, S.</author></authors></contributors><auth-address>Rajat Sandhir, Smriti Gupta, Department of Biochemistry, Panjab University, Chandigarh 160014, India.</auth-address><titles><title>Molecular and biochemical trajectories from diabetes to Alzheimer&apos;s disease: A critical appraisal</title><secondary-title>World J Diabetes</secondary-title></titles><pages>1223-42</pages><volume>6</volume><number>12</number><keywords><keyword>Alzheimer&apos;s disease</keyword><keyword>Diabetes mellitus</keyword><keyword>Insulin</keyword><keyword>Type 2 diabetes</keyword><keyword>Type 3 diabetes</keyword></keywords><dates><year>2015</year><pub-dates><date>Sep 25</date></pub-dates></dates><isbn>1948-9358 (Print)&#xD;1948-9358 (Linking)</isbn><accession-num>26464760</accession-num><urls><related-urls><url>. Nevertheless, sulfonylureas also attenuated AD-like dementia symptoms in T2D patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXJ2YWxobzwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+

PFJlY051bT4zODI5PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MzM0LDMzNTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM4Mjk8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxOTUxOSI+MzgyOTwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Q2FydmFsaG8sIEMuPC9hdXRo

b3I+PGF1dGhvcj5Db3JyZWlhLCBTLjwvYXV0aG9yPjxhdXRob3I+U2FudG9zLCBNLiBTLjwvYXV0

aG9yPjxhdXRob3I+U2VpY2EsIFIuPC9hdXRob3I+PGF1dGhvcj5PbGl2ZWlyYSwgQy4gUi48L2F1

dGhvcj48YXV0aG9yPk1vcmVpcmEsIFAuIEkuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBab29sb2d5IC0gRmFjdWx0eSBvZiBTY2ll

bmNlcyBhbmQgVGVjaG5vbG9neSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhLCBDb2ltYnJhIDMwMDAt

MzU0LCBQb3J0dWdhbC48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5NZXRmb3JtaW4gcHJv

bW90ZXMgaXNvbGF0ZWQgcmF0IGxpdmVyIG1pdG9jaG9uZHJpYSBpbXBhaXJtZW50PC90aXRsZT48

c2Vjb25kYXJ5LXRpdGxlPk1vbCBDZWxsIEJpb2NoZW08L3NlY29uZGFyeS10aXRsZT48L3RpdGxl

cz48cGFnZXM+NzUtODM8L3BhZ2VzPjx2b2x1bWU+MzA4PC92b2x1bWU+PG51bWJlcj4xLTI8L251

bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5DZWxsIFJl

c3BpcmF0aW9uL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5IeWRyb2dlbiBQZXJveGlk

ZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkxpcGlkIFBlcm94aWRhdGlvbi9kcnVnIGVm

ZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NZW1icmFuZSBQ

b3RlbnRpYWwsIE1pdG9jaG9uZHJpYWwvZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPk1l

dGZvcm1pbi8qcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1pdG9jaG9uZHJpYSwgTGl2

ZXIvKmRydWcgZWZmZWN0cy8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1pdG9jaG9uZHJp

YWwgTWVtYnJhbmUgVHJhbnNwb3J0IFByb3RlaW5zL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+T3hpZGF0aXZlIFBob3NwaG9yeWxhdGlvbi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdv

cmQ+T3hpZGF0aXZlIFN0cmVzcy9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+T3h5Z2Vu

IENvbnN1bXB0aW9uL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5SYXRzPC9rZXl3b3Jk

PjxrZXl3b3JkPlJhdHMsIFdpc3Rhcjwva2V5d29yZD48a2V5d29yZD5TdWxmaHlkcnlsIENvbXBv

dW5kcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlRoaW9iYXJiaXR1cmljIEFjaWQgUmVh

Y3RpdmUgU3Vic3RhbmNlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5

ZWFyPjIwMDg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KYW48L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4wMzAwLTgxNzcgKFByaW50KSYjeEQ7MDMwMC04MTc3IChMaW5raW5nKTwvaXNi

bj48YWNjZXNzaW9uLW51bT4xNzkwOTk0NDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11

cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNzkwOTk0NDwvdXJs

PjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9z

MTEwMTAtMDA3LTk2MTQtMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRl

PjxDaXRlPjxBdXRob3I+Q2lnbmFyZWxsaTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJlY051

bT4zODMwPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zODMwPC9yZWMtbnVtYmVyPjxmb3Jl

aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRz

enpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTk3MDUiPjM4MzA8L2tleT48L2ZvcmVpZ24ta2V5

cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1

dG9ycz48YXV0aG9ycz48YXV0aG9yPkNpZ25hcmVsbGksIEEuPC9hdXRob3I+PGF1dGhvcj5HaW9y

Z2lubywgRi48L2F1dGhvcj48YXV0aG9yPlZldHRvciwgUi48L2F1dGhvcj48L2F1dGhvcnM+PC9j

b250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIEVtZXJnZW5jeSBhbmQgT3Jn

YW4gVHJhbnNwbGFudGF0aW9uLCBTZWN0aW9uIG9mIEludGVybmFsIE1lZGljaW5lLCBFbmRvY3Jp

bm9sb2d5LCBBbmRyb2xvZ3ksIGFuZCBNZXRhYm9saWMgRGlzZWFzZXMsIFVuaXZlcnNpdHkgb2Yg

QmFyaSAmcXVvdDtBbGRvIE1vcm8mcXVvdDsgLCBCYXJpICwgSXRhbHkgYW5kLjwvYXV0aC1hZGRy

ZXNzPjx0aXRsZXM+PHRpdGxlPlBoYXJtYWNvbG9naWMgYWdlbnRzIGZvciB0eXBlIDIgZGlhYmV0

ZXMgdGhlcmFweSBhbmQgcmVndWxhdGlvbiBvZiBhZGlwb2dlbmVzaXM8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+QXJjaCBQaHlzaW9sIEJpb2NoZW08L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48

cGFnZXM+MTM5LTUwPC9wYWdlcz48dm9sdW1lPjExOTwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVy

PjxrZXl3b3Jkcz48a2V5d29yZD5BZGlwb2dlbmVzaXMvKmRydWcgZWZmZWN0czwva2V5d29yZD48

a2V5d29yZD5BZGlwb3NlIFRpc3N1ZS9kcnVnIGVmZmVjdHMvcGF0aG9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgTWVsbGl0dXMsIFR5cGUg

Mi8qZHJ1ZyB0aGVyYXB5L21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1

bWFuczwva2V5d29yZD48a2V5d29yZD5IeXBvZ2x5Y2VtaWMgQWdlbnRzLypwaGFybWFjb2xvZ3kv

KnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5JbnN1bGluL2FuYWxvZ3MgJmFtcDsg

ZGVyaXZhdGl2ZXMvcGhhcm1hY29sb2d5L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29y

ZD5MaXBvZ2VuZXNpcy9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPk9jdDwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxpc2JuPjE3NDQtNDE2MCAoRWxlY3Ryb25pYykmI3hEOzEzODEtMzQ1NSAoTGlua2luZyk8

L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjM3MjQ5NDc8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0

ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjM3MjQ5NDc8

L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjMx

MDkvMTM4MTM0NTUuMjAxMy43OTY5OTY8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3Jk

PjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXJ2YWxobzwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+

PFJlY051bT4zODI5PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MzM0LDMzNTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM4Mjk8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxOTUxOSI+MzgyOTwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Q2FydmFsaG8sIEMuPC9hdXRo

b3I+PGF1dGhvcj5Db3JyZWlhLCBTLjwvYXV0aG9yPjxhdXRob3I+U2FudG9zLCBNLiBTLjwvYXV0

aG9yPjxhdXRob3I+U2VpY2EsIFIuPC9hdXRob3I+PGF1dGhvcj5PbGl2ZWlyYSwgQy4gUi48L2F1

dGhvcj48YXV0aG9yPk1vcmVpcmEsIFAuIEkuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBab29sb2d5IC0gRmFjdWx0eSBvZiBTY2ll

bmNlcyBhbmQgVGVjaG5vbG9neSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhLCBDb2ltYnJhIDMwMDAt

MzU0LCBQb3J0dWdhbC48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5NZXRmb3JtaW4gcHJv

bW90ZXMgaXNvbGF0ZWQgcmF0IGxpdmVyIG1pdG9jaG9uZHJpYSBpbXBhaXJtZW50PC90aXRsZT48

c2Vjb25kYXJ5LXRpdGxlPk1vbCBDZWxsIEJpb2NoZW08L3NlY29uZGFyeS10aXRsZT48L3RpdGxl

cz48cGFnZXM+NzUtODM8L3BhZ2VzPjx2b2x1bWU+MzA4PC92b2x1bWU+PG51bWJlcj4xLTI8L251

bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5DZWxsIFJl

c3BpcmF0aW9uL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5IeWRyb2dlbiBQZXJveGlk

ZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkxpcGlkIFBlcm94aWRhdGlvbi9kcnVnIGVm

ZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NZW1icmFuZSBQ

b3RlbnRpYWwsIE1pdG9jaG9uZHJpYWwvZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPk1l

dGZvcm1pbi8qcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1pdG9jaG9uZHJpYSwgTGl2

ZXIvKmRydWcgZWZmZWN0cy8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1pdG9jaG9uZHJp

YWwgTWVtYnJhbmUgVHJhbnNwb3J0IFByb3RlaW5zL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+T3hpZGF0aXZlIFBob3NwaG9yeWxhdGlvbi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdv

cmQ+T3hpZGF0aXZlIFN0cmVzcy9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+T3h5Z2Vu

IENvbnN1bXB0aW9uL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5SYXRzPC9rZXl3b3Jk

PjxrZXl3b3JkPlJhdHMsIFdpc3Rhcjwva2V5d29yZD48a2V5d29yZD5TdWxmaHlkcnlsIENvbXBv

dW5kcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlRoaW9iYXJiaXR1cmljIEFjaWQgUmVh

Y3RpdmUgU3Vic3RhbmNlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5

ZWFyPjIwMDg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KYW48L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4wMzAwLTgxNzcgKFByaW50KSYjeEQ7MDMwMC04MTc3IChMaW5raW5nKTwvaXNi

bj48YWNjZXNzaW9uLW51bT4xNzkwOTk0NDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11

cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNzkwOTk0NDwvdXJs

PjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9z

MTEwMTAtMDA3LTk2MTQtMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRl

PjxDaXRlPjxBdXRob3I+Q2lnbmFyZWxsaTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJlY051

bT4zODMwPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zODMwPC9yZWMtbnVtYmVyPjxmb3Jl

aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRz

enpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTk3MDUiPjM4MzA8L2tleT48L2ZvcmVpZ24ta2V5

cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1

dG9ycz48YXV0aG9ycz48YXV0aG9yPkNpZ25hcmVsbGksIEEuPC9hdXRob3I+PGF1dGhvcj5HaW9y

Z2lubywgRi48L2F1dGhvcj48YXV0aG9yPlZldHRvciwgUi48L2F1dGhvcj48L2F1dGhvcnM+PC9j

b250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIEVtZXJnZW5jeSBhbmQgT3Jn

YW4gVHJhbnNwbGFudGF0aW9uLCBTZWN0aW9uIG9mIEludGVybmFsIE1lZGljaW5lLCBFbmRvY3Jp

bm9sb2d5LCBBbmRyb2xvZ3ksIGFuZCBNZXRhYm9saWMgRGlzZWFzZXMsIFVuaXZlcnNpdHkgb2Yg

QmFyaSAmcXVvdDtBbGRvIE1vcm8mcXVvdDsgLCBCYXJpICwgSXRhbHkgYW5kLjwvYXV0aC1hZGRy

ZXNzPjx0aXRsZXM+PHRpdGxlPlBoYXJtYWNvbG9naWMgYWdlbnRzIGZvciB0eXBlIDIgZGlhYmV0

ZXMgdGhlcmFweSBhbmQgcmVndWxhdGlvbiBvZiBhZGlwb2dlbmVzaXM8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+QXJjaCBQaHlzaW9sIEJpb2NoZW08L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48

cGFnZXM+MTM5LTUwPC9wYWdlcz48dm9sdW1lPjExOTwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVy

PjxrZXl3b3Jkcz48a2V5d29yZD5BZGlwb2dlbmVzaXMvKmRydWcgZWZmZWN0czwva2V5d29yZD48

a2V5d29yZD5BZGlwb3NlIFRpc3N1ZS9kcnVnIGVmZmVjdHMvcGF0aG9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgTWVsbGl0dXMsIFR5cGUg

Mi8qZHJ1ZyB0aGVyYXB5L21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1

bWFuczwva2V5d29yZD48a2V5d29yZD5IeXBvZ2x5Y2VtaWMgQWdlbnRzLypwaGFybWFjb2xvZ3kv

KnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5JbnN1bGluL2FuYWxvZ3MgJmFtcDsg

ZGVyaXZhdGl2ZXMvcGhhcm1hY29sb2d5L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29y

ZD5MaXBvZ2VuZXNpcy9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPk9jdDwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxpc2JuPjE3NDQtNDE2MCAoRWxlY3Ryb25pYykmI3hEOzEzODEtMzQ1NSAoTGlua2luZyk8

L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjM3MjQ5NDc8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0

ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjM3MjQ5NDc8

L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjMx

MDkvMTM4MTM0NTUuMjAxMy43OTY5OTY8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3Jk

PjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 334,335. Similarly, Glipizide improved learning in diabetic individuals ADDIN EN.CITE <EndNote><Cite><Author>Exalto</Author><Year>2012</Year><RecNum>3831</RecNum><DisplayText><style face="superscript">336</style></DisplayText><record><rec-number>3831</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535919791">3831</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Exalto, L. G.</author><author>Whitmer, R. A.</author><author>Kappele, L. J.</author><author>Biessels, G. J.</author></authors></contributors><auth-address>Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands. l.g.exalto-2@umcutrecht.nl</auth-address><titles><title>An update on type 2 diabetes, vascular dementia and Alzheimer&apos;s disease</title><secondary-title>Exp Gerontol</secondary-title></titles><pages>858-64</pages><volume>47</volume><number>11</number><keywords><keyword>Alzheimer Disease/*physiopathology/prevention &amp; control</keyword><keyword>Clinical Trials as Topic</keyword><keyword>Comorbidity</keyword><keyword>Dementia, Vascular/*physiopathology/prevention &amp; control</keyword><keyword>Diabetes Mellitus, Type 2/*physiopathology/prevention &amp; control</keyword><keyword>Humans</keyword></keywords><dates><year>2012</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1873-6815 (Electronic)&#xD;0531-5565 (Linking)</isbn><accession-num>22884853</accession-num><urls><related-urls><url> and Glimepiride protected neurons against Aβ-induced synaptic injury ADDIN EN.CITE <EndNote><Cite><Author>Gradman</Author><Year>1993</Year><RecNum>3832</RecNum><DisplayText><style face="superscript">337</style></DisplayText><record><rec-number>3832</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535919867">3832</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gradman, T. J.</author><author>Laws, A.</author><author>Thompson, L. W.</author><author>Reaven, G. M.</author></authors></contributors><auth-address>Department of Medicine, Stanford University School of Medicine, California.</auth-address><titles><title>Verbal learning and/or memory improves with glycemic control in older subjects with non-insulin-dependent diabetes mellitus</title><secondary-title>J Am Geriatr Soc</secondary-title></titles><pages>1305-12</pages><volume>41</volume><number>12</number><keywords><keyword>Aged</keyword><keyword>Attention/physiology</keyword><keyword>Blood Glucose/analysis</keyword><keyword>Diabetes Mellitus, Type 2/blood/drug therapy/*psychology</keyword><keyword>Female</keyword><keyword>Glipizide/therapeutic use</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Memory/*physiology</keyword><keyword>Middle Aged</keyword><keyword>Multivariate Analysis</keyword><keyword>Psychomotor Performance/physiology</keyword><keyword>Verbal Learning/*physiology</keyword></keywords><dates><year>1993</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0002-8614 (Print)&#xD;0002-8614 (Linking)</isbn><accession-num>8227912</accession-num><urls><related-urls><url>. A lower risk for dementia was also described in a prospective cohort study involving sulfonylureas plus metformin PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXJ2YWxobzwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+

PFJlY051bT4zODI5PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MzM0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzgyOTwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5NTE5Ij4zODI5PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DYXJ2YWxobywgQy48L2F1dGhvcj48

YXV0aG9yPkNvcnJlaWEsIFMuPC9hdXRob3I+PGF1dGhvcj5TYW50b3MsIE0uIFMuPC9hdXRob3I+

PGF1dGhvcj5TZWljYSwgUi48L2F1dGhvcj48YXV0aG9yPk9saXZlaXJhLCBDLiBSLjwvYXV0aG9y

PjxhdXRob3I+TW9yZWlyYSwgUC4gSS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+

PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIFpvb2xvZ3kgLSBGYWN1bHR5IG9mIFNjaWVuY2Vz

IGFuZCBUZWNobm9sb2d5LCBVbml2ZXJzaXR5IG9mIENvaW1icmEsIENvaW1icmEgMzAwMC0zNTQs

IFBvcnR1Z2FsLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPk1ldGZvcm1pbiBwcm9tb3Rl

cyBpc29sYXRlZCByYXQgbGl2ZXIgbWl0b2Nob25kcmlhIGltcGFpcm1lbnQ8L3RpdGxlPjxzZWNv

bmRhcnktdGl0bGU+TW9sIENlbGwgQmlvY2hlbTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxw

YWdlcz43NS04MzwvcGFnZXM+PHZvbHVtZT4zMDg8L3ZvbHVtZT48bnVtYmVyPjEtMjwvbnVtYmVy

PjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgUmVzcGly

YXRpb24vZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkh5ZHJvZ2VuIFBlcm94aWRlL21l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TGlwaWQgUGVyb3hpZGF0aW9uL2RydWcgZWZmZWN0

czwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbWJyYW5lIFBvdGVu

dGlhbCwgTWl0b2Nob25kcmlhbC9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+TWV0Zm9y

bWluLypwaGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2Nob25kcmlhLCBMaXZlci8q

ZHJ1ZyBlZmZlY3RzLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2Nob25kcmlhbCBN

ZW1icmFuZSBUcmFuc3BvcnQgUHJvdGVpbnMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5P

eGlkYXRpdmUgUGhvc3Bob3J5bGF0aW9uL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5P

eGlkYXRpdmUgU3RyZXNzL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5PeHlnZW4gQ29u

c3VtcHRpb24vZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPlJhdHM8L2tleXdvcmQ+PGtl

eXdvcmQ+UmF0cywgV2lzdGFyPC9rZXl3b3JkPjxrZXl3b3JkPlN1bGZoeWRyeWwgQ29tcG91bmRz

L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+VGhpb2JhcmJpdHVyaWMgQWNpZCBSZWFjdGl2

ZSBTdWJzdGFuY2VzL21ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+

MjAwODwveWVhcj48cHViLWRhdGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVz

Pjxpc2JuPjAzMDAtODE3NyAoUHJpbnQpJiN4RDswMzAwLTgxNzcgKExpbmtpbmcpPC9pc2JuPjxh

Y2Nlc3Npb24tbnVtPjE3OTA5OTQ0PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE3OTA5OTQ0PC91cmw+PC9y

ZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDA3L3MxMTAx

MC0wMDctOTYxNC0zPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXJ2YWxobzwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+

PFJlY051bT4zODI5PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MzM0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzgyOTwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5NTE5Ij4zODI5PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DYXJ2YWxobywgQy48L2F1dGhvcj48

YXV0aG9yPkNvcnJlaWEsIFMuPC9hdXRob3I+PGF1dGhvcj5TYW50b3MsIE0uIFMuPC9hdXRob3I+

PGF1dGhvcj5TZWljYSwgUi48L2F1dGhvcj48YXV0aG9yPk9saXZlaXJhLCBDLiBSLjwvYXV0aG9y

PjxhdXRob3I+TW9yZWlyYSwgUC4gSS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+

PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIFpvb2xvZ3kgLSBGYWN1bHR5IG9mIFNjaWVuY2Vz

IGFuZCBUZWNobm9sb2d5LCBVbml2ZXJzaXR5IG9mIENvaW1icmEsIENvaW1icmEgMzAwMC0zNTQs

IFBvcnR1Z2FsLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPk1ldGZvcm1pbiBwcm9tb3Rl

cyBpc29sYXRlZCByYXQgbGl2ZXIgbWl0b2Nob25kcmlhIGltcGFpcm1lbnQ8L3RpdGxlPjxzZWNv

bmRhcnktdGl0bGU+TW9sIENlbGwgQmlvY2hlbTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxw

YWdlcz43NS04MzwvcGFnZXM+PHZvbHVtZT4zMDg8L3ZvbHVtZT48bnVtYmVyPjEtMjwvbnVtYmVy

PjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgUmVzcGly

YXRpb24vZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkh5ZHJvZ2VuIFBlcm94aWRlL21l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TGlwaWQgUGVyb3hpZGF0aW9uL2RydWcgZWZmZWN0

czwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbWJyYW5lIFBvdGVu

dGlhbCwgTWl0b2Nob25kcmlhbC9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+TWV0Zm9y

bWluLypwaGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2Nob25kcmlhLCBMaXZlci8q

ZHJ1ZyBlZmZlY3RzLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2Nob25kcmlhbCBN

ZW1icmFuZSBUcmFuc3BvcnQgUHJvdGVpbnMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5P

eGlkYXRpdmUgUGhvc3Bob3J5bGF0aW9uL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5P

eGlkYXRpdmUgU3RyZXNzL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5PeHlnZW4gQ29u

c3VtcHRpb24vZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPlJhdHM8L2tleXdvcmQ+PGtl

eXdvcmQ+UmF0cywgV2lzdGFyPC9rZXl3b3JkPjxrZXl3b3JkPlN1bGZoeWRyeWwgQ29tcG91bmRz

L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+VGhpb2JhcmJpdHVyaWMgQWNpZCBSZWFjdGl2

ZSBTdWJzdGFuY2VzL21ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+

MjAwODwveWVhcj48cHViLWRhdGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVz

Pjxpc2JuPjAzMDAtODE3NyAoUHJpbnQpJiN4RDswMzAwLTgxNzcgKExpbmtpbmcpPC9pc2JuPjxh

Y2Nlc3Npb24tbnVtPjE3OTA5OTQ0PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE3OTA5OTQ0PC91cmw+PC9y

ZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDA3L3MxMTAx

MC0wMDctOTYxNC0zPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPgB=

ADDIN EN.CITE.DATA 334. Although the mechanisms remain unclear, one may hypothesize a role for the inhibition of mTOR pathway upon sulfonylureas PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Pc2Jvcm5lPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjM4MzM8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMzg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zODMzPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTk5NTUiPjM4MzM8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk9zYm9ybmUsIEMuPC9hdXRob3I+PGF1

dGhvcj5XZXN0LCBFLjwvYXV0aG9yPjxhdXRob3I+Tm9sYW4sIFcuPC9hdXRob3I+PGF1dGhvcj5N

Y0hhbGUtT3dlbiwgSC48L2F1dGhvcj48YXV0aG9yPldpbGxpYW1zLCBBLjwvYXV0aG9yPjxhdXRo

b3I+QmF0ZSwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVz

cz5EZXBhcnRtZW50IG9mIFBhdGhvbG9neSBhbmQgUGF0aG9nZW4gQmlvbG9neSwgUm95YWwgVmV0

ZXJpbmFyeSBDb2xsZWdlLCBIYXdrc2hlYWQgTGFuZSwgTm9ydGggTXltbXMsIEhlcnRzLCBBTDkg

N1RBLCBVbml0ZWQgS2luZ2RvbS4mI3hEO0RlcGFydG1lbnQgb2YgVmV0ZXJpbmFyeSBNZWRpY2lu

ZSwgVW5pdmVyc2l0eSBvZiBDYW1icmlkZ2UsIE1hZGluZ2xleSBSb2FkLCBDYW1icmlkZ2UsIENC

MyAwRVMsIFVuaXRlZCBLaW5nZG9tLiYjeEQ7RGVwYXJ0bWVudCBvZiBQYXRob2xvZ3kgYW5kIFBh

dGhvZ2VuIEJpb2xvZ3ksIFJveWFsIFZldGVyaW5hcnkgQ29sbGVnZSwgSGF3a3NoZWFkIExhbmUs

IE5vcnRoIE15bW1zLCBIZXJ0cywgQUw5IDdUQSwgVW5pdGVkIEtpbmdkb20uIEVsZWN0cm9uaWMg

YWRkcmVzczogY2JhdGVAcnZjLmFjLnVrLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkds

aW1lcGlyaWRlIHByb3RlY3RzIG5ldXJvbnMgYWdhaW5zdCBhbXlsb2lkLWJldGEtaW5kdWNlZCBz

eW5hcHNlIGRhbWFnZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb3BoYXJtYWNvbG9neTwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvcGhh

cm1hY29sb2d5PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjI1LTM2PC9wYWdlcz48

dm9sdW1lPjEwMTwvdm9sdW1lPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3

b3JkPkFsemhlaW1lciBEaXNlYXNlL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lk

IGJldGEtUGVwdGlkZXMvKnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5DZWxsIE1lbWJy

YW5lIFN0cnVjdHVyZXMvZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGxzLCBDdWx0

dXJlZDwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0ZXJvbC9tZXRhYm9saXNtPC9rZXl3b3JkPjxr

ZXl3b3JkPkVuenltZS1MaW5rZWQgSW1tdW5vc29yYmVudCBBc3NheTwva2V5d29yZD48a2V5d29y

ZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVu

b3N1cHByZXNzaXZlIEFnZW50cy8qcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJv

bnMvKmRydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5QZXB0aWRlIEZyYWdtZW50cy8qcGhh

cm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBob3NwaG9saXBhc2VzIEEyL21ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+UHJpb25zL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+U3Vs

Zm9ueWx1cmVhIENvbXBvdW5kcy8qcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlN5bmFw

dG9waHlzaW4vbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5TeW5hcHRvc29tZXMvZHJ1ZyBl

ZmZlY3RzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+VGVtcG9yYWwgTG9iZS9wYXRob2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxr

ZXl3b3JkPkFteWxvaWQtYmV0YTwva2V5d29yZD48a2V5d29yZD5HbGltZXBpcmlkZTwva2V5d29y

ZD48a2V5d29yZD5HbHljb3N5bHBob3NwaGF0aWR5bGlub3NpdG9sczwva2V5d29yZD48a2V5d29y

ZD5QaG9zcGhvbGlwYXNlIEEoMik8L2tleXdvcmQ+PGtleXdvcmQ+UHJpb248L2tleXdvcmQ+PGtl

eXdvcmQ+U3luYXBzZXM8L2tleXdvcmQ+PGtleXdvcmQ+U3luYXB0b3BoeXNpbjwva2V5d29yZD48

L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RmViPC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTg3My03MDY0IChFbGVjdHJvbmljKSYjeEQ7

MDAyOC0zOTA4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNjQzMjEwNTwvYWNjZXNz

aW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWgu

Z292L3B1Ym1lZC8yNjQzMjEwNTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLm5ldXJvcGhhcm0uMjAxNS4wOS4wMzA8L2VsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Pc2Jvcm5lPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjM4MzM8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMzg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zODMzPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTk5NTUiPjM4MzM8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk9zYm9ybmUsIEMuPC9hdXRob3I+PGF1

dGhvcj5XZXN0LCBFLjwvYXV0aG9yPjxhdXRob3I+Tm9sYW4sIFcuPC9hdXRob3I+PGF1dGhvcj5N

Y0hhbGUtT3dlbiwgSC48L2F1dGhvcj48YXV0aG9yPldpbGxpYW1zLCBBLjwvYXV0aG9yPjxhdXRo

b3I+QmF0ZSwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVz

cz5EZXBhcnRtZW50IG9mIFBhdGhvbG9neSBhbmQgUGF0aG9nZW4gQmlvbG9neSwgUm95YWwgVmV0

ZXJpbmFyeSBDb2xsZWdlLCBIYXdrc2hlYWQgTGFuZSwgTm9ydGggTXltbXMsIEhlcnRzLCBBTDkg

N1RBLCBVbml0ZWQgS2luZ2RvbS4mI3hEO0RlcGFydG1lbnQgb2YgVmV0ZXJpbmFyeSBNZWRpY2lu

ZSwgVW5pdmVyc2l0eSBvZiBDYW1icmlkZ2UsIE1hZGluZ2xleSBSb2FkLCBDYW1icmlkZ2UsIENC

MyAwRVMsIFVuaXRlZCBLaW5nZG9tLiYjeEQ7RGVwYXJ0bWVudCBvZiBQYXRob2xvZ3kgYW5kIFBh

dGhvZ2VuIEJpb2xvZ3ksIFJveWFsIFZldGVyaW5hcnkgQ29sbGVnZSwgSGF3a3NoZWFkIExhbmUs

IE5vcnRoIE15bW1zLCBIZXJ0cywgQUw5IDdUQSwgVW5pdGVkIEtpbmdkb20uIEVsZWN0cm9uaWMg

YWRkcmVzczogY2JhdGVAcnZjLmFjLnVrLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkds

aW1lcGlyaWRlIHByb3RlY3RzIG5ldXJvbnMgYWdhaW5zdCBhbXlsb2lkLWJldGEtaW5kdWNlZCBz

eW5hcHNlIGRhbWFnZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb3BoYXJtYWNvbG9neTwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvcGhh

cm1hY29sb2d5PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjI1LTM2PC9wYWdlcz48

dm9sdW1lPjEwMTwvdm9sdW1lPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3

b3JkPkFsemhlaW1lciBEaXNlYXNlL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lk

IGJldGEtUGVwdGlkZXMvKnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5DZWxsIE1lbWJy

YW5lIFN0cnVjdHVyZXMvZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGxzLCBDdWx0

dXJlZDwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0ZXJvbC9tZXRhYm9saXNtPC9rZXl3b3JkPjxr

ZXl3b3JkPkVuenltZS1MaW5rZWQgSW1tdW5vc29yYmVudCBBc3NheTwva2V5d29yZD48a2V5d29y

ZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVu

b3N1cHByZXNzaXZlIEFnZW50cy8qcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJv

bnMvKmRydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5QZXB0aWRlIEZyYWdtZW50cy8qcGhh

cm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBob3NwaG9saXBhc2VzIEEyL21ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+UHJpb25zL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+U3Vs

Zm9ueWx1cmVhIENvbXBvdW5kcy8qcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlN5bmFw

dG9waHlzaW4vbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5TeW5hcHRvc29tZXMvZHJ1ZyBl

ZmZlY3RzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+VGVtcG9yYWwgTG9iZS9wYXRob2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxr

ZXl3b3JkPkFteWxvaWQtYmV0YTwva2V5d29yZD48a2V5d29yZD5HbGltZXBpcmlkZTwva2V5d29y

ZD48a2V5d29yZD5HbHljb3N5bHBob3NwaGF0aWR5bGlub3NpdG9sczwva2V5d29yZD48a2V5d29y

ZD5QaG9zcGhvbGlwYXNlIEEoMik8L2tleXdvcmQ+PGtleXdvcmQ+UHJpb248L2tleXdvcmQ+PGtl

eXdvcmQ+U3luYXBzZXM8L2tleXdvcmQ+PGtleXdvcmQ+U3luYXB0b3BoeXNpbjwva2V5d29yZD48

L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RmViPC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTg3My03MDY0IChFbGVjdHJvbmljKSYjeEQ7

MDAyOC0zOTA4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNjQzMjEwNTwvYWNjZXNz

aW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWgu

Z292L3B1Ym1lZC8yNjQzMjEwNTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLm5ldXJvcGhhcm0uMjAxNS4wOS4wMzA8L2VsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 338, or in brain inflammasome (as described for Glyburide) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaGFuZmFyPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM4MzQ8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMzk8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zODM0PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MjAwMTkiPjM4MzQ8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPktoYW5mYXIsIE0uIEEuPC9hdXRob3I+

PGF1dGhvcj5BYnVLaGFkZXIsIE0uIE0uPC9hdXRob3I+PGF1dGhvcj5BbHF0YWlzaGF0LCBTLjwv

YXV0aG9yPjxhdXRob3I+VGFoYSwgTS4gTy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5EcnVnIERpc2NvdmVyeSBVbml0LCBEZXBhcnRtZW50IG9mIFBoYXJt

YWNldXRpY2FsIFNjaWVuY2VzLCBGYWN1bHR5IG9mIFBoYXJtYWN5LCBVbml2ZXJzaXR5IG9mIEpv

cmRhbiwgQW1tYW4gMTE5NDIsIEpvcmRhbi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Q

aGFybWFjb3Bob3JlIG1vZGVsaW5nLCBob21vbG9neSBtb2RlbGluZywgYW5kIGluIHNpbGljbyBz

Y3JlZW5pbmcgcmV2ZWFsIG1hbW1hbGlhbiB0YXJnZXQgb2YgcmFwYW15Y2luIGluaGliaXRvcnkg

YWN0aXZpdGllcyBmb3Igc290YWxvbCwgZ2x5YnVyaWRlLCBtZXRpcHJhbm9sb2wsIHN1bGZhbWV0

aGl6b2xlLCBnbGlwaXppZGUsIGFuZCBwaW9nbGl0YXpvbmU8L3RpdGxlPjxzZWNvbmRhcnktdGl0

bGU+SiBNb2wgR3JhcGggTW9kZWw8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+Mzkt

NDk8L3BhZ2VzPjx2b2x1bWU+NDI8L3ZvbHVtZT48a2V5d29yZHM+PGtleXdvcmQ+QWRyZW5lcmdp

YyBiZXRhLUFudGFnb25pc3RzLypwaGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW1pbm8g

QWNpZCBTZXF1ZW5jZTwva2V5d29yZD48a2V5d29yZD5BbnRpLUluZmVjdGl2ZSBBZ2VudHMvKnBo

YXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5DYXRhbHl0aWMgRG9tYWluPC9rZXl3b3JkPjxr

ZXl3b3JkPkNyeXN0YWxsb2dyYXBoeSwgWC1SYXk8L2tleXdvcmQ+PGtleXdvcmQ+R2xpcGl6aWRl

L3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5HbHlidXJpZGUvcGhhcm1hY29sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IeXBvZ2x5Y2VtaWMgQWdl

bnRzLypwaGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWV0aXByYW5vbG9sL3BoYXJtYWNv

bG9neTwva2V5d29yZD48a2V5d29yZD5Nb2RlbHMsIE1vbGVjdWxhcjwva2V5d29yZD48a2V5d29y

ZD5Nb2xlY3VsYXIgRG9ja2luZyBTaW11bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlBob3NwaGF0

aWR5bGlub3NpdG9sIDMtS2luYXNlcy8qY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPlF1YW50

aXRhdGl2ZSBTdHJ1Y3R1cmUtQWN0aXZpdHkgUmVsYXRpb25zaGlwPC9rZXl3b3JkPjxrZXl3b3Jk

PlJPQyBDdXJ2ZTwva2V5d29yZD48a2V5d29yZD5TZXF1ZW5jZSBBbGlnbm1lbnQ8L2tleXdvcmQ+

PGtleXdvcmQ+U290YWxvbC9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+U3VsZmFtZXRo

aXpvbGUvcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlRPUiBTZXJpbmUtVGhyZW9uaW5l

IEtpbmFzZXMvKmFudGFnb25pc3RzICZhbXA7IGluaGliaXRvcnM8L2tleXdvcmQ+PGtleXdvcmQ+

VGhpYXpvbGlkaW5lZGlvbmVzL3BoYXJtYWNvbG9neTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRl

cz48eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWF5PC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PGlzYm4+MTg3My00MjQzIChFbGVjdHJvbmljKSYjeEQ7MTA5My0zMjYzIChMaW5r

aW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzU0NTMzMzwvYWNjZXNzaW9uLW51bT48dXJscz48

cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMzU0

NTMzMzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

MTAuMTAxNi9qLmptZ20uMjAxMy4wMi4wMDk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVj

b3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaGFuZmFyPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM4MzQ8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMzk8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zODM0PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MjAwMTkiPjM4MzQ8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPktoYW5mYXIsIE0uIEEuPC9hdXRob3I+

PGF1dGhvcj5BYnVLaGFkZXIsIE0uIE0uPC9hdXRob3I+PGF1dGhvcj5BbHF0YWlzaGF0LCBTLjwv

YXV0aG9yPjxhdXRob3I+VGFoYSwgTS4gTy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5EcnVnIERpc2NvdmVyeSBVbml0LCBEZXBhcnRtZW50IG9mIFBoYXJt

YWNldXRpY2FsIFNjaWVuY2VzLCBGYWN1bHR5IG9mIFBoYXJtYWN5LCBVbml2ZXJzaXR5IG9mIEpv

cmRhbiwgQW1tYW4gMTE5NDIsIEpvcmRhbi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Q

aGFybWFjb3Bob3JlIG1vZGVsaW5nLCBob21vbG9neSBtb2RlbGluZywgYW5kIGluIHNpbGljbyBz

Y3JlZW5pbmcgcmV2ZWFsIG1hbW1hbGlhbiB0YXJnZXQgb2YgcmFwYW15Y2luIGluaGliaXRvcnkg

YWN0aXZpdGllcyBmb3Igc290YWxvbCwgZ2x5YnVyaWRlLCBtZXRpcHJhbm9sb2wsIHN1bGZhbWV0

aGl6b2xlLCBnbGlwaXppZGUsIGFuZCBwaW9nbGl0YXpvbmU8L3RpdGxlPjxzZWNvbmRhcnktdGl0

bGU+SiBNb2wgR3JhcGggTW9kZWw8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+Mzkt

NDk8L3BhZ2VzPjx2b2x1bWU+NDI8L3ZvbHVtZT48a2V5d29yZHM+PGtleXdvcmQ+QWRyZW5lcmdp

YyBiZXRhLUFudGFnb25pc3RzLypwaGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW1pbm8g

QWNpZCBTZXF1ZW5jZTwva2V5d29yZD48a2V5d29yZD5BbnRpLUluZmVjdGl2ZSBBZ2VudHMvKnBo

YXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5DYXRhbHl0aWMgRG9tYWluPC9rZXl3b3JkPjxr

ZXl3b3JkPkNyeXN0YWxsb2dyYXBoeSwgWC1SYXk8L2tleXdvcmQ+PGtleXdvcmQ+R2xpcGl6aWRl

L3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5HbHlidXJpZGUvcGhhcm1hY29sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IeXBvZ2x5Y2VtaWMgQWdl

bnRzLypwaGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWV0aXByYW5vbG9sL3BoYXJtYWNv

bG9neTwva2V5d29yZD48a2V5d29yZD5Nb2RlbHMsIE1vbGVjdWxhcjwva2V5d29yZD48a2V5d29y

ZD5Nb2xlY3VsYXIgRG9ja2luZyBTaW11bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlBob3NwaGF0

aWR5bGlub3NpdG9sIDMtS2luYXNlcy8qY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPlF1YW50

aXRhdGl2ZSBTdHJ1Y3R1cmUtQWN0aXZpdHkgUmVsYXRpb25zaGlwPC9rZXl3b3JkPjxrZXl3b3Jk

PlJPQyBDdXJ2ZTwva2V5d29yZD48a2V5d29yZD5TZXF1ZW5jZSBBbGlnbm1lbnQ8L2tleXdvcmQ+

PGtleXdvcmQ+U290YWxvbC9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+U3VsZmFtZXRo

aXpvbGUvcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlRPUiBTZXJpbmUtVGhyZW9uaW5l

IEtpbmFzZXMvKmFudGFnb25pc3RzICZhbXA7IGluaGliaXRvcnM8L2tleXdvcmQ+PGtleXdvcmQ+

VGhpYXpvbGlkaW5lZGlvbmVzL3BoYXJtYWNvbG9neTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRl

cz48eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWF5PC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PGlzYm4+MTg3My00MjQzIChFbGVjdHJvbmljKSYjeEQ7MTA5My0zMjYzIChMaW5r

aW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzU0NTMzMzwvYWNjZXNzaW9uLW51bT48dXJscz48

cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMzU0

NTMzMzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

MTAuMTAxNi9qLmptZ20uMjAxMy4wMi4wMDk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVj

b3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 339. Conversely, others did not find any protection against AD after long-term treatment with sulfonylureas PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW1rYW5maTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+

PFJlY051bT4zODM1PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MzQwPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzgzNTwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTIwMDg4Ij4zODM1PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5MYW1rYW5maSwgTS48L2F1dGhvcj48

YXV0aG9yPk11ZWxsZXIsIEouIEwuPC9hdXRob3I+PGF1dGhvcj5WaXRhcmksIEEuIEMuPC9hdXRo

b3I+PGF1dGhvcj5NaXNhZ2hpLCBTLjwvYXV0aG9yPjxhdXRob3I+RmVkb3JvdmEsIEEuPC9hdXRo

b3I+PGF1dGhvcj5EZXNoYXllcywgSy48L2F1dGhvcj48YXV0aG9yPkxlZSwgVy4gUC48L2F1dGhv

cj48YXV0aG9yPkhvZmZtYW4sIEguIE0uPC9hdXRob3I+PGF1dGhvcj5EaXhpdCwgVi4gTS48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9m

IFBoeXNpb2xvZ2ljYWwgQ2hlbWlzdHJ5LCBHZW5lbnRlY2gsIFNvdXRoIFNhbiBGcmFuY2lzY28s

IENBIDk0MDgwLCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+R2x5YnVyaWRlIGlu

aGliaXRzIHRoZSBDcnlvcHlyaW4vTmFscDMgaW5mbGFtbWFzb21lPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPkogQ2VsbCBCaW9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjYxLTcw

PC9wYWdlcz48dm9sdW1lPjE4Nzwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxrZXl3b3Jkcz48

a2V5d29yZD5BZGVub3NpbmUgVHJpcGhvc3BoYXRhc2VzL2ltbXVub2xvZ3kvbWV0YWJvbGlzbTwv

a2V5d29yZD48a2V5d29yZD5BZGVub3NpbmUgVHJpcGhvc3BoYXRlL3BoYXJtYWNvbG9neTwva2V5

d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkNhcnJpZXIgUHJvdGVpbnMv

KmFudGFnb25pc3RzICZhbXA7IGluaGliaXRvcnMvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+

Q2FzcGFzZSAxL2ltbXVub2xvZ3kvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DZWxscywg

Q3VsdHVyZWQ8L2tleXdvcmQ+PGtleXdvcmQ+RW56eW1lIEFjdGl2YXRpb24vZHJ1ZyBlZmZlY3Rz

PC9rZXl3b3JkPjxrZXl3b3JkPkdseWJ1cmlkZS9jaGVtaXN0cnkvKmltbXVub2xvZ3kvbWV0YWJv

bGlzbS9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3

b3JkPkh5cG9nbHljZW1pYyBBZ2VudHMvY2hlbWlzdHJ5LyppbW11bm9sb2d5L21ldGFib2xpc20v

cGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1hdGlvbi9lbnp5bW9sb2d5L2lt

bXVub2xvZ3kvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXJsZXVraW4tMTgvc2Vj

cmV0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkludGVybGV1a2luLTFiZXRhL3NlY3JldGlvbjwva2V5

d29yZD48a2V5d29yZD5MaXBvcG9seXNhY2NoYXJpZGVzL2ltbXVub2xvZ3kvbWV0YWJvbGlzbS9w

aGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWFjcm9waGFnZXMvaW1tdW5vbG9neS9tZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5

d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQkFMQiBDPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2Us

IEluYnJlZCBDNTdCTDwva2V5d29yZD48a2V5d29yZD5NaWNlLCBLbm9ja291dDwva2V5d29yZD48

a2V5d29yZD5Nb25vY3l0ZXMvaW1tdW5vbG9neS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

Pk11dGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk5MUiBGYW1pbHksIFB5cmluIERvbWFpbi1Db250

YWluaW5nIDMgUHJvdGVpbjwva2V5d29yZD48a2V5d29yZD5SYW5kb20gQWxsb2NhdGlvbjwva2V5

d29yZD48a2V5d29yZD5TYWxtb25lbGxhIHR5cGhpbXVyaXVtL2NsYXNzaWZpY2F0aW9uL2dlbmV0

aWNzL2ltbXVub2xvZ3kvcGh5c2lvbG9neTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVh

cj4yMDA5PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+T2N0IDU8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4xNTQwLTgxNDAgKEVsZWN0cm9uaWMpJiN4RDswMDIxLTk1MjUgKExpbmtpbmcp

PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjE5ODA1NjI5PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh

dGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE5ODA1NjI5

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzI3NjIwOTk8L2N1c3RvbTI+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwODMvamNiLjIwMDkwMzEyNDwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW1rYW5maTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+

PFJlY051bT4zODM1PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MzQwPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzgzNTwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTIwMDg4Ij4zODM1PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5MYW1rYW5maSwgTS48L2F1dGhvcj48

YXV0aG9yPk11ZWxsZXIsIEouIEwuPC9hdXRob3I+PGF1dGhvcj5WaXRhcmksIEEuIEMuPC9hdXRo

b3I+PGF1dGhvcj5NaXNhZ2hpLCBTLjwvYXV0aG9yPjxhdXRob3I+RmVkb3JvdmEsIEEuPC9hdXRo

b3I+PGF1dGhvcj5EZXNoYXllcywgSy48L2F1dGhvcj48YXV0aG9yPkxlZSwgVy4gUC48L2F1dGhv

cj48YXV0aG9yPkhvZmZtYW4sIEguIE0uPC9hdXRob3I+PGF1dGhvcj5EaXhpdCwgVi4gTS48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9m

IFBoeXNpb2xvZ2ljYWwgQ2hlbWlzdHJ5LCBHZW5lbnRlY2gsIFNvdXRoIFNhbiBGcmFuY2lzY28s

IENBIDk0MDgwLCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+R2x5YnVyaWRlIGlu

aGliaXRzIHRoZSBDcnlvcHlyaW4vTmFscDMgaW5mbGFtbWFzb21lPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPkogQ2VsbCBCaW9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjYxLTcw

PC9wYWdlcz48dm9sdW1lPjE4Nzwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxrZXl3b3Jkcz48

a2V5d29yZD5BZGVub3NpbmUgVHJpcGhvc3BoYXRhc2VzL2ltbXVub2xvZ3kvbWV0YWJvbGlzbTwv

a2V5d29yZD48a2V5d29yZD5BZGVub3NpbmUgVHJpcGhvc3BoYXRlL3BoYXJtYWNvbG9neTwva2V5

d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkNhcnJpZXIgUHJvdGVpbnMv

KmFudGFnb25pc3RzICZhbXA7IGluaGliaXRvcnMvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+

Q2FzcGFzZSAxL2ltbXVub2xvZ3kvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DZWxscywg

Q3VsdHVyZWQ8L2tleXdvcmQ+PGtleXdvcmQ+RW56eW1lIEFjdGl2YXRpb24vZHJ1ZyBlZmZlY3Rz

PC9rZXl3b3JkPjxrZXl3b3JkPkdseWJ1cmlkZS9jaGVtaXN0cnkvKmltbXVub2xvZ3kvbWV0YWJv

bGlzbS9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3

b3JkPkh5cG9nbHljZW1pYyBBZ2VudHMvY2hlbWlzdHJ5LyppbW11bm9sb2d5L21ldGFib2xpc20v

cGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1hdGlvbi9lbnp5bW9sb2d5L2lt

bXVub2xvZ3kvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXJsZXVraW4tMTgvc2Vj

cmV0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkludGVybGV1a2luLTFiZXRhL3NlY3JldGlvbjwva2V5

d29yZD48a2V5d29yZD5MaXBvcG9seXNhY2NoYXJpZGVzL2ltbXVub2xvZ3kvbWV0YWJvbGlzbS9w

aGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWFjcm9waGFnZXMvaW1tdW5vbG9neS9tZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5

d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQkFMQiBDPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2Us

IEluYnJlZCBDNTdCTDwva2V5d29yZD48a2V5d29yZD5NaWNlLCBLbm9ja291dDwva2V5d29yZD48

a2V5d29yZD5Nb25vY3l0ZXMvaW1tdW5vbG9neS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

Pk11dGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk5MUiBGYW1pbHksIFB5cmluIERvbWFpbi1Db250

YWluaW5nIDMgUHJvdGVpbjwva2V5d29yZD48a2V5d29yZD5SYW5kb20gQWxsb2NhdGlvbjwva2V5

d29yZD48a2V5d29yZD5TYWxtb25lbGxhIHR5cGhpbXVyaXVtL2NsYXNzaWZpY2F0aW9uL2dlbmV0

aWNzL2ltbXVub2xvZ3kvcGh5c2lvbG9neTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVh

cj4yMDA5PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+T2N0IDU8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4xNTQwLTgxNDAgKEVsZWN0cm9uaWMpJiN4RDswMDIxLTk1MjUgKExpbmtpbmcp

PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjE5ODA1NjI5PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh

dGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE5ODA1NjI5

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzI3NjIwOTk8L2N1c3RvbTI+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwODMvamNiLjIwMDkwMzEyNDwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 340. These controversial observations, together with the need to clarify the precise roles of sulfonylureas in CNS and their potential adverse effects, may explain why, to the best of our knowledge, no clinical trials are undergoing with these second-generation sulfonylureas in AD.The potential of thiazolidinediones to tackle ADThe main thiazolidinediones (TZDs) used in T2D are Rosiglitazone, Pioglitazone and Troglitazone ADDIN EN.CITE <EndNote><Cite><Author>Corbett</Author><Year>2013</Year><RecNum>3749</RecNum><DisplayText><style face="superscript">323</style></DisplayText><record><rec-number>3749</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535917507">3749</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Corbett, A.</author><author>Ballard, C.</author></authors></contributors><titles><title>Is a potential Alzheimer&apos;s therapy already in use for other conditions? Can medications for hypertension, diabetes and acne help with the symptoms?</title><secondary-title>Expert Opin Investig Drugs</secondary-title></titles><pages>941-3</pages><volume>22</volume><number>8</number><keywords><keyword>Alzheimer Disease/*drug therapy</keyword><keyword>Angiotensin Receptor Antagonists/therapeutic use</keyword><keyword>Anti-Bacterial Agents/therapeutic use</keyword><keyword>Calcium Channel Blockers/therapeutic use</keyword><keyword>*Drug Repositioning</keyword><keyword>Humans</keyword><keyword>Hypoglycemic Agents/therapeutic use</keyword></keywords><dates><year>2013</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1744-7658 (Electronic)&#xD;1354-3784 (Linking)</isbn><accession-num>23808708</accession-num><urls><related-urls><url>. Though TZDs are relatively expensive, they are very efficient in the long-term management of T2D PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMsMzI0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMsMzI0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 323,324. These drugs act as PPARγ agonists to promote the transcription of genes related to lipid and glucose metabolism PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYWhyYW5pPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjM4MjM8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMzMsMzQxPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzgyMzwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MzUzIj4zODIzPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5UYWhyYW5pLCBBLiBBLjwvYXV0

aG9yPjxhdXRob3I+QmFybmV0dCwgQS4gSC48L2F1dGhvcj48YXV0aG9yPkJhaWxleSwgQy4gSi48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DZW50cmUgb2Yg

RW5kb2NyaW5vbG9neSwgRGlhYmV0ZXMgYW5kIE1ldGFib2xpc20sIDJuZCBGbG9vciwgSW5zdGl0

dXRlIG9mIEJpb21lZGljYWwgUmVzZWFyY2gsIFVuaXZlcnNpdHkgb2YgQmlybWluZ2hhbSwgQmly

bWluZ2hhbSwgQjE1IDJUVCwgVUsuJiN4RDtEZXBhcnRtZW50IG9mIERpYWJldGVzIGFuZCBFbmRv

Y3Jpbm9sb2d5LCBIZWFydCBvZiBFbmdsYW5kIE5IUyBGb3VuZGF0aW9uIFRydXN0LCBCaXJtaW5n

aGFtLCBCOSA1U1MsIFVLLiYjeEQ7U2Nob29sIG9mIExpZmUgYW5kIEhlYWx0aCBTY2llbmNlcywg

QXN0b24gVW5pdmVyc2l0eSwgQmlybWluZ2hhbSwgQjQgN0VULCBVSy48L2F1dGgtYWRkcmVzcz48

dGl0bGVzPjx0aXRsZT5QaGFybWFjb2xvZ3kgYW5kIHRoZXJhcGV1dGljIGltcGxpY2F0aW9ucyBv

ZiBjdXJyZW50IGRydWdzIGZvciB0eXBlIDIgZGlhYmV0ZXMgbWVsbGl0dXM8L3RpdGxlPjxzZWNv

bmRhcnktdGl0bGU+TmF0IFJldiBFbmRvY3Jpbm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBhZ2VzPjU2Ni05MjwvcGFnZXM+PHZvbHVtZT4xMjwvdm9sdW1lPjxudW1iZXI+MTA8L251bWJl

cj48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPk9jdDwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE3NTktNTAzNyAoRWxlY3Ryb25pYykmI3hEOzE3NTktNTAy

OSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjczMzk4ODk8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMjczMzk4ODk8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjEwMzgvbnJlbmRvLjIwMTYuODY8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwv

cmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkltZmVsZDwvQXV0aG9yPjxZZWFyPjIwMTI8L1ll

YXI+PFJlY051bT4zNzcyPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zNzcyPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTkxMTkiPjM3NzI8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkltZmVsZCwgUGF0cmljazwvYXV0aG9yPjxh

dXRob3I+Qm9kbWVyLCBNaWNoYWVsPC9hdXRob3I+PGF1dGhvcj5KaWNrLCBTdXNhbiBTLjwvYXV0

aG9yPjxhdXRob3I+TWVpZXIsIENocmlzdG9waCBSLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy

aWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5NZXRmb3JtaW4sIE90aGVyIEFudGlkaWFiZXRpYyBEcnVn

cywgYW5kIFJpc2sgb2YgQWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlOiBBIFBvcHVsYXRpb24tQmFz

ZWQgQ2FzZS1Db250cm9sIFN0dWR5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkpvdXJuYWwgb2Yg

dGhlIEFtZXJpY2FuIEdlcmlhdHJpY3MgU29jaWV0eTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwYWdlcz45MTYtOTIxPC9wYWdlcz48dm9sdW1lPjYwPC92b2x1bWU+PG51bWJlcj41PC9udW1i

ZXI+PGRhdGVzPjx5ZWFyPjIwMTI8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDEyLzAzLzI4PC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5XaWxleTwvcHVibGlzaGVyPjxpc2Ju

PjAwMDItODYxNDwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5v

cmcvMTAuMTExMS9qLjE1MzItNTQxNS4yMDEyLjAzOTE2Lng8L3VybD48L3JlbGF0ZWQtdXJscz48

L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExMTEvai4xNTMyLTU0MTUuMjAxMi4w

MzkxNi54PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3Rl

PgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYWhyYW5pPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjM4MjM8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMzMsMzQxPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzgyMzwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MzUzIj4zODIzPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5UYWhyYW5pLCBBLiBBLjwvYXV0

aG9yPjxhdXRob3I+QmFybmV0dCwgQS4gSC48L2F1dGhvcj48YXV0aG9yPkJhaWxleSwgQy4gSi48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DZW50cmUgb2Yg

RW5kb2NyaW5vbG9neSwgRGlhYmV0ZXMgYW5kIE1ldGFib2xpc20sIDJuZCBGbG9vciwgSW5zdGl0

dXRlIG9mIEJpb21lZGljYWwgUmVzZWFyY2gsIFVuaXZlcnNpdHkgb2YgQmlybWluZ2hhbSwgQmly

bWluZ2hhbSwgQjE1IDJUVCwgVUsuJiN4RDtEZXBhcnRtZW50IG9mIERpYWJldGVzIGFuZCBFbmRv

Y3Jpbm9sb2d5LCBIZWFydCBvZiBFbmdsYW5kIE5IUyBGb3VuZGF0aW9uIFRydXN0LCBCaXJtaW5n

aGFtLCBCOSA1U1MsIFVLLiYjeEQ7U2Nob29sIG9mIExpZmUgYW5kIEhlYWx0aCBTY2llbmNlcywg

QXN0b24gVW5pdmVyc2l0eSwgQmlybWluZ2hhbSwgQjQgN0VULCBVSy48L2F1dGgtYWRkcmVzcz48

dGl0bGVzPjx0aXRsZT5QaGFybWFjb2xvZ3kgYW5kIHRoZXJhcGV1dGljIGltcGxpY2F0aW9ucyBv

ZiBjdXJyZW50IGRydWdzIGZvciB0eXBlIDIgZGlhYmV0ZXMgbWVsbGl0dXM8L3RpdGxlPjxzZWNv

bmRhcnktdGl0bGU+TmF0IFJldiBFbmRvY3Jpbm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBhZ2VzPjU2Ni05MjwvcGFnZXM+PHZvbHVtZT4xMjwvdm9sdW1lPjxudW1iZXI+MTA8L251bWJl

cj48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPk9jdDwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE3NTktNTAzNyAoRWxlY3Ryb25pYykmI3hEOzE3NTktNTAy

OSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjczMzk4ODk8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMjczMzk4ODk8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjEwMzgvbnJlbmRvLjIwMTYuODY8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwv

cmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkltZmVsZDwvQXV0aG9yPjxZZWFyPjIwMTI8L1ll

YXI+PFJlY051bT4zNzcyPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zNzcyPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTkxMTkiPjM3NzI8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkltZmVsZCwgUGF0cmljazwvYXV0aG9yPjxh

dXRob3I+Qm9kbWVyLCBNaWNoYWVsPC9hdXRob3I+PGF1dGhvcj5KaWNrLCBTdXNhbiBTLjwvYXV0

aG9yPjxhdXRob3I+TWVpZXIsIENocmlzdG9waCBSLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy

aWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5NZXRmb3JtaW4sIE90aGVyIEFudGlkaWFiZXRpYyBEcnVn

cywgYW5kIFJpc2sgb2YgQWx6aGVpbWVyJmFwb3M7cyBEaXNlYXNlOiBBIFBvcHVsYXRpb24tQmFz

ZWQgQ2FzZS1Db250cm9sIFN0dWR5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkpvdXJuYWwgb2Yg

dGhlIEFtZXJpY2FuIEdlcmlhdHJpY3MgU29jaWV0eTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwYWdlcz45MTYtOTIxPC9wYWdlcz48dm9sdW1lPjYwPC92b2x1bWU+PG51bWJlcj41PC9udW1i

ZXI+PGRhdGVzPjx5ZWFyPjIwMTI8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDEyLzAzLzI4PC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5XaWxleTwvcHVibGlzaGVyPjxpc2Ju

PjAwMDItODYxNDwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5v

cmcvMTAuMTExMS9qLjE1MzItNTQxNS4yMDEyLjAzOTE2Lng8L3VybD48L3JlbGF0ZWQtdXJscz48

L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExMTEvai4xNTMyLTU0MTUuMjAxMi4w

MzkxNi54PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3Rl

PgB=

ADDIN EN.CITE.DATA 333,341. More specifically, TZDs increase insulin-induced glucose uptake (most likely via GLUT-1 and -4) and decrease lipid accumulation by skeletal muscle, stimulate triglyceride storage in adipocytes, hepatic fatty acid oxidation and inhibit hepatic gluconeogenesis ADDIN EN.CITE <EndNote><Cite><Author>Sandhir</Author><Year>2015</Year><RecNum>3750</RecNum><DisplayText><style face="superscript">324</style></DisplayText><record><rec-number>3750</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535917565">3750</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sandhir, R.</author><author>Gupta, S.</author></authors></contributors><auth-address>Rajat Sandhir, Smriti Gupta, Department of Biochemistry, Panjab University, Chandigarh 160014, India.</auth-address><titles><title>Molecular and biochemical trajectories from diabetes to Alzheimer&apos;s disease: A critical appraisal</title><secondary-title>World J Diabetes</secondary-title></titles><pages>1223-42</pages><volume>6</volume><number>12</number><keywords><keyword>Alzheimer&apos;s disease</keyword><keyword>Diabetes mellitus</keyword><keyword>Insulin</keyword><keyword>Type 2 diabetes</keyword><keyword>Type 3 diabetes</keyword></keywords><dates><year>2015</year><pub-dates><date>Sep 25</date></pub-dates></dates><isbn>1948-9358 (Print)&#xD;1948-9358 (Linking)</isbn><accession-num>26464760</accession-num><urls><related-urls><url>. Among their adverse effects are a possible weight gain and increased risk of myocardial infarction ADDIN EN.CITE <EndNote><Cite><Author>Sandhir</Author><Year>2015</Year><RecNum>3750</RecNum><DisplayText><style face="superscript">324</style></DisplayText><record><rec-number>3750</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535917565">3750</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sandhir, R.</author><author>Gupta, S.</author></authors></contributors><auth-address>Rajat Sandhir, Smriti Gupta, Department of Biochemistry, Panjab University, Chandigarh 160014, India.</auth-address><titles><title>Molecular and biochemical trajectories from diabetes to Alzheimer&apos;s disease: A critical appraisal</title><secondary-title>World J Diabetes</secondary-title></titles><pages>1223-42</pages><volume>6</volume><number>12</number><keywords><keyword>Alzheimer&apos;s disease</keyword><keyword>Diabetes mellitus</keyword><keyword>Insulin</keyword><keyword>Type 2 diabetes</keyword><keyword>Type 3 diabetes</keyword></keywords><dates><year>2015</year><pub-dates><date>Sep 25</date></pub-dates></dates><isbn>1948-9358 (Print)&#xD;1948-9358 (Linking)</isbn><accession-num>26464760</accession-num><urls><related-urls><url> neuroprotective effects were described for TZDs, including a decrease in stroke-related damage and neurological deficits in T2D mice ADDIN EN.CITE <EndNote><Cite><Author>Gavin</Author><Year>2010</Year><RecNum>3836</RecNum><DisplayText><style face="superscript">342</style></DisplayText><record><rec-number>3836</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535921077">3836</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gavin, J. R., 3rd</author><author>Stolar, M. W.</author><author>Freeman, J. S.</author><author>Spellman, C. W.</author></authors></contributors><auth-address>Healing Our Village, Inc, Lanham, MD 20706-4393, USA. drgavin@</auth-address><titles><title>Improving outcomes in patients with type 2 diabetes mellitus: practical solutions for clinical challenges</title><secondary-title>J Am Osteopath Assoc</secondary-title></titles><pages>S2-14; quiz S15-6</pages><volume>110</volume><number>5 Suppl 6</number><keywords><keyword>Algorithms</keyword><keyword>Blood Glucose/analysis</keyword><keyword>Blood Glucose Self-Monitoring</keyword><keyword>Cardiovascular Diseases/prevention &amp; control</keyword><keyword>Clinical Trials as Topic</keyword><keyword>Diabetes Complications/*prevention &amp; control</keyword><keyword>Diabetes Mellitus, Type 2/*blood/*therapy</keyword><keyword>Glycated Hemoglobin A/analysis</keyword><keyword>Humans</keyword><keyword>Hypoglycemic Agents/therapeutic use</keyword><keyword>Life Style</keyword><keyword>Medication Adherence</keyword><keyword>Postprandial Period</keyword><keyword>Practice Guidelines as Topic</keyword></keywords><dates><year>2010</year><pub-dates><date>May</date></pub-dates></dates><isbn>1945-1997 (Electronic)&#xD;0098-6151 (Linking)</isbn><accession-num>20554501</accession-num><urls><related-urls><url>. Others suggested that TZDs-mediated reduction in brain oxidative stress and rescue in STAT3/Wnt signaling pathways may promote neuronal progenitor cells proliferation and differentiation upon T2D PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UdXJleWVuPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48

UmVjTnVtPjM4Mzc8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zNDM8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zODM3PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MjExNDgiPjM4Mzc8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlR1cmV5ZW4sIEsuPC9hdXRob3I+PGF1

dGhvcj5LYXBhZGlhLCBSLjwvYXV0aG9yPjxhdXRob3I+Qm93ZW4sIEsuIEsuPC9hdXRob3I+PGF1

dGhvcj5TYXRyaW90b21vLCBJLjwvYXV0aG9yPjxhdXRob3I+TGlhbmcsIEouPC9hdXRob3I+PGF1

dGhvcj5GZWluc3RlaW4sIEQuIEwuPC9hdXRob3I+PGF1dGhvcj5WZW11Z2FudGksIFIuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBO

ZXVyb2xvZ2ljYWwgU3VyZ2VyeSwgVW5pdmVyc2l0eSBvZiBXaXNjb25zaW4sIE1hZGlzb24sIFdp

c2NvbnNpbiA1Mzc5MiwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlBlcm94aXNv

bWUgcHJvbGlmZXJhdG9yLWFjdGl2YXRlZCByZWNlcHRvci1nYW1tYSBhZ29uaXN0cyBpbmR1Y2Ug

bmV1cm9wcm90ZWN0aW9uIGZvbGxvd2luZyB0cmFuc2llbnQgZm9jYWwgaXNjaGVtaWEgaW4gbm9y

bW90ZW5zaXZlLCBub3Jtb2dseWNlbWljIGFzIHdlbGwgYXMgaHlwZXJ0ZW5zaXZlIGFuZCB0eXBl

LTIgZGlhYmV0aWMgcm9kZW50czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIE5ldXJvY2hlbTwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9j

aGVtPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NDEtNTY8L3BhZ2VzPjx2b2x1bWU+

MTAxPC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFuaWxpZGVz

L3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3Jk

PkNlcmVicmFsIEluZmFyY3Rpb24vKmRydWcgdGhlcmFweS9waHlzaW9wYXRob2xvZ3kvcHJldmVu

dGlvbiAmYW1wOyBjb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPkNoZW1vdGF4aXMsIExldWtvY3l0

ZS9kcnVnIGVmZmVjdHMvcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5DeXRva2luZXMvZ2Vu

ZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBNZWxsaXR1cywgVHlw

ZSAyL2dlbmV0aWNzLypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBN

b2RlbHMsIEFuaW1hbDwva2V5d29yZD48a2V5d29yZD5FbmNlcGhhbGl0aXMvZHJ1ZyB0aGVyYXB5

L21ldGFib2xpc20vcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh5cGVydGVuc2lv

bi9nZW5ldGljcy8qcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkludGVyY2VsbHVs

YXIgQWRoZXNpb24gTW9sZWN1bGUtMS9kcnVnIGVmZmVjdHMvbWV0YWJvbGlzbTwva2V5d29yZD48

a2V5d29yZD5Jc2NoZW1pYyBBdHRhY2ssIFRyYW5zaWVudC8qZHJ1ZyB0aGVyYXB5L3BoeXNpb3Bh

dGhvbG9neTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIElu

YnJlZCBDNTdCTDwva2V5d29yZD48a2V5d29yZD5NaWNlLCBNdXRhbnQgU3RyYWluczwva2V5d29y

ZD48a2V5d29yZD5OZXVyb3Byb3RlY3RpdmUgQWdlbnRzL2NoZW1pc3RyeS9waGFybWFjb2xvZ3kv

dGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPlBQQVIgZ2FtbWEvKmFnb25pc3RzL2Fu

dGFnb25pc3RzICZhbXA7IGluaGliaXRvcnMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5S

YXRzPC9rZXl3b3JkPjxrZXl3b3JkPlJhdHMsIEluYnJlZCBTSFI8L2tleXdvcmQ+PGtleXdvcmQ+

UmF0cywgU3ByYWd1ZS1EYXdsZXk8L2tleXdvcmQ+PGtleXdvcmQ+U3VwZXJveGlkZSBEaXNtdXRh

c2UvZHJ1ZyBlZmZlY3RzL2dlbmV0aWNzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+U3Vw

ZXJveGlkZSBEaXNtdXRhc2UtMTwva2V5d29yZD48a2V5d29yZD5TdXBwcmVzc29yIG9mIEN5dG9r

aW5lIFNpZ25hbGluZyAzIFByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+U3VwcHJlc3NvciBvZiBD

eXRva2luZSBTaWduYWxpbmcgUHJvdGVpbnMvZHJ1ZyBlZmZlY3RzL21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+VGhpYXpvbGlkaW5lZGlvbmVzL2NoZW1pc3RyeS8qcGhhcm1hY29sb2d5L3Ro

ZXJhcGV1dGljIHVzZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA3PC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+QXByPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDAy

Mi0zMDQyIChQcmludCkmI3hEOzAwMjItMzA0MiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1u

dW0+MTczOTQ0NjA8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6

Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTczOTQ0NjA8L3VybD48L3JlbGF0ZWQtdXJs

cz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExMTEvai4xNDcxLTQxNTkuMjAw

Ni4wNDM3Ni54PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmRO

b3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UdXJleWVuPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48

UmVjTnVtPjM4Mzc8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zNDM8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zODM3PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MjExNDgiPjM4Mzc8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlR1cmV5ZW4sIEsuPC9hdXRob3I+PGF1

dGhvcj5LYXBhZGlhLCBSLjwvYXV0aG9yPjxhdXRob3I+Qm93ZW4sIEsuIEsuPC9hdXRob3I+PGF1

dGhvcj5TYXRyaW90b21vLCBJLjwvYXV0aG9yPjxhdXRob3I+TGlhbmcsIEouPC9hdXRob3I+PGF1

dGhvcj5GZWluc3RlaW4sIEQuIEwuPC9hdXRob3I+PGF1dGhvcj5WZW11Z2FudGksIFIuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBO

ZXVyb2xvZ2ljYWwgU3VyZ2VyeSwgVW5pdmVyc2l0eSBvZiBXaXNjb25zaW4sIE1hZGlzb24sIFdp

c2NvbnNpbiA1Mzc5MiwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlBlcm94aXNv

bWUgcHJvbGlmZXJhdG9yLWFjdGl2YXRlZCByZWNlcHRvci1nYW1tYSBhZ29uaXN0cyBpbmR1Y2Ug

bmV1cm9wcm90ZWN0aW9uIGZvbGxvd2luZyB0cmFuc2llbnQgZm9jYWwgaXNjaGVtaWEgaW4gbm9y

bW90ZW5zaXZlLCBub3Jtb2dseWNlbWljIGFzIHdlbGwgYXMgaHlwZXJ0ZW5zaXZlIGFuZCB0eXBl

LTIgZGlhYmV0aWMgcm9kZW50czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIE5ldXJvY2hlbTwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9j

aGVtPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NDEtNTY8L3BhZ2VzPjx2b2x1bWU+

MTAxPC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFuaWxpZGVz

L3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3Jk

PkNlcmVicmFsIEluZmFyY3Rpb24vKmRydWcgdGhlcmFweS9waHlzaW9wYXRob2xvZ3kvcHJldmVu

dGlvbiAmYW1wOyBjb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPkNoZW1vdGF4aXMsIExldWtvY3l0

ZS9kcnVnIGVmZmVjdHMvcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5DeXRva2luZXMvZ2Vu

ZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBNZWxsaXR1cywgVHlw

ZSAyL2dlbmV0aWNzLypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBN

b2RlbHMsIEFuaW1hbDwva2V5d29yZD48a2V5d29yZD5FbmNlcGhhbGl0aXMvZHJ1ZyB0aGVyYXB5

L21ldGFib2xpc20vcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh5cGVydGVuc2lv

bi9nZW5ldGljcy8qcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkludGVyY2VsbHVs

YXIgQWRoZXNpb24gTW9sZWN1bGUtMS9kcnVnIGVmZmVjdHMvbWV0YWJvbGlzbTwva2V5d29yZD48

a2V5d29yZD5Jc2NoZW1pYyBBdHRhY2ssIFRyYW5zaWVudC8qZHJ1ZyB0aGVyYXB5L3BoeXNpb3Bh

dGhvbG9neTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIElu

YnJlZCBDNTdCTDwva2V5d29yZD48a2V5d29yZD5NaWNlLCBNdXRhbnQgU3RyYWluczwva2V5d29y

ZD48a2V5d29yZD5OZXVyb3Byb3RlY3RpdmUgQWdlbnRzL2NoZW1pc3RyeS9waGFybWFjb2xvZ3kv

dGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPlBQQVIgZ2FtbWEvKmFnb25pc3RzL2Fu

dGFnb25pc3RzICZhbXA7IGluaGliaXRvcnMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5S

YXRzPC9rZXl3b3JkPjxrZXl3b3JkPlJhdHMsIEluYnJlZCBTSFI8L2tleXdvcmQ+PGtleXdvcmQ+

UmF0cywgU3ByYWd1ZS1EYXdsZXk8L2tleXdvcmQ+PGtleXdvcmQ+U3VwZXJveGlkZSBEaXNtdXRh

c2UvZHJ1ZyBlZmZlY3RzL2dlbmV0aWNzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+U3Vw

ZXJveGlkZSBEaXNtdXRhc2UtMTwva2V5d29yZD48a2V5d29yZD5TdXBwcmVzc29yIG9mIEN5dG9r

aW5lIFNpZ25hbGluZyAzIFByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+U3VwcHJlc3NvciBvZiBD

eXRva2luZSBTaWduYWxpbmcgUHJvdGVpbnMvZHJ1ZyBlZmZlY3RzL21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+VGhpYXpvbGlkaW5lZGlvbmVzL2NoZW1pc3RyeS8qcGhhcm1hY29sb2d5L3Ro

ZXJhcGV1dGljIHVzZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA3PC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+QXByPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDAy

Mi0zMDQyIChQcmludCkmI3hEOzAwMjItMzA0MiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1u

dW0+MTczOTQ0NjA8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6

Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTczOTQ0NjA8L3VybD48L3JlbGF0ZWQtdXJs

cz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExMTEvai4xNDcxLTQxNTkuMjAw

Ni4wNDM3Ni54PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmRO

b3RlPn==

ADDIN EN.CITE.DATA 343. This, together with a protection against amyloidogenic processing of APP, Tau hyperphosphorylation, neuroinflammation and Aβ-induced neuronal insulin resistance may account for the recovery in memory and cognitive performance in patients and rodent models PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMsMzI0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMsMzI0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 323,324. In line with this, in a randomized clinical trial, Rosiglitazone improved cognitive function in mild to moderate AD patients ADDIN EN.CITE <EndNote><Cite><Author>Peymani</Author><Year>2013</Year><RecNum>3775</RecNum><DisplayText><style face="superscript">344</style></DisplayText><record><rec-number>3775</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535919119">3775</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Peymani, Maryam</author><author>Ghoochani, Ali</author><author>Ghaedi, Kamran</author><author>Karamali, Fereshteh</author><author>Karbalaie, Khadijeh</author><author>Kiani-Esfahani, Abbas</author><author>Rabiee, Farzaneh</author><author>Nasr-Esfahani, Mohammad Hossein</author><author>Baharvand, Hossein</author></authors></contributors><titles><title>Dual effects of peroxisome proliferator-activated receptor γ on embryonic stem cell self-renewal in presence and absence of leukemia inhibitory factor</title><secondary-title>European Journal of Cell Biology</secondary-title></titles><pages>160-168</pages><volume>92</volume><number>4-5</number><dates><year>2013</year><pub-dates><date>2013/04</date></pub-dates></dates><publisher>Elsevier BV</publisher><isbn>0171-9335</isbn><urls><related-urls><url>, whereas in a Phase III study the drug did not show beneficial effects in AD patients, and the long-term use of thiazolidinediones did not attenuate the risk for AD ADDIN EN.CITE <EndNote><Cite><Author>Risner</Author><Year>2006</Year><RecNum>3776</RecNum><DisplayText><style face="superscript">345</style></DisplayText><record><rec-number>3776</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535919119">3776</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Risner, M. E.</author><author>Saunders, A. M.</author><author>Altman, J. F. B.</author><author>Ormandy, G. C.</author><author>Craft, S.</author><author>Foley, I. M.</author><author>Zvartau-Hind, M. E.</author><author>Hosford, D. A.</author><author>Roses, A. D.</author></authors></contributors><titles><title>Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer&apos;s disease</title><secondary-title>The Pharmacogenomics Journal</secondary-title></titles><pages>246-254</pages><volume>6</volume><number>4</number><dates><year>2006</year><pub-dates><date>2006/01/31</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>1470-269X&#xD;1473-1150</isbn><urls><related-urls><url> to , a Phase III clinical trial is currently analyzing the potential of Pioglitazone as a β-secretase inhibitor (TOMMORROW; NCT01931566) in people aged 65-83 years, at risk of MCI due to AD. A masked extension of this study (NCT02284906; phase III) is planned with 316 individuals with an MCI diagnosis due to AD that complete the TOMMORROW study.Is it still worthy to evaluate (intranasal) insulin for AD treatment? The pros and cons…Insulin has been increasingly used in T2D, not only for blood glucose management but also to prevent its chronic microvascular complications and death PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb2xkPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48UmVj

TnVtPjM4Mzg8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4z

NDY8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zODM4PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MjEyOTUiPjM4Mzg8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkdvbGQsIE0uPC9hdXRob3I+PGF1dGhvcj5B

bGRlcnRvbiwgQy48L2F1dGhvcj48YXV0aG9yPlp2YXJ0YXUtSGluZCwgTS48L2F1dGhvcj48YXV0

aG9yPkVnZ2ludG9uLCBTLjwvYXV0aG9yPjxhdXRob3I+U2F1bmRlcnMsIEEuIE0uPC9hdXRob3I+

PGF1dGhvcj5Jcml6YXJyeSwgTS48L2F1dGhvcj48YXV0aG9yPkNyYWZ0LCBTLjwvYXV0aG9yPjxh

dXRob3I+TGFuZHJldGgsIEcuPC9hdXRob3I+PGF1dGhvcj5MaW5uYW1hZ2ksIFUuPC9hdXRob3I+

PGF1dGhvcj5TYXdjaGFrLCBTLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0

aC1hZGRyZXNzPk5ldXJvc2NpZW5jZXMgTWVkaWNpbmVzIERldmVsb3BtZW50IENlbnRlciwgR2xh

eG9TbWl0aEtsaW5lLCBTdG9ja2xleSBQYXJrLCBIYXJsb3csIFVLLiBtaWNoYWVsLjIuZ29sZEBn

c2suY29tPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Um9zaWdsaXRhem9uZSBtb25vdGhl

cmFweSBpbiBtaWxkLXRvLW1vZGVyYXRlIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogcmVzdWx0

cyBmcm9tIGEgcmFuZG9taXplZCwgZG91YmxlLWJsaW5kLCBwbGFjZWJvLWNvbnRyb2xsZWQgcGhh

c2UgSUlJIHN0dWR5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkRlbWVudCBHZXJpYXRyIENvZ24g

RGlzb3JkPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+

RGVtZW50IEdlcmlhdHIgQ29nbiBEaXNvcmQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdl

cz4xMzEtNDY8L3BhZ2VzPjx2b2x1bWU+MzA8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48a2V5

d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwv

a2V5d29yZD48a2V5d29yZD5BbGxlbGVzPC9rZXl3b3JkPjxrZXl3b3JkPipBbHpoZWltZXIgRGlz

ZWFzZS9kcnVnIHRoZXJhcHkvZ2VuZXRpY3MvbWV0YWJvbGlzbS9waHlzaW9wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+QXBvbGlwb3Byb3RlaW5zIEUvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdv

cmQ+Q2hvbGluZXN0ZXJhc2UgSW5oaWJpdG9ycy9hZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2Uv

YWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkRydWctUmVsYXRlZCBTaWRlIEVmZmVj

dHMgYW5kIEFkdmVyc2UgUmVhY3Rpb25zPC9rZXl3b3JkPjxrZXl3b3JkPkVkZW1hL2NoZW1pY2Fs

bHkgaW5kdWNlZDwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+R2Vu

b3R5cGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHlj

ZW1pYyBBZ2VudHMvYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlL2FkdmVyc2UgZWZmZWN0czwv

a2V5d29yZD48a2V5d29yZD5JbmRhbnMvYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlL2FkdmVy

c2UgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5JbnRlbGxpZ2VuY2UgVGVzdHM8L2tleXdvcmQ+

PGtleXdvcmQ+SW50ZXJ2aWV3LCBQc3ljaG9sb2dpY2FsPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8

L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmFzb3BoYXJ5

bmdpdGlzL2NoZW1pY2FsbHkgaW5kdWNlZDwva2V5d29yZD48a2V5d29yZD5QUEFSIGdhbW1hL2Fn

b25pc3RzPC9rZXl3b3JkPjxrZXl3b3JkPlBpcGVyaWRpbmVzL2FkbWluaXN0cmF0aW9uICZhbXA7

IGRvc2FnZS9hZHZlcnNlIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+KlRoaWF6b2xpZGluZWRp

b25lcy9hZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2UvYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3Jk

PjxrZXl3b3JkPlRyZWF0bWVudCBPdXRjb21lPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5

ZWFyPjIwMTA8L3llYXI+PC9kYXRlcz48aXNibj4xNDIxLTk4MjQgKEVsZWN0cm9uaWMpJiN4RDsx

NDIwLTgwMDggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIwNzMzMzA2PC9hY2Nlc3Np

b24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5n

b3YvcHVibWVkLzIwNzMzMzA2PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBN

QzMyMTQ4ODI8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExNTkvMDAwMzE4

ODQ1PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb2xkPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48UmVj

TnVtPjM4Mzg8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4z

NDY8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zODM4PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MjEyOTUiPjM4Mzg8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkdvbGQsIE0uPC9hdXRob3I+PGF1dGhvcj5B

bGRlcnRvbiwgQy48L2F1dGhvcj48YXV0aG9yPlp2YXJ0YXUtSGluZCwgTS48L2F1dGhvcj48YXV0

aG9yPkVnZ2ludG9uLCBTLjwvYXV0aG9yPjxhdXRob3I+U2F1bmRlcnMsIEEuIE0uPC9hdXRob3I+

PGF1dGhvcj5Jcml6YXJyeSwgTS48L2F1dGhvcj48YXV0aG9yPkNyYWZ0LCBTLjwvYXV0aG9yPjxh

dXRob3I+TGFuZHJldGgsIEcuPC9hdXRob3I+PGF1dGhvcj5MaW5uYW1hZ2ksIFUuPC9hdXRob3I+

PGF1dGhvcj5TYXdjaGFrLCBTLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0

aC1hZGRyZXNzPk5ldXJvc2NpZW5jZXMgTWVkaWNpbmVzIERldmVsb3BtZW50IENlbnRlciwgR2xh

eG9TbWl0aEtsaW5lLCBTdG9ja2xleSBQYXJrLCBIYXJsb3csIFVLLiBtaWNoYWVsLjIuZ29sZEBn

c2suY29tPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Um9zaWdsaXRhem9uZSBtb25vdGhl

cmFweSBpbiBtaWxkLXRvLW1vZGVyYXRlIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogcmVzdWx0

cyBmcm9tIGEgcmFuZG9taXplZCwgZG91YmxlLWJsaW5kLCBwbGFjZWJvLWNvbnRyb2xsZWQgcGhh

c2UgSUlJIHN0dWR5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkRlbWVudCBHZXJpYXRyIENvZ24g

RGlzb3JkPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+

RGVtZW50IEdlcmlhdHIgQ29nbiBEaXNvcmQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdl

cz4xMzEtNDY8L3BhZ2VzPjx2b2x1bWU+MzA8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48a2V5

d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwv

a2V5d29yZD48a2V5d29yZD5BbGxlbGVzPC9rZXl3b3JkPjxrZXl3b3JkPipBbHpoZWltZXIgRGlz

ZWFzZS9kcnVnIHRoZXJhcHkvZ2VuZXRpY3MvbWV0YWJvbGlzbS9waHlzaW9wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+QXBvbGlwb3Byb3RlaW5zIEUvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdv

cmQ+Q2hvbGluZXN0ZXJhc2UgSW5oaWJpdG9ycy9hZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2Uv

YWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkRydWctUmVsYXRlZCBTaWRlIEVmZmVj

dHMgYW5kIEFkdmVyc2UgUmVhY3Rpb25zPC9rZXl3b3JkPjxrZXl3b3JkPkVkZW1hL2NoZW1pY2Fs

bHkgaW5kdWNlZDwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+R2Vu

b3R5cGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHlj

ZW1pYyBBZ2VudHMvYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlL2FkdmVyc2UgZWZmZWN0czwv

a2V5d29yZD48a2V5d29yZD5JbmRhbnMvYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlL2FkdmVy

c2UgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5JbnRlbGxpZ2VuY2UgVGVzdHM8L2tleXdvcmQ+

PGtleXdvcmQ+SW50ZXJ2aWV3LCBQc3ljaG9sb2dpY2FsPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8

L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmFzb3BoYXJ5

bmdpdGlzL2NoZW1pY2FsbHkgaW5kdWNlZDwva2V5d29yZD48a2V5d29yZD5QUEFSIGdhbW1hL2Fn

b25pc3RzPC9rZXl3b3JkPjxrZXl3b3JkPlBpcGVyaWRpbmVzL2FkbWluaXN0cmF0aW9uICZhbXA7

IGRvc2FnZS9hZHZlcnNlIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+KlRoaWF6b2xpZGluZWRp

b25lcy9hZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2UvYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3Jk

PjxrZXl3b3JkPlRyZWF0bWVudCBPdXRjb21lPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5

ZWFyPjIwMTA8L3llYXI+PC9kYXRlcz48aXNibj4xNDIxLTk4MjQgKEVsZWN0cm9uaWMpJiN4RDsx

NDIwLTgwMDggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIwNzMzMzA2PC9hY2Nlc3Np

b24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5n

b3YvcHVibWVkLzIwNzMzMzA2PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBN

QzMyMTQ4ODI8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExNTkvMDAwMzE4

ODQ1PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 346. However, some controversy persists on its efficacy, which may be lost upon T2D progression.Physiologically, brain insulin signaling promotes synaptic remodeling and memory formation ADDIN EN.CITE <EndNote><Cite><Author>Morsink</Author><Year>2013</Year><RecNum>3778</RecNum><DisplayText><style face="superscript">347,348</style></DisplayText><record><rec-number>3778</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535919119">3778</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Morsink, Linde M.</author><author>Smits, Mark M.</author><author>Diamant, Michaela</author></authors></contributors><titles><title>Advances in Pharmacologic Therapies for Type 2 Diabetes</title><secondary-title>Current Atherosclerosis Reports</secondary-title></titles><volume>15</volume><number>2</number><dates><year>2013</year><pub-dates><date>2013/01/09</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>1523-3804&#xD;1534-6242</isbn><urls><related-urls><url> app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535919119">3779</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Craft, Suzanne</author></authors></contributors><titles><title>Insulin and Alzheimer Disease—Reply</title><secondary-title>Archives of Neurology</secondary-title></titles><pages>670</pages><volume>69</volume><number>5</number><dates><year>2012</year><pub-dates><date>2012/05/01</date></pub-dates></dates><publisher>American Medical Association (AMA)</publisher><isbn>0003-9942</isbn><urls><related-urls><url>. We also found that restoring insulin and IGF-1 signaling recovered both peripheral and brain glucose metabolism, and motor function in vitro and in vivo Huntington’s disease models PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYWlhPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48UmVj

TnVtPjM3ODE8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4z

NDktMzUxPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc4MTwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5Ij4zNzgxPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5OYWlhLCBMdWFuYTwvYXV0aG9yPjxh

dXRob3I+RmVycmVpcmEsIEkuIEx1w61zYTwvYXV0aG9yPjxhdXRob3I+Q3VuaGEtT2xpdmVpcmEs

IFRlcmVzYTwvYXV0aG9yPjxhdXRob3I+RHVhcnRlLCBBbmEgSS48L2F1dGhvcj48YXV0aG9yPlJp

YmVpcm8sIE3DoXJjaW88L2F1dGhvcj48YXV0aG9yPlJvc2Vuc3RvY2ssIFRhdGlhbmEgUi48L2F1

dGhvcj48YXV0aG9yPkxhw6dvLCBNw6FyaW8gTi48L2F1dGhvcj48YXV0aG9yPlJpYmVpcm8sIE1h

cmlhIEouPC9hdXRob3I+PGF1dGhvcj5PbGl2ZWlyYSwgQ2F0YXJpbmEgUi48L2F1dGhvcj48YXV0

aG9yPlNhdWRvdSwgRnLDqWTDqXJpYzwvYXV0aG9yPjxhdXRob3I+SHVtYmVydCwgU2FuZHJpbmU8

L2F1dGhvcj48YXV0aG9yPlJlZ28sIEEuIENyaXN0aW5hPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkFjdGl2YXRpb24gb2YgSUdGLTEgYW5kIEluc3VsaW4g

U2lnbmFsaW5nIFBhdGh3YXlzIEFtZWxpb3JhdGUgTWl0b2Nob25kcmlhbCBGdW5jdGlvbiBhbmQg

RW5lcmd5IE1ldGFib2xpc20gaW4gSHVudGluZ3RvbuKAmXMgRGlzZWFzZSBIdW1hbiBMeW1waG9i

bGFzdHM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TW9sZWN1bGFyIE5ldXJvYmlvbG9neTwvc2Vj

b25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4zMzEtMzQ4PC9wYWdlcz48dm9sdW1lPjUxPC92

b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT4yMDE0LzA1LzIwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5T

cHJpbmdlciBOYXR1cmU8L3B1Ymxpc2hlcj48aXNibj4wODkzLTc2NDgmI3hEOzE1NTktMTE4Mjwv

aXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAwNy9z

MTIwMzUtMDE0LTg3MzUtNDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+MTAuMTAwNy9zMTIwMzUtMDE0LTg3MzUtNDwvZWxlY3Ryb25pYy1yZXNvdXJj

ZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TmFpYTwvQXV0aG9yPjxZZWFyPjIw

MTY8L1llYXI+PFJlY051bT4zNzgwPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zNzgwPC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTkxMTkiPjM3ODA8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk5haWEsIEx1YW5hPC9hdXRob3I+

PGF1dGhvcj5SaWJlaXJvLCBNw6FyY2lvPC9hdXRob3I+PGF1dGhvcj5Sb2RyaWd1ZXMsIEpvYW5h

PC9hdXRob3I+PGF1dGhvcj5EdWFydGUsIEFuYSBJLjwvYXV0aG9yPjxhdXRob3I+TG9wZXMsIENh

cmxhPC9hdXRob3I+PGF1dGhvcj5Sb3NlbnN0b2NrLCBUYXRpYW5hIFIuPC9hdXRob3I+PGF1dGhv

cj5IYXlkZW4sIE1pY2hhZWwgUi48L2F1dGhvcj48YXV0aG9yPlJlZ28sIEEuIENyaXN0aW5hPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkluc3VsaW4gYW5k

IElHRi0xIHJlZ3VsYXJpemUgZW5lcmd5IG1ldGFib2xpdGVzIGluIG5ldXJhbCBjZWxscyBleHBy

ZXNzaW5nIGZ1bGwtbGVuZ3RoIG11dGFudCBodW50aW5ndGluPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPk5ldXJvcGVwdGlkZXM8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NzMtODE8

L3BhZ2VzPjx2b2x1bWU+NTg8L3ZvbHVtZT48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRh

dGVzPjxkYXRlPjIwMTYvMDg8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVs

c2V2aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MDE0My00MTc5PC9pc2JuPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2oubnBlcC4yMDE2LjAxLjAwOTwv

dXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAx

Ni9qLm5wZXAuMjAxNi4wMS4wMDk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48Q2l0ZT48QXV0aG9yPkxvcGVzPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVt

PjM3ODI8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3ODI8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxOTExOSI+Mzc4Mjwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+TG9wZXMsIENhcmxhPC9hdXRob3I+PGF1dGhvcj5SaWJlaXJv

LCBNw6FyY2lvPC9hdXRob3I+PGF1dGhvcj5EdWFydGUsIEFuYSBJLjwvYXV0aG9yPjxhdXRob3I+

SHVtYmVydCwgU2FuZHJpbmU8L2F1dGhvcj48YXV0aG9yPlNhdWRvdSwgRnJlZGVyaWM8L2F1dGhv

cj48YXV0aG9yPlBlcmVpcmEgZGUgQWxtZWlkYSwgTHXDrXM8L2F1dGhvcj48YXV0aG9yPkhheWRl

biwgTWljaGFlbDwvYXV0aG9yPjxhdXRob3I+UmVnbywgQS4gQ3Jpc3RpbmE8L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+SUdGLTEgSW50cmFuYXNhbCBBZG1p

bmlzdHJhdGlvbiBSZXNjdWVzIEh1bnRpbmd0b24mYXBvcztzIERpc2Vhc2UgUGhlbm90eXBlcyBp

biBZQUMxMjggTWljZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Nb2xlY3VsYXIgTmV1cm9iaW9s

b2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjExMjYtMTE0MjwvcGFnZXM+PHZv

bHVtZT40OTwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDEzPC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+MjAxMy8xMi8xODwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxw

dWJsaXNoZXI+U3ByaW5nZXIgTmF0dXJlPC9wdWJsaXNoZXI+PGlzYm4+MDg5My03NjQ4JiN4RDsx

NTU5LTExODI8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3Jn

LzEwLjEwMDcvczEyMDM1LTAxMy04NTg1LTU8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDcvczEyMDM1LTAxMy04NTg1LTU8L2VsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYWlhPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48UmVj

TnVtPjM3ODE8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4z

NDktMzUxPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc4MTwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5Ij4zNzgxPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5OYWlhLCBMdWFuYTwvYXV0aG9yPjxh

dXRob3I+RmVycmVpcmEsIEkuIEx1w61zYTwvYXV0aG9yPjxhdXRob3I+Q3VuaGEtT2xpdmVpcmEs

IFRlcmVzYTwvYXV0aG9yPjxhdXRob3I+RHVhcnRlLCBBbmEgSS48L2F1dGhvcj48YXV0aG9yPlJp

YmVpcm8sIE3DoXJjaW88L2F1dGhvcj48YXV0aG9yPlJvc2Vuc3RvY2ssIFRhdGlhbmEgUi48L2F1

dGhvcj48YXV0aG9yPkxhw6dvLCBNw6FyaW8gTi48L2F1dGhvcj48YXV0aG9yPlJpYmVpcm8sIE1h

cmlhIEouPC9hdXRob3I+PGF1dGhvcj5PbGl2ZWlyYSwgQ2F0YXJpbmEgUi48L2F1dGhvcj48YXV0

aG9yPlNhdWRvdSwgRnLDqWTDqXJpYzwvYXV0aG9yPjxhdXRob3I+SHVtYmVydCwgU2FuZHJpbmU8

L2F1dGhvcj48YXV0aG9yPlJlZ28sIEEuIENyaXN0aW5hPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkFjdGl2YXRpb24gb2YgSUdGLTEgYW5kIEluc3VsaW4g

U2lnbmFsaW5nIFBhdGh3YXlzIEFtZWxpb3JhdGUgTWl0b2Nob25kcmlhbCBGdW5jdGlvbiBhbmQg

RW5lcmd5IE1ldGFib2xpc20gaW4gSHVudGluZ3RvbuKAmXMgRGlzZWFzZSBIdW1hbiBMeW1waG9i

bGFzdHM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TW9sZWN1bGFyIE5ldXJvYmlvbG9neTwvc2Vj

b25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4zMzEtMzQ4PC9wYWdlcz48dm9sdW1lPjUxPC92

b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT4yMDE0LzA1LzIwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5T

cHJpbmdlciBOYXR1cmU8L3B1Ymxpc2hlcj48aXNibj4wODkzLTc2NDgmI3hEOzE1NTktMTE4Mjwv

aXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAwNy9z

MTIwMzUtMDE0LTg3MzUtNDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+MTAuMTAwNy9zMTIwMzUtMDE0LTg3MzUtNDwvZWxlY3Ryb25pYy1yZXNvdXJj

ZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TmFpYTwvQXV0aG9yPjxZZWFyPjIw

MTY8L1llYXI+PFJlY051bT4zNzgwPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zNzgwPC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTkxMTkiPjM3ODA8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk5haWEsIEx1YW5hPC9hdXRob3I+

PGF1dGhvcj5SaWJlaXJvLCBNw6FyY2lvPC9hdXRob3I+PGF1dGhvcj5Sb2RyaWd1ZXMsIEpvYW5h

PC9hdXRob3I+PGF1dGhvcj5EdWFydGUsIEFuYSBJLjwvYXV0aG9yPjxhdXRob3I+TG9wZXMsIENh

cmxhPC9hdXRob3I+PGF1dGhvcj5Sb3NlbnN0b2NrLCBUYXRpYW5hIFIuPC9hdXRob3I+PGF1dGhv

cj5IYXlkZW4sIE1pY2hhZWwgUi48L2F1dGhvcj48YXV0aG9yPlJlZ28sIEEuIENyaXN0aW5hPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkluc3VsaW4gYW5k

IElHRi0xIHJlZ3VsYXJpemUgZW5lcmd5IG1ldGFib2xpdGVzIGluIG5ldXJhbCBjZWxscyBleHBy

ZXNzaW5nIGZ1bGwtbGVuZ3RoIG11dGFudCBodW50aW5ndGluPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPk5ldXJvcGVwdGlkZXM8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NzMtODE8

L3BhZ2VzPjx2b2x1bWU+NTg8L3ZvbHVtZT48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRh

dGVzPjxkYXRlPjIwMTYvMDg8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVs

c2V2aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MDE0My00MTc5PC9pc2JuPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2oubnBlcC4yMDE2LjAxLjAwOTwv

dXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAx

Ni9qLm5wZXAuMjAxNi4wMS4wMDk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48Q2l0ZT48QXV0aG9yPkxvcGVzPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVt

PjM3ODI8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3ODI8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxOTExOSI+Mzc4Mjwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+TG9wZXMsIENhcmxhPC9hdXRob3I+PGF1dGhvcj5SaWJlaXJv

LCBNw6FyY2lvPC9hdXRob3I+PGF1dGhvcj5EdWFydGUsIEFuYSBJLjwvYXV0aG9yPjxhdXRob3I+

SHVtYmVydCwgU2FuZHJpbmU8L2F1dGhvcj48YXV0aG9yPlNhdWRvdSwgRnJlZGVyaWM8L2F1dGhv

cj48YXV0aG9yPlBlcmVpcmEgZGUgQWxtZWlkYSwgTHXDrXM8L2F1dGhvcj48YXV0aG9yPkhheWRl

biwgTWljaGFlbDwvYXV0aG9yPjxhdXRob3I+UmVnbywgQS4gQ3Jpc3RpbmE8L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+SUdGLTEgSW50cmFuYXNhbCBBZG1p

bmlzdHJhdGlvbiBSZXNjdWVzIEh1bnRpbmd0b24mYXBvcztzIERpc2Vhc2UgUGhlbm90eXBlcyBp

biBZQUMxMjggTWljZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Nb2xlY3VsYXIgTmV1cm9iaW9s

b2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjExMjYtMTE0MjwvcGFnZXM+PHZv

bHVtZT40OTwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDEzPC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+MjAxMy8xMi8xODwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxw

dWJsaXNoZXI+U3ByaW5nZXIgTmF0dXJlPC9wdWJsaXNoZXI+PGlzYm4+MDg5My03NjQ4JiN4RDsx

NTU5LTExODI8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3Jn

LzEwLjEwMDcvczEyMDM1LTAxMy04NTg1LTU8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDcvczEyMDM1LTAxMy04NTg1LTU8L2VsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 349-351. Moreover, insulin decreased synaptic Aβ accumulation, oxidative damage and mitochondrial dysfunction PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3JlaXJhPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48

UmVjTnVtPjMyOTA8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4yODAsMzUyPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzI5MDwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTA2MzgwIj4zMjkwPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Nb3JlaXJhLCBQLiBJLjwvYXV0

aG9yPjxhdXRob3I+U2FudG9zLCBNLiBTLjwvYXV0aG9yPjxhdXRob3I+U2VuYSwgQy48L2F1dGhv

cj48YXV0aG9yPlNlaWNhLCBSLjwvYXV0aG9yPjxhdXRob3I+T2xpdmVpcmEsIEMuIFIuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+Q2VudGVyIGZvciBOZXVy

b3NjaWVuY2Ugb2YgQ29pbWJyYSwgRGVwYXJ0bWVudCBvZiBab29sb2d5LCBGYWN1bHR5IG9mIFNj

aWVuY2VzIGFuZCBUZWNobm9sb2d5LCBVbml2ZXJzaXR5IG9mIENvaW1icmEsIDMwMDQtNTE3IENv

aW1icmEsIFBvcnR1Z2FsLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkluc3VsaW4gcHJv

dGVjdHMgYWdhaW5zdCBhbXlsb2lkIGJldGEtcGVwdGlkZSB0b3hpY2l0eSBpbiBicmFpbiBtaXRv

Y2hvbmRyaWEgb2YgZGlhYmV0aWMgcmF0czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb2Jp

b2wgRGlzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+

TmV1cm9iaW9sIERpczwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjYyOC0zNzwvcGFn

ZXM+PHZvbHVtZT4xODwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29y

ZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvKnRveGljaXR5PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1h

bHM8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKmRydWcgZWZmZWN0cy9tZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPkRpYWJldGVzIE1lbGxpdHVzLCBFeHBlcmltZW50YWwvKmRydWcgdGhlcmFw

eS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkdsdXRhdGhpb25lL21ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+SW5zdWxpbi9waGFybWFjb2xvZ3kvKnRoZXJhcGV1dGljIHVzZTwva2V5

d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pdG9jaG9uZHJpYS8qZHJ1ZyBl

ZmZlY3RzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9wcm90ZWN0aXZlIEFnZW50

cy9waGFybWFjb2xvZ3kvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPlBlcHRpZGUg

RnJhZ21lbnRzLyp0b3hpY2l0eTwva2V5d29yZD48a2V5d29yZD5SYXRzPC9rZXl3b3JkPjxrZXl3

b3JkPlJhdHMsIFdpc3Rhcjwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA1PC95

ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXByPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+

MDk2OS05OTYxIChQcmludCkmI3hEOzA5NjktOTk2MSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lv

bi1udW0+MTU3NTU2ODg8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0

dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTU3NTU2ODg8L3VybD48L3JlbGF0ZWQt

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uYmQuMjAwNC4x

MC4wMTc8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPkR1YXJ0ZTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJlY051bT4zNzgzPC9SZWNOdW0+

PHJlY29yZD48cmVjLW51bWJlcj4zNzgzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBh

cHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1l

c3RhbXA9IjE1MzU5MTkxMTkiPjM3ODM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt

ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48

YXV0aG9yPkR1YXJ0ZSwgQS4gSS48L2F1dGhvcj48YXV0aG9yPlBldGl0LCBHLiBILjwvYXV0aG9y

PjxhdXRob3I+UmFuZ2FuYXRoYW4sIFMuPC9hdXRob3I+PGF1dGhvcj5MaSwgSi4gWS48L2F1dGhv

cj48YXV0aG9yPk9saXZlaXJhLCBDLiBSLjwvYXV0aG9yPjxhdXRob3I+QnJ1bmRpbiwgUC48L2F1

dGhvcj48YXV0aG9yPkJqw7Zya3F2aXN0LCBNLjwvYXV0aG9yPjxhdXRob3I+UmVnbywgQS4gQy48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+SUdGLTEgcHJv

dGVjdHMgYWdhaW5zdCBkaWFiZXRpYyBmZWF0dXJlcyBpbiBhbiBpbiB2aXZvIG1vZGVsIG9mIEh1

bnRpbmd0b24mYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+RXhwZXJpbWVu

dGFsIE5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4zMTQtMzE5PC9w

YWdlcz48dm9sdW1lPjIzMTwvdm9sdW1lPjxudW1iZXI+MjwvbnVtYmVyPjxkYXRlcz48eWVhcj4y

MDExPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxMS8xMDwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxwdWJsaXNoZXI+RWxzZXZpZXIgQlY8L3B1Ymxpc2hlcj48aXNibj4wMDE0LTQ4ODY8L2lz

Ym4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjEwMTYvai5l

eHBuZXVyb2wuMjAxMS4wNi4wMTY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5leHBuZXVyb2wuMjAxMS4wNi4wMTY8L2VsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3JlaXJhPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48

UmVjTnVtPjMyOTA8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4yODAsMzUyPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzI5MDwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTA2MzgwIj4zMjkwPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Nb3JlaXJhLCBQLiBJLjwvYXV0

aG9yPjxhdXRob3I+U2FudG9zLCBNLiBTLjwvYXV0aG9yPjxhdXRob3I+U2VuYSwgQy48L2F1dGhv

cj48YXV0aG9yPlNlaWNhLCBSLjwvYXV0aG9yPjxhdXRob3I+T2xpdmVpcmEsIEMuIFIuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+Q2VudGVyIGZvciBOZXVy

b3NjaWVuY2Ugb2YgQ29pbWJyYSwgRGVwYXJ0bWVudCBvZiBab29sb2d5LCBGYWN1bHR5IG9mIFNj

aWVuY2VzIGFuZCBUZWNobm9sb2d5LCBVbml2ZXJzaXR5IG9mIENvaW1icmEsIDMwMDQtNTE3IENv

aW1icmEsIFBvcnR1Z2FsLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkluc3VsaW4gcHJv

dGVjdHMgYWdhaW5zdCBhbXlsb2lkIGJldGEtcGVwdGlkZSB0b3hpY2l0eSBpbiBicmFpbiBtaXRv

Y2hvbmRyaWEgb2YgZGlhYmV0aWMgcmF0czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb2Jp

b2wgRGlzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+

TmV1cm9iaW9sIERpczwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjYyOC0zNzwvcGFn

ZXM+PHZvbHVtZT4xODwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29y

ZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvKnRveGljaXR5PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1h

bHM8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKmRydWcgZWZmZWN0cy9tZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPkRpYWJldGVzIE1lbGxpdHVzLCBFeHBlcmltZW50YWwvKmRydWcgdGhlcmFw

eS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkdsdXRhdGhpb25lL21ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+SW5zdWxpbi9waGFybWFjb2xvZ3kvKnRoZXJhcGV1dGljIHVzZTwva2V5

d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pdG9jaG9uZHJpYS8qZHJ1ZyBl

ZmZlY3RzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9wcm90ZWN0aXZlIEFnZW50

cy9waGFybWFjb2xvZ3kvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPlBlcHRpZGUg

RnJhZ21lbnRzLyp0b3hpY2l0eTwva2V5d29yZD48a2V5d29yZD5SYXRzPC9rZXl3b3JkPjxrZXl3

b3JkPlJhdHMsIFdpc3Rhcjwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA1PC95

ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXByPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+

MDk2OS05OTYxIChQcmludCkmI3hEOzA5NjktOTk2MSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lv

bi1udW0+MTU3NTU2ODg8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0

dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTU3NTU2ODg8L3VybD48L3JlbGF0ZWQt

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uYmQuMjAwNC4x

MC4wMTc8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPkR1YXJ0ZTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJlY051bT4zNzgzPC9SZWNOdW0+

PHJlY29yZD48cmVjLW51bWJlcj4zNzgzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBh

cHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1l

c3RhbXA9IjE1MzU5MTkxMTkiPjM3ODM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt

ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48

YXV0aG9yPkR1YXJ0ZSwgQS4gSS48L2F1dGhvcj48YXV0aG9yPlBldGl0LCBHLiBILjwvYXV0aG9y

PjxhdXRob3I+UmFuZ2FuYXRoYW4sIFMuPC9hdXRob3I+PGF1dGhvcj5MaSwgSi4gWS48L2F1dGhv

cj48YXV0aG9yPk9saXZlaXJhLCBDLiBSLjwvYXV0aG9yPjxhdXRob3I+QnJ1bmRpbiwgUC48L2F1

dGhvcj48YXV0aG9yPkJqw7Zya3F2aXN0LCBNLjwvYXV0aG9yPjxhdXRob3I+UmVnbywgQS4gQy48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+SUdGLTEgcHJv

dGVjdHMgYWdhaW5zdCBkaWFiZXRpYyBmZWF0dXJlcyBpbiBhbiBpbiB2aXZvIG1vZGVsIG9mIEh1

bnRpbmd0b24mYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+RXhwZXJpbWVu

dGFsIE5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4zMTQtMzE5PC9w

YWdlcz48dm9sdW1lPjIzMTwvdm9sdW1lPjxudW1iZXI+MjwvbnVtYmVyPjxkYXRlcz48eWVhcj4y

MDExPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxMS8xMDwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxwdWJsaXNoZXI+RWxzZXZpZXIgQlY8L3B1Ymxpc2hlcj48aXNibj4wMDE0LTQ4ODY8L2lz

Ym4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjEwMTYvai5l

eHBuZXVyb2wuMjAxMS4wNi4wMTY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5leHBuZXVyb2wuMjAxMS4wNi4wMTY8L2VsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 280,352. This was accompanied by a protection against Aβ-induced neuronal insulin resistance PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYW5kaW5pPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3ODQ8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zNTMsMzU0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc4NDwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5Ij4zNzg0PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5QYW5kaW5pLCBHaXVzZXBwZTwv

YXV0aG9yPjxhdXRob3I+UGFjZSwgVmluY2VuemE8L2F1dGhvcj48YXV0aG9yPkNvcGFuaSwgQWdh

dGE8L2F1dGhvcj48YXV0aG9yPlNxdWF0cml0bywgU2ViYXN0aWFubzwvYXV0aG9yPjxhdXRob3I+

TWlsYXJkaSwgRGFuaWxvPC9hdXRob3I+PGF1dGhvcj5WaWduZXJpLCBSaWNjYXJkbzwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5JbnN1bGluIEhhcyBNdWx0

aXBsZSBBbnRpYW15bG9pZG9nZW5pYyBFZmZlY3RzIG9uIEh1bWFuIE5ldXJvbmFsIENlbGxzPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkVuZG9jcmlub2xvZ3k8L3NlY29uZGFyeS10aXRsZT48L3Rp

dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5FbmRvY3Jpbm9sb2d5PC9mdWxsLXRpdGxlPjwv

cGVyaW9kaWNhbD48cGFnZXM+Mzc1LTM4NzwvcGFnZXM+PHZvbHVtZT4xNTQ8L3ZvbHVtZT48bnVt

YmVyPjE8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIw

MTMvMDE8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPlRoZSBFbmRvY3JpbmUg

U29jaWV0eTwvcHVibGlzaGVyPjxpc2JuPjAwMTMtNzIyNyYjeEQ7MTk0NS03MTcwPC9pc2JuPjx1

cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMjEwL2VuLjIwMTIt

MTY2MTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

MTAuMTIxMC9lbi4yMDEyLTE2NjE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48Q2l0ZT48QXV0aG9yPkRlIEZlbGljZTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl

Y051bT4zODQ0PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zODQ0PC9yZWMtbnVtYmVyPjxm

b3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5

enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MjE3NTEiPjM4NDQ8L2tleT48L2ZvcmVpZ24t

a2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRy

aWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkRlIEZlbGljZSwgRi4gRy48L2F1dGhvcj48YXV0aG9y

PkxvdXJlbmNvLCBNLiBWLjwvYXV0aG9yPjxhdXRob3I+RmVycmVpcmEsIFMuIFQuPC9hdXRob3I+

PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+SW5zdGl0dXRlIG9mIE1lZGlj

YWwgQmlvY2hlbWlzdHJ5IExlb3BvbGRvIGRlIE1laXMsIEZlZGVyYWwgVW5pdmVyc2l0eSBvZiBS

aW8gZGUgSmFuZWlybywgUmlvIGRlIEphbmVpcm8sIEJyYXppbC4gRWxlY3Ryb25pYyBhZGRyZXNz

OiBmZWxpY2VAYmlvcW1lZC51ZnJqLmJyLiYjeEQ7SW5zdGl0dXRlIG9mIE1lZGljYWwgQmlvY2hl

bWlzdHJ5IExlb3BvbGRvIGRlIE1laXMsIEZlZGVyYWwgVW5pdmVyc2l0eSBvZiBSaW8gZGUgSmFu

ZWlybywgUmlvIGRlIEphbmVpcm8sIEJyYXppbC48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRs

ZT5Ib3cgZG9lcyBicmFpbiBpbnN1bGluIHJlc2lzdGFuY2UgZGV2ZWxvcCBpbiBBbHpoZWltZXIm

YXBvcztzIGRpc2Vhc2U/PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFsemhlaW1lcnMgRGVtZW50

PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPlMyNi0zMjwvcGFnZXM+PHZvbHVtZT4x

MDwvdm9sdW1lPjxudW1iZXI+MSBTdXBwbDwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpo

ZWltZXIgRGlzZWFzZS8qY29tcGxpY2F0aW9ucy8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKnBoeXNpb3BhdGhvbG9neTwva2V5d29y

ZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+Kkluc3VsaW4gUmVzaXN0YW5jZTwv

a2V5d29yZD48a2V5d29yZD5NZXRhYm9saWMgRGlzZWFzZXMvKmV0aW9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lk

LWJldGEgb2xpZ29tZXJzPC9rZXl3b3JkPjxrZXl3b3JkPkdMUC0xUiBhZ29uaXN0czwva2V5d29y

ZD48a2V5d29yZD5JbnN1bGluIHJlc2lzdGFuY2U8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxpbiB0

aGVyYXB5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1k

YXRlcz48ZGF0ZT5GZWI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTUyLTUyNzkg

KEVsZWN0cm9uaWMpJiN4RDsxNTUyLTUyNjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVt

PjI0NTI5NTIxPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8v

d3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI0NTI5NTIxPC91cmw+PC9yZWxhdGVkLXVybHM+

PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ouamFsei4yMDEzLjEyLjAw

NDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYW5kaW5pPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3ODQ8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zNTMsMzU0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc4NDwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5Ij4zNzg0PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5QYW5kaW5pLCBHaXVzZXBwZTwv

YXV0aG9yPjxhdXRob3I+UGFjZSwgVmluY2VuemE8L2F1dGhvcj48YXV0aG9yPkNvcGFuaSwgQWdh

dGE8L2F1dGhvcj48YXV0aG9yPlNxdWF0cml0bywgU2ViYXN0aWFubzwvYXV0aG9yPjxhdXRob3I+

TWlsYXJkaSwgRGFuaWxvPC9hdXRob3I+PGF1dGhvcj5WaWduZXJpLCBSaWNjYXJkbzwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5JbnN1bGluIEhhcyBNdWx0

aXBsZSBBbnRpYW15bG9pZG9nZW5pYyBFZmZlY3RzIG9uIEh1bWFuIE5ldXJvbmFsIENlbGxzPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkVuZG9jcmlub2xvZ3k8L3NlY29uZGFyeS10aXRsZT48L3Rp

dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5FbmRvY3Jpbm9sb2d5PC9mdWxsLXRpdGxlPjwv

cGVyaW9kaWNhbD48cGFnZXM+Mzc1LTM4NzwvcGFnZXM+PHZvbHVtZT4xNTQ8L3ZvbHVtZT48bnVt

YmVyPjE8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIw

MTMvMDE8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPlRoZSBFbmRvY3JpbmUg

U29jaWV0eTwvcHVibGlzaGVyPjxpc2JuPjAwMTMtNzIyNyYjeEQ7MTk0NS03MTcwPC9pc2JuPjx1

cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMjEwL2VuLjIwMTIt

MTY2MTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

MTAuMTIxMC9lbi4yMDEyLTE2NjE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48Q2l0ZT48QXV0aG9yPkRlIEZlbGljZTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl

Y051bT4zODQ0PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zODQ0PC9yZWMtbnVtYmVyPjxm

b3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5

enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MjE3NTEiPjM4NDQ8L2tleT48L2ZvcmVpZ24t

a2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRy

aWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkRlIEZlbGljZSwgRi4gRy48L2F1dGhvcj48YXV0aG9y

PkxvdXJlbmNvLCBNLiBWLjwvYXV0aG9yPjxhdXRob3I+RmVycmVpcmEsIFMuIFQuPC9hdXRob3I+

PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+SW5zdGl0dXRlIG9mIE1lZGlj

YWwgQmlvY2hlbWlzdHJ5IExlb3BvbGRvIGRlIE1laXMsIEZlZGVyYWwgVW5pdmVyc2l0eSBvZiBS

aW8gZGUgSmFuZWlybywgUmlvIGRlIEphbmVpcm8sIEJyYXppbC4gRWxlY3Ryb25pYyBhZGRyZXNz

OiBmZWxpY2VAYmlvcW1lZC51ZnJqLmJyLiYjeEQ7SW5zdGl0dXRlIG9mIE1lZGljYWwgQmlvY2hl

bWlzdHJ5IExlb3BvbGRvIGRlIE1laXMsIEZlZGVyYWwgVW5pdmVyc2l0eSBvZiBSaW8gZGUgSmFu

ZWlybywgUmlvIGRlIEphbmVpcm8sIEJyYXppbC48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRs

ZT5Ib3cgZG9lcyBicmFpbiBpbnN1bGluIHJlc2lzdGFuY2UgZGV2ZWxvcCBpbiBBbHpoZWltZXIm

YXBvcztzIGRpc2Vhc2U/PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFsemhlaW1lcnMgRGVtZW50

PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPlMyNi0zMjwvcGFnZXM+PHZvbHVtZT4x

MDwvdm9sdW1lPjxudW1iZXI+MSBTdXBwbDwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpo

ZWltZXIgRGlzZWFzZS8qY29tcGxpY2F0aW9ucy8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKnBoeXNpb3BhdGhvbG9neTwva2V5d29y

ZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+Kkluc3VsaW4gUmVzaXN0YW5jZTwv

a2V5d29yZD48a2V5d29yZD5NZXRhYm9saWMgRGlzZWFzZXMvKmV0aW9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lk

LWJldGEgb2xpZ29tZXJzPC9rZXl3b3JkPjxrZXl3b3JkPkdMUC0xUiBhZ29uaXN0czwva2V5d29y

ZD48a2V5d29yZD5JbnN1bGluIHJlc2lzdGFuY2U8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxpbiB0

aGVyYXB5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1k

YXRlcz48ZGF0ZT5GZWI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTUyLTUyNzkg

KEVsZWN0cm9uaWMpJiN4RDsxNTUyLTUyNjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVt

PjI0NTI5NTIxPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8v

d3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI0NTI5NTIxPC91cmw+PC9yZWxhdGVkLXVybHM+

PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ouamFsei4yMDEzLjEyLjAw

NDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 353,354. However, associated with insulin administration is the high risk of recurrent hypoglycemia, which has been increasingly related to neuronal dysfunction/death and cognitive deficits PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZSBGZWxpY2U8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFy

PjxSZWNOdW0+Mzg0MTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjM1NSwzNTY8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zODQx

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MjE2NDEiPjM4NDE8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkRlIEZlbGljZSwgRi4gRy48

L2F1dGhvcj48YXV0aG9yPlZpZWlyYSwgTS4gTi48L2F1dGhvcj48YXV0aG9yPkJvbWZpbSwgVC4g

Ui48L2F1dGhvcj48YXV0aG9yPkRlY2tlciwgSC48L2F1dGhvcj48YXV0aG9yPlZlbGFzY28sIFAu

IFQuPC9hdXRob3I+PGF1dGhvcj5MYW1iZXJ0LCBNLiBQLjwvYXV0aG9yPjxhdXRob3I+VmlvbGEs

IEsuIEwuPC9hdXRob3I+PGF1dGhvcj5aaGFvLCBXLiBRLjwvYXV0aG9yPjxhdXRob3I+RmVycmVp

cmEsIFMuIFQuPC9hdXRob3I+PGF1dGhvcj5LbGVpbiwgVy4gTC48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSBh

bmQgUGh5c2lvbG9neSwgTm9ydGh3ZXN0ZXJuIFVuaXZlcnNpdHksIEV2YW5zdG9uLCBJTCA2MDIw

OCwgVVNBLiBmZWxpY2VAYmlvcW1lZC51ZnJqLmJyPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+UHJvdGVjdGlvbiBvZiBzeW5hcHNlcyBhZ2FpbnN0IEFsemhlaW1lciZhcG9zO3MtbGlua2Vk

IHRveGluczogaW5zdWxpbiBzaWduYWxpbmcgcHJldmVudHMgdGhlIHBhdGhvZ2VuaWMgYmluZGlu

ZyBvZiBBYmV0YSBvbGlnb21lcnM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UHJvYyBOYXRsIEFj

YWQgU2NpIFUgUyBBPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwt

dGl0bGU+UHJvYyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48

cGFnZXM+MTk3MS02PC9wYWdlcz48dm9sdW1lPjEwNjwvdm9sdW1lPjxudW1iZXI+NjwvbnVtYmVy

PjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9wcmV2ZW50aW9uICZhbXA7IGNv

bnRyb2w8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzLyphZHZlcnNlIGVm

ZmVjdHMvZHJ1ZyBlZmZlY3RzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwv

a2V5d29yZD48a2V5d29yZD5DYXR0bGU8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVk

PC9rZXl3b3JkPjxrZXl3b3JkPkRpbWVyaXphdGlvbjwva2V5d29yZD48a2V5d29yZD5IaXBwb2Nh

bXB1cy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3Jk

Pkluc3VsaW4vKnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5OZXVyb25zL3BhdGhvbG9n

eTwva2V5d29yZD48a2V5d29yZD5PeGlkYXRpdmUgU3RyZXNzL2RydWcgZWZmZWN0czwva2V5d29y

ZD48a2V5d29yZD5Qcm90ZWN0aXZlIEFnZW50czwva2V5d29yZD48a2V5d29yZD5Qcm90ZWluIEJp

bmRpbmc8L2tleXdvcmQ+PGtleXdvcmQ+UmVjZXB0b3IsIEluc3VsaW4vZGVmaWNpZW5jeS9kcnVn

IGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+U2lnbmFsIFRyYW5zZHVjdGlvbjwva2V5d29yZD48

a2V5d29yZD5TeW5hcHNlcy8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlRoaWF6b2xpZGlu

ZWRpb25lcy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAw

OTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkZlYiAxMDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVz

Pjxpc2JuPjEwOTEtNjQ5MCAoRWxlY3Ryb25pYykmI3hEOzAwMjctODQyNCAoTGlua2luZyk8L2lz

Ym4+PGFjY2Vzc2lvbi1udW0+MTkxODg2MDk8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQt

dXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTkxODg2MDk8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMjYzNDgwOTwvY3VzdG9tMj48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA3My9wbmFzLjA4MDkxNTgxMDY8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkNhcmRvc288L0F1dGhv

cj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNOdW0+Mzg1MTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1i

ZXI+Mzg1MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3

YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTIxODQ3

Ij4zODUxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs

ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DYXJkb3NvLCBT

LjwvYXV0aG9yPjxhdXRob3I+U2FudG9zLCBSLiBYLjwvYXV0aG9yPjxhdXRob3I+Q29ycmVpYSwg

Uy4gQy48L2F1dGhvcj48YXV0aG9yPkNhcnZhbGhvLCBDLjwvYXV0aG9yPjxhdXRob3I+U2FudG9z

LCBNLiBTLjwvYXV0aG9yPjxhdXRob3I+QmFsZGVpcmFzLCBJLjwvYXV0aG9yPjxhdXRob3I+T2xp

dmVpcmEsIEMuIFIuPC9hdXRob3I+PGF1dGhvcj5Nb3JlaXJhLCBQLiBJLjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkNlbnRlciBmb3IgTmV1cm9zY2llbmNl

IGFuZCBDZWxsIEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgUG9ydHVnYWw7IERlcGFy

dG1lbnQgb2YgTGlmZSBTY2llbmNlcywgRmFjdWx0eSBvZiBTY2llbmNlcyBhbmQgVGVjaG5vbG9n

eSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhLCBQb3J0dWdhbC4mI3hEO0NlbnRlciBmb3IgTmV1cm9z

Y2llbmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgUG9ydHVnYWw7

IExhYm9yYXRvcnkgb2YgTmV1cm9jaGVtaXN0cnksIENvaW1icmEgVW5pdmVyc2l0eSBIb3NwaXRh

bCwgUG9ydHVnYWw7IE5ldXJvbG9neSBEZXBhcnRtZW50LCBGYWN1bHR5IG9mIE1lZGljaW5lLCBV

bml2ZXJzaXR5IG9mIENvaW1icmEsIFBvcnR1Z2FsLiYjeEQ7Q2VudGVyIGZvciBOZXVyb3NjaWVu

Y2UgYW5kIENlbGwgQmlvbG9neSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhLCBQb3J0dWdhbDsgSW5z

dGl0dXRlIG9mIEJpb2NoZW1pc3RyeSwgRmFjdWx0eSBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBv

ZiBDb2ltYnJhLCBQb3J0dWdhbC4mI3hEO0NlbnRlciBmb3IgTmV1cm9zY2llbmNlIGFuZCBDZWxs

IEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgUG9ydHVnYWw7IEluc3RpdHV0ZSBvZiBQ

aHlzaW9sb2d5LCBGYWN1bHR5IG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIENvaW1icmEsIDMw

MDAtMzU0IENvaW1icmEsIFBvcnR1Z2FsLiBFbGVjdHJvbmljIGFkZHJlc3M6IHZlbnRhQGNpLnVj

LnB0LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkluc3VsaW4taW5kdWNlZCByZWN1cnJl

bnQgaHlwb2dseWNlbWlhIGV4YWNlcmJhdGVzIGRpYWJldGljIGJyYWluIG1pdG9jaG9uZHJpYWwg

ZHlzZnVuY3Rpb24gYW5kIG94aWRhdGl2ZSBpbWJhbGFuY2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0

bGU+TmV1cm9iaW9sIERpczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxm

dWxsLXRpdGxlPk5ldXJvYmlvbCBEaXM8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4x

LTEyPC9wYWdlcz48dm9sdW1lPjQ5PC92b2x1bWU+PGtleXdvcmRzPjxrZXl3b3JkPkFjb25pdGF0

ZSBIeWRyYXRhc2UvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3Jk

PjxrZXl3b3JkPkJyYWluL2RydWcgZWZmZWN0cy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29y

ZD5DYXNwYXNlIDkvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBNZWxsaXR1

cywgRXhwZXJpbWVudGFsLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkVuZXJneSBNZXRh

Ym9saXNtL2RydWcgZWZmZWN0cy9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkdsdXRhdGhp

b25lL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+R2x1dGF0aGlvbmUgRGlzdWxmaWRlL21l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+R2x1dGF0aGlvbmUgUGVyb3hpZGFzZS9tZXRhYm9s

aXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYS9jaGVtaWNhbGx5IGluZHVjZWQvKm1l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SHlwb2dseWNlbWljIEFnZW50cy9hZG1pbmlzdHJh

dGlvbiAmYW1wOyBkb3NhZ2UvKmFkdmVyc2UgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5JbnN1

bGluL2FkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS8qYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3Jk

PjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWFsb25kaWFsZGVoeWRlL21ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2Nob25kcmlhL2RydWcgZWZmZWN0cy8qbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5SYW5kb20gQWxsb2NhdGlvbjwva2V5d29yZD48a2V5d29yZD5S

YXRzLCBXaXN0YXI8L2tleXdvcmQ+PGtleXdvcmQ+U3VwZXJveGlkZSBEaXNtdXRhc2UvbWV0YWJv

bGlzbTwva2V5d29yZD48a2V5d29yZD5TeW5hcHRvcGh5c2luL21ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+YWxwaGEtVG9jb3BoZXJvbC9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkNv

cnRleDwva2V5d29yZD48a2V5d29yZD5IaXBwb2NhbXB1czwva2V5d29yZD48a2V5d29yZD5Mb25n

LXRlcm0gaHlwZXJnbHljZW1pYTwva2V5d29yZD48a2V5d29yZD5NaXRvY2hvbmRyaWE8L2tleXdv

cmQ+PGtleXdvcmQ+TmV1cm9kZWdlbmVyYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+T3hpZGF0aXZl

IHN0cmVzczwva2V5d29yZD48a2V5d29yZD5SZWN1cnJlbnQgaHlwb2dseWNlbWlhPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KYW48

L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMDk1LTk1M1ggKEVsZWN0cm9uaWMpJiN4

RDswOTY5LTk5NjEgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIyOTQwNjMxPC9hY2Nl

c3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5p

aC5nb3YvcHVibWVkLzIyOTQwNjMxPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJv

bmljLXJlc291cmNlLW51bT4xMC4xMDE2L2oubmJkLjIwMTIuMDguMDA4PC9lbGVjdHJvbmljLXJl

c291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZSBGZWxpY2U8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFy

PjxSZWNOdW0+Mzg0MTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjM1NSwzNTY8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zODQx

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MjE2NDEiPjM4NDE8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkRlIEZlbGljZSwgRi4gRy48

L2F1dGhvcj48YXV0aG9yPlZpZWlyYSwgTS4gTi48L2F1dGhvcj48YXV0aG9yPkJvbWZpbSwgVC4g

Ui48L2F1dGhvcj48YXV0aG9yPkRlY2tlciwgSC48L2F1dGhvcj48YXV0aG9yPlZlbGFzY28sIFAu

IFQuPC9hdXRob3I+PGF1dGhvcj5MYW1iZXJ0LCBNLiBQLjwvYXV0aG9yPjxhdXRob3I+VmlvbGEs

IEsuIEwuPC9hdXRob3I+PGF1dGhvcj5aaGFvLCBXLiBRLjwvYXV0aG9yPjxhdXRob3I+RmVycmVp

cmEsIFMuIFQuPC9hdXRob3I+PGF1dGhvcj5LbGVpbiwgVy4gTC48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSBh

bmQgUGh5c2lvbG9neSwgTm9ydGh3ZXN0ZXJuIFVuaXZlcnNpdHksIEV2YW5zdG9uLCBJTCA2MDIw

OCwgVVNBLiBmZWxpY2VAYmlvcW1lZC51ZnJqLmJyPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+UHJvdGVjdGlvbiBvZiBzeW5hcHNlcyBhZ2FpbnN0IEFsemhlaW1lciZhcG9zO3MtbGlua2Vk

IHRveGluczogaW5zdWxpbiBzaWduYWxpbmcgcHJldmVudHMgdGhlIHBhdGhvZ2VuaWMgYmluZGlu

ZyBvZiBBYmV0YSBvbGlnb21lcnM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UHJvYyBOYXRsIEFj

YWQgU2NpIFUgUyBBPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwt

dGl0bGU+UHJvYyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48

cGFnZXM+MTk3MS02PC9wYWdlcz48dm9sdW1lPjEwNjwvdm9sdW1lPjxudW1iZXI+NjwvbnVtYmVy

PjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9wcmV2ZW50aW9uICZhbXA7IGNv

bnRyb2w8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzLyphZHZlcnNlIGVm

ZmVjdHMvZHJ1ZyBlZmZlY3RzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwv

a2V5d29yZD48a2V5d29yZD5DYXR0bGU8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVk

PC9rZXl3b3JkPjxrZXl3b3JkPkRpbWVyaXphdGlvbjwva2V5d29yZD48a2V5d29yZD5IaXBwb2Nh

bXB1cy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3Jk

Pkluc3VsaW4vKnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5OZXVyb25zL3BhdGhvbG9n

eTwva2V5d29yZD48a2V5d29yZD5PeGlkYXRpdmUgU3RyZXNzL2RydWcgZWZmZWN0czwva2V5d29y

ZD48a2V5d29yZD5Qcm90ZWN0aXZlIEFnZW50czwva2V5d29yZD48a2V5d29yZD5Qcm90ZWluIEJp

bmRpbmc8L2tleXdvcmQ+PGtleXdvcmQ+UmVjZXB0b3IsIEluc3VsaW4vZGVmaWNpZW5jeS9kcnVn

IGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+U2lnbmFsIFRyYW5zZHVjdGlvbjwva2V5d29yZD48

a2V5d29yZD5TeW5hcHNlcy8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlRoaWF6b2xpZGlu

ZWRpb25lcy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAw

OTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkZlYiAxMDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVz

Pjxpc2JuPjEwOTEtNjQ5MCAoRWxlY3Ryb25pYykmI3hEOzAwMjctODQyNCAoTGlua2luZyk8L2lz

Ym4+PGFjY2Vzc2lvbi1udW0+MTkxODg2MDk8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQt

dXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTkxODg2MDk8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMjYzNDgwOTwvY3VzdG9tMj48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA3My9wbmFzLjA4MDkxNTgxMDY8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkNhcmRvc288L0F1dGhv

cj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNOdW0+Mzg1MTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1i

ZXI+Mzg1MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3

YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTIxODQ3

Ij4zODUxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs

ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DYXJkb3NvLCBT

LjwvYXV0aG9yPjxhdXRob3I+U2FudG9zLCBSLiBYLjwvYXV0aG9yPjxhdXRob3I+Q29ycmVpYSwg

Uy4gQy48L2F1dGhvcj48YXV0aG9yPkNhcnZhbGhvLCBDLjwvYXV0aG9yPjxhdXRob3I+U2FudG9z

LCBNLiBTLjwvYXV0aG9yPjxhdXRob3I+QmFsZGVpcmFzLCBJLjwvYXV0aG9yPjxhdXRob3I+T2xp

dmVpcmEsIEMuIFIuPC9hdXRob3I+PGF1dGhvcj5Nb3JlaXJhLCBQLiBJLjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkNlbnRlciBmb3IgTmV1cm9zY2llbmNl

IGFuZCBDZWxsIEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgUG9ydHVnYWw7IERlcGFy

dG1lbnQgb2YgTGlmZSBTY2llbmNlcywgRmFjdWx0eSBvZiBTY2llbmNlcyBhbmQgVGVjaG5vbG9n

eSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhLCBQb3J0dWdhbC4mI3hEO0NlbnRlciBmb3IgTmV1cm9z

Y2llbmNlIGFuZCBDZWxsIEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgUG9ydHVnYWw7

IExhYm9yYXRvcnkgb2YgTmV1cm9jaGVtaXN0cnksIENvaW1icmEgVW5pdmVyc2l0eSBIb3NwaXRh

bCwgUG9ydHVnYWw7IE5ldXJvbG9neSBEZXBhcnRtZW50LCBGYWN1bHR5IG9mIE1lZGljaW5lLCBV

bml2ZXJzaXR5IG9mIENvaW1icmEsIFBvcnR1Z2FsLiYjeEQ7Q2VudGVyIGZvciBOZXVyb3NjaWVu

Y2UgYW5kIENlbGwgQmlvbG9neSwgVW5pdmVyc2l0eSBvZiBDb2ltYnJhLCBQb3J0dWdhbDsgSW5z

dGl0dXRlIG9mIEJpb2NoZW1pc3RyeSwgRmFjdWx0eSBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBv

ZiBDb2ltYnJhLCBQb3J0dWdhbC4mI3hEO0NlbnRlciBmb3IgTmV1cm9zY2llbmNlIGFuZCBDZWxs

IEJpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgQ29pbWJyYSwgUG9ydHVnYWw7IEluc3RpdHV0ZSBvZiBQ

aHlzaW9sb2d5LCBGYWN1bHR5IG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIENvaW1icmEsIDMw

MDAtMzU0IENvaW1icmEsIFBvcnR1Z2FsLiBFbGVjdHJvbmljIGFkZHJlc3M6IHZlbnRhQGNpLnVj

LnB0LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkluc3VsaW4taW5kdWNlZCByZWN1cnJl

bnQgaHlwb2dseWNlbWlhIGV4YWNlcmJhdGVzIGRpYWJldGljIGJyYWluIG1pdG9jaG9uZHJpYWwg

ZHlzZnVuY3Rpb24gYW5kIG94aWRhdGl2ZSBpbWJhbGFuY2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0

bGU+TmV1cm9iaW9sIERpczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxm

dWxsLXRpdGxlPk5ldXJvYmlvbCBEaXM8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4x

LTEyPC9wYWdlcz48dm9sdW1lPjQ5PC92b2x1bWU+PGtleXdvcmRzPjxrZXl3b3JkPkFjb25pdGF0

ZSBIeWRyYXRhc2UvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3Jk

PjxrZXl3b3JkPkJyYWluL2RydWcgZWZmZWN0cy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29y

ZD5DYXNwYXNlIDkvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBNZWxsaXR1

cywgRXhwZXJpbWVudGFsLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkVuZXJneSBNZXRh

Ym9saXNtL2RydWcgZWZmZWN0cy9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkdsdXRhdGhp

b25lL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+R2x1dGF0aGlvbmUgRGlzdWxmaWRlL21l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+R2x1dGF0aGlvbmUgUGVyb3hpZGFzZS9tZXRhYm9s

aXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYS9jaGVtaWNhbGx5IGluZHVjZWQvKm1l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SHlwb2dseWNlbWljIEFnZW50cy9hZG1pbmlzdHJh

dGlvbiAmYW1wOyBkb3NhZ2UvKmFkdmVyc2UgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5JbnN1

bGluL2FkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS8qYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3Jk

PjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWFsb25kaWFsZGVoeWRlL21ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+TWl0b2Nob25kcmlhL2RydWcgZWZmZWN0cy8qbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5SYW5kb20gQWxsb2NhdGlvbjwva2V5d29yZD48a2V5d29yZD5S

YXRzLCBXaXN0YXI8L2tleXdvcmQ+PGtleXdvcmQ+U3VwZXJveGlkZSBEaXNtdXRhc2UvbWV0YWJv

bGlzbTwva2V5d29yZD48a2V5d29yZD5TeW5hcHRvcGh5c2luL21ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+YWxwaGEtVG9jb3BoZXJvbC9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkNv

cnRleDwva2V5d29yZD48a2V5d29yZD5IaXBwb2NhbXB1czwva2V5d29yZD48a2V5d29yZD5Mb25n

LXRlcm0gaHlwZXJnbHljZW1pYTwva2V5d29yZD48a2V5d29yZD5NaXRvY2hvbmRyaWE8L2tleXdv

cmQ+PGtleXdvcmQ+TmV1cm9kZWdlbmVyYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+T3hpZGF0aXZl

IHN0cmVzczwva2V5d29yZD48a2V5d29yZD5SZWN1cnJlbnQgaHlwb2dseWNlbWlhPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KYW48

L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMDk1LTk1M1ggKEVsZWN0cm9uaWMpJiN4

RDswOTY5LTk5NjEgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIyOTQwNjMxPC9hY2Nl

c3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5p

aC5nb3YvcHVibWVkLzIyOTQwNjMxPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJv

bmljLXJlc291cmNlLW51bT4xMC4xMDE2L2oubmJkLjIwMTIuMDguMDA4PC9lbGVjdHJvbmljLXJl

c291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 355,356. But since restoring brain insulin signaling constitutes a promising approach against AD, an alternative could be the potential use of intranasal insulin herein.Intranasal insulin promoted brain insulin signaling in AD, without affecting blood insulin or glucose levels ADDIN EN.CITE <EndNote><Cite><Author>Cardoso</Author><Year>2010</Year><RecNum>3788</RecNum><DisplayText><style face="superscript">357</style></DisplayText><record><rec-number>3788</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535919119">3788</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cardoso, Susana</author><author>Carvalho, Cristina</author><author>Santos, Renato</author><author>Correia, Sónia</author><author>Santos, Maria S.</author><author>Sei?a, Raquel</author><author>Oliveira, Catarina R.</author><author>Moreira, Paula I.</author></authors></contributors><titles><title>Impact of STZ-induced hyperglycemia and insulin-induced hypoglycemia in plasma amino acids and cortical synaptosomal neurotransmitters</title><secondary-title>Synapse</secondary-title></titles><periodical><full-title>Synapse</full-title></periodical><pages>457-466</pages><volume>65</volume><number>6</number><dates><year>2010</year><pub-dates><date>2010/10/20</date></pub-dates></dates><publisher>Wiley</publisher><isbn>0887-4476</isbn><urls><related-urls><url>. Clinical trials involving MCI or early AD patients showed that intranasal insulin improved brain glucose metabolism and stabilized or even rescued their memory and cognitive deficits PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3JzaW5rPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3Nzg8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zNDcsMzU4LDM1OTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM3

Nzg8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1

MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxOTExOSI+Mzc3

ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3

PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TW9yc2luaywgTGluZGUg

TS48L2F1dGhvcj48YXV0aG9yPlNtaXRzLCBNYXJrIE0uPC9hdXRob3I+PGF1dGhvcj5EaWFtYW50

LCBNaWNoYWVsYTwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRs

ZT5BZHZhbmNlcyBpbiBQaGFybWFjb2xvZ2ljIFRoZXJhcGllcyBmb3IgVHlwZSAyIERpYWJldGVz

PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkN1cnJlbnQgQXRoZXJvc2NsZXJvc2lzIFJlcG9ydHM8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48dm9sdW1lPjE1PC92b2x1bWU+PG51bWJlcj4yPC9u

dW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDEzLzAxLzA5

PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5TcHJpbmdlciBOYXR1cmU8L3B1

Ymxpc2hlcj48aXNibj4xNTIzLTM4MDQmI3hEOzE1MzQtNjI0MjwvaXNibj48dXJscz48cmVsYXRl

ZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAwNy9zMTE4ODMtMDEyLTAzMDItODwv

dXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAw

Ny9zMTE4ODMtMDEyLTAzMDItODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9D

aXRlPjxDaXRlPjxBdXRob3I+TWFpbWFpdGk8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNO

dW0+Mzc4OTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc4OTwvcmVjLW51bWJlcj48Zm9y

ZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0

c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5Ij4zNzg5PC9rZXk+PC9mb3JlaWduLWtl

eXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmli

dXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5NYWltYWl0aSwgU2hhbml5YTwvYXV0aG9yPjxhdXRob3I+

RnJhemllciwgSGlsYXJlZSBOLjwvYXV0aG9yPjxhdXRob3I+QW5kZXJzb24sIEthdGllIEwuPC9h

dXRob3I+PGF1dGhvcj5HaG93ZXJpLCBBZGFtIE8uPC9hdXRob3I+PGF1dGhvcj5CcmV3ZXIsIExh

d3JlbmNlIEQuPC9hdXRob3I+PGF1dGhvcj5Qb3J0ZXIsIE5hZGEgTS48L2F1dGhvcj48YXV0aG9y

PlRoaWJhdWx0LCBPbGl2aWVyPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRs

ZXM+PHRpdGxlPk5vdmVsIGNhbGNpdW0tcmVsYXRlZCB0YXJnZXRzIG9mIGluc3VsaW4gaW4gaGlw

cG9jYW1wYWwgbmV1cm9uczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb3NjaWVuY2U8L3Nl

Y29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb3NjaWVu

Y2U8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMzAtMTQyPC9wYWdlcz48dm9sdW1l

PjM2NDwvdm9sdW1lPjxkYXRlcz48eWVhcj4yMDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAx

Ny8xMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxwdWJsaXNoZXI+RWxzZXZpZXIgQlY8L3B1

Ymxpc2hlcj48aXNibj4wMzA2LTQ1MjI8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0

dHA6Ly9keC5kb2kub3JnLzEwLjEwMTYvai5uZXVyb3NjaWVuY2UuMjAxNy4wOS4wMTk8L3VybD48

L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5u

ZXVyb3NjaWVuY2UuMjAxNy4wOS4wMTk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3Jk

PjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkNyYWZ0PC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48UmVj

TnVtPjM4NTM8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM4NTM8L3JlYy1udW1iZXI+PGZv

cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6

dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkyMjAyMCI+Mzg1Mzwva2V5PjwvZm9yZWlnbi1r

ZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJp

YnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Q3JhZnQsIFMuPC9hdXRob3I+PGF1dGhvcj5DbGF4dG9u

LCBBLjwvYXV0aG9yPjxhdXRob3I+QmFrZXIsIEwuIEQuPC9hdXRob3I+PGF1dGhvcj5IYW5zb24s

IEEuIEouPC9hdXRob3I+PGF1dGhvcj5DaG9sZXJ0b24sIEIuPC9hdXRob3I+PGF1dGhvcj5Ucml0

dHNjaHVoLCBFLiBILjwvYXV0aG9yPjxhdXRob3I+RGFobCwgRC48L2F1dGhvcj48YXV0aG9yPkNh

dWxkZXIsIEUuPC9hdXRob3I+PGF1dGhvcj5OZXRoLCBCLjwvYXV0aG9yPjxhdXRob3I+TW9udGlu

ZSwgVC4gSi48L2F1dGhvcj48YXV0aG9yPkp1bmcsIFkuPC9hdXRob3I+PGF1dGhvcj5NYWxkamlh

biwgSi48L2F1dGhvcj48YXV0aG9yPldoaXRsb3csIEMuPC9hdXRob3I+PGF1dGhvcj5GcmllZG1h

biwgUy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBh

cnRtZW50IG9mIEludGVybmFsIE1lZGljaW5lLCBXYWtlIEZvcmVzdCBTY2hvb2wgb2YgTWVkaWNp

bmUsIFdpbnN0b24tU2FsZW0sIE5DLCBVU0EuJiN4RDtBbGtlcm1lcywgSW5jLiwgV2FsdGhhbSwg

TUEsIFVTQS4mI3hEO0RlcGFydG1lbnQgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgV2FzaGlu

Z3RvbiBTY2hvb2wgb2YgTWVkaWNpbmUsIFNlYXR0bGUsIFdBLCBVU0EuJiN4RDtEZXBhcnRtZW50

IG9mIFBhdGhvbG9neSwgU3RhbmZvcmQgVW5pdmVyc2l0eSwgU3RhbmZvcmQsIENBLCBVU0EuJiN4

RDtEZXBhcnRtZW50IG9mIFBzeWNoaWF0cnkgJmFtcDsgQmVoYXZpb3JhbCBTY2llbmNlLCBVbml2

ZXJzaXR5IG9mIFdhc2hpbmd0b24gU2Nob29sIG9mIE1lZGljaW5lLCBTZWF0dGxlLCBXQSwgVVNB

LiYjeEQ7R2VyaWF0cmljIFJlc2VhcmNoLCBFZHVjYXRpb24sICZhbXA7IENsaW5pY2FsIENlbnRl

ciwgVmV0ZXJhbnMgQWZmYWlycyBQdWdldCBTb3VuZCBIZWFsdGggQ2FyZSBTeXN0ZW0sIFNlYXR0

bGUsIFdBLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIFJhZGlvbG9neSwgV2FrZSBGb3Jlc3QgU2No

b29sIG9mIE1lZGljaW5lLCBXaW5zdG9uLVNhbGVtLCBOQywgVVNBLiYjeEQ7RGVwYXJ0bWVudCBv

ZiBCaW9tZWRpY2FsIEVuZ2luZWVyaW5nLCBXYWtlIEZvcmVzdCBTY2hvb2wgb2YgTWVkaWNpbmUs

IFdpbnN0b24tU2FsZW0sIE5DLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIFJhZGlvbG9neSwgVW5p

dmVyc2l0eSBvZiBUZXhhcyBTb3V0aHdlc3Rlcm4gTWVkaWNhbCBDZW50ZXIsIERhbGxhcywgVFgs

IFVTQS4mI3hEO1NlYXR0bGUgQ2hpbGRyZW4mYXBvcztzIEhvc3BpdGFsLCBTZWF0dGxlLCBXQSwg

VVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkVmZmVjdHMgb2YgUmVndWxhciBhbmQg

TG9uZy1BY3RpbmcgSW5zdWxpbiBvbiBDb2duaXRpb24gYW5kIEFsemhlaW1lciZhcG9zO3MgRGlz

ZWFzZSBCaW9tYXJrZXJzOiBBIFBpbG90IENsaW5pY2FsIFRyaWFsPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPkogQWx6aGVpbWVycyBEaXM8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9k

aWNhbD48ZnVsbC10aXRsZT5KIEFsemhlaW1lcnMgRGlzPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNh

bD48cGFnZXM+MTMyNS0xMzM0PC9wYWdlcz48dm9sdW1lPjU3PC92b2x1bWU+PG51bWJlcj40PC9u

dW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFjdGl2aXRpZXMgb2YgRGFpbHkgTGl2aW5nPC9rZXl3

b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvY2Vy

ZWJyb3NwaW5hbCBmbHVpZC9kaWFnbm9zdGljIGltYWdpbmcvKmRydWcgdGhlcmFweS9wc3ljaG9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9jZXJlYnJvc3BpbmFs

IGZsdWlkPC9rZXl3b3JkPjxrZXl3b3JkPkJpb21hcmtlcnMvY2VyZWJyb3NwaW5hbCBmbHVpZDwv

a2V5d29yZD48a2V5d29yZD5CcmFpbi9kaWFnbm9zdGljIGltYWdpbmcvZHJ1ZyBlZmZlY3RzPC9r

ZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbi8qZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3Jk

PkRvdWJsZS1CbGluZCBNZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxr

ZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbnN1bGlucy8qdGhlcmFwZXV0aWMgdXNl

PC9rZXl3b3JkPjxrZXl3b3JkPk1hZ25ldGljIFJlc29uYW5jZSBJbWFnaW5nPC9rZXl3b3JkPjxr

ZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+Tm9vdHJvcGljIEFnZW50cy8qdGhlcmFwZXV0

aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPk9yZ2FuIFNpemU8L2tleXdvcmQ+PGtleXdvcmQ+UGVw

dGlkZSBGcmFnbWVudHMvY2VyZWJyb3NwaW5hbCBmbHVpZDwva2V5d29yZD48a2V5d29yZD5UcmVh

dG1lbnQgT3V0Y29tZTwva2V5d29yZD48a2V5d29yZD50YXUgUHJvdGVpbnMvY2VyZWJyb3NwaW5h

bCBmbHVpZDwva2V5d29yZD48a2V5d29yZD4qQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3

b3JkPjxrZXl3b3JkPipjbGluaWNhbCB0cmlhbDwva2V5d29yZD48a2V5d29yZD4qaW5zdWxpbjwv

a2V5d29yZD48a2V5d29yZD4qaW50cmFuYXNhbDwva2V5d29yZD48a2V5d29yZD4qbWFnbmV0aWMg

cmVzb25hbmNlIGltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+Km1lbW9yeTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDE3PC95ZWFyPjwvZGF0ZXM+PGlzYm4+MTg3NS04OTA4IChF

bGVjdHJvbmljKSYjeEQ7MTM4Ny0yODc3IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4y

ODM3MjMzNTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3

dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yODM3MjMzNTwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48Y3VzdG9tMj5QTUM1NDA5MDUwPC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4zMjMzL0pBRC0xNjEyNTY8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3JzaW5rPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3Nzg8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zNDcsMzU4LDM1OTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM3

Nzg8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1

MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxOTExOSI+Mzc3

ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3

PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TW9yc2luaywgTGluZGUg

TS48L2F1dGhvcj48YXV0aG9yPlNtaXRzLCBNYXJrIE0uPC9hdXRob3I+PGF1dGhvcj5EaWFtYW50

LCBNaWNoYWVsYTwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRs

ZT5BZHZhbmNlcyBpbiBQaGFybWFjb2xvZ2ljIFRoZXJhcGllcyBmb3IgVHlwZSAyIERpYWJldGVz

PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkN1cnJlbnQgQXRoZXJvc2NsZXJvc2lzIFJlcG9ydHM8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48dm9sdW1lPjE1PC92b2x1bWU+PG51bWJlcj4yPC9u

dW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDEzLzAxLzA5

PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5TcHJpbmdlciBOYXR1cmU8L3B1

Ymxpc2hlcj48aXNibj4xNTIzLTM4MDQmI3hEOzE1MzQtNjI0MjwvaXNibj48dXJscz48cmVsYXRl

ZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAwNy9zMTE4ODMtMDEyLTAzMDItODwv

dXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAw

Ny9zMTE4ODMtMDEyLTAzMDItODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9D

aXRlPjxDaXRlPjxBdXRob3I+TWFpbWFpdGk8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNO

dW0+Mzc4OTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc4OTwvcmVjLW51bWJlcj48Zm9y

ZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0

c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5Ij4zNzg5PC9rZXk+PC9mb3JlaWduLWtl

eXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmli

dXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5NYWltYWl0aSwgU2hhbml5YTwvYXV0aG9yPjxhdXRob3I+

RnJhemllciwgSGlsYXJlZSBOLjwvYXV0aG9yPjxhdXRob3I+QW5kZXJzb24sIEthdGllIEwuPC9h

dXRob3I+PGF1dGhvcj5HaG93ZXJpLCBBZGFtIE8uPC9hdXRob3I+PGF1dGhvcj5CcmV3ZXIsIExh

d3JlbmNlIEQuPC9hdXRob3I+PGF1dGhvcj5Qb3J0ZXIsIE5hZGEgTS48L2F1dGhvcj48YXV0aG9y

PlRoaWJhdWx0LCBPbGl2aWVyPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRs

ZXM+PHRpdGxlPk5vdmVsIGNhbGNpdW0tcmVsYXRlZCB0YXJnZXRzIG9mIGluc3VsaW4gaW4gaGlw

cG9jYW1wYWwgbmV1cm9uczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb3NjaWVuY2U8L3Nl

Y29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb3NjaWVu

Y2U8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMzAtMTQyPC9wYWdlcz48dm9sdW1l

PjM2NDwvdm9sdW1lPjxkYXRlcz48eWVhcj4yMDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAx

Ny8xMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxwdWJsaXNoZXI+RWxzZXZpZXIgQlY8L3B1

Ymxpc2hlcj48aXNibj4wMzA2LTQ1MjI8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0

dHA6Ly9keC5kb2kub3JnLzEwLjEwMTYvai5uZXVyb3NjaWVuY2UuMjAxNy4wOS4wMTk8L3VybD48

L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5u

ZXVyb3NjaWVuY2UuMjAxNy4wOS4wMTk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3Jk

PjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkNyYWZ0PC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48UmVj

TnVtPjM4NTM8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM4NTM8L3JlYy1udW1iZXI+PGZv

cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6

dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkyMjAyMCI+Mzg1Mzwva2V5PjwvZm9yZWlnbi1r

ZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJp

YnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Q3JhZnQsIFMuPC9hdXRob3I+PGF1dGhvcj5DbGF4dG9u

LCBBLjwvYXV0aG9yPjxhdXRob3I+QmFrZXIsIEwuIEQuPC9hdXRob3I+PGF1dGhvcj5IYW5zb24s

IEEuIEouPC9hdXRob3I+PGF1dGhvcj5DaG9sZXJ0b24sIEIuPC9hdXRob3I+PGF1dGhvcj5Ucml0

dHNjaHVoLCBFLiBILjwvYXV0aG9yPjxhdXRob3I+RGFobCwgRC48L2F1dGhvcj48YXV0aG9yPkNh

dWxkZXIsIEUuPC9hdXRob3I+PGF1dGhvcj5OZXRoLCBCLjwvYXV0aG9yPjxhdXRob3I+TW9udGlu

ZSwgVC4gSi48L2F1dGhvcj48YXV0aG9yPkp1bmcsIFkuPC9hdXRob3I+PGF1dGhvcj5NYWxkamlh

biwgSi48L2F1dGhvcj48YXV0aG9yPldoaXRsb3csIEMuPC9hdXRob3I+PGF1dGhvcj5GcmllZG1h

biwgUy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBh

cnRtZW50IG9mIEludGVybmFsIE1lZGljaW5lLCBXYWtlIEZvcmVzdCBTY2hvb2wgb2YgTWVkaWNp

bmUsIFdpbnN0b24tU2FsZW0sIE5DLCBVU0EuJiN4RDtBbGtlcm1lcywgSW5jLiwgV2FsdGhhbSwg

TUEsIFVTQS4mI3hEO0RlcGFydG1lbnQgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgV2FzaGlu

Z3RvbiBTY2hvb2wgb2YgTWVkaWNpbmUsIFNlYXR0bGUsIFdBLCBVU0EuJiN4RDtEZXBhcnRtZW50

IG9mIFBhdGhvbG9neSwgU3RhbmZvcmQgVW5pdmVyc2l0eSwgU3RhbmZvcmQsIENBLCBVU0EuJiN4

RDtEZXBhcnRtZW50IG9mIFBzeWNoaWF0cnkgJmFtcDsgQmVoYXZpb3JhbCBTY2llbmNlLCBVbml2

ZXJzaXR5IG9mIFdhc2hpbmd0b24gU2Nob29sIG9mIE1lZGljaW5lLCBTZWF0dGxlLCBXQSwgVVNB

LiYjeEQ7R2VyaWF0cmljIFJlc2VhcmNoLCBFZHVjYXRpb24sICZhbXA7IENsaW5pY2FsIENlbnRl

ciwgVmV0ZXJhbnMgQWZmYWlycyBQdWdldCBTb3VuZCBIZWFsdGggQ2FyZSBTeXN0ZW0sIFNlYXR0

bGUsIFdBLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIFJhZGlvbG9neSwgV2FrZSBGb3Jlc3QgU2No

b29sIG9mIE1lZGljaW5lLCBXaW5zdG9uLVNhbGVtLCBOQywgVVNBLiYjeEQ7RGVwYXJ0bWVudCBv

ZiBCaW9tZWRpY2FsIEVuZ2luZWVyaW5nLCBXYWtlIEZvcmVzdCBTY2hvb2wgb2YgTWVkaWNpbmUs

IFdpbnN0b24tU2FsZW0sIE5DLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIFJhZGlvbG9neSwgVW5p

dmVyc2l0eSBvZiBUZXhhcyBTb3V0aHdlc3Rlcm4gTWVkaWNhbCBDZW50ZXIsIERhbGxhcywgVFgs

IFVTQS4mI3hEO1NlYXR0bGUgQ2hpbGRyZW4mYXBvcztzIEhvc3BpdGFsLCBTZWF0dGxlLCBXQSwg

VVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkVmZmVjdHMgb2YgUmVndWxhciBhbmQg

TG9uZy1BY3RpbmcgSW5zdWxpbiBvbiBDb2duaXRpb24gYW5kIEFsemhlaW1lciZhcG9zO3MgRGlz

ZWFzZSBCaW9tYXJrZXJzOiBBIFBpbG90IENsaW5pY2FsIFRyaWFsPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPkogQWx6aGVpbWVycyBEaXM8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9k

aWNhbD48ZnVsbC10aXRsZT5KIEFsemhlaW1lcnMgRGlzPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNh

bD48cGFnZXM+MTMyNS0xMzM0PC9wYWdlcz48dm9sdW1lPjU3PC92b2x1bWU+PG51bWJlcj40PC9u

dW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFjdGl2aXRpZXMgb2YgRGFpbHkgTGl2aW5nPC9rZXl3

b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvY2Vy

ZWJyb3NwaW5hbCBmbHVpZC9kaWFnbm9zdGljIGltYWdpbmcvKmRydWcgdGhlcmFweS9wc3ljaG9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9jZXJlYnJvc3BpbmFs

IGZsdWlkPC9rZXl3b3JkPjxrZXl3b3JkPkJpb21hcmtlcnMvY2VyZWJyb3NwaW5hbCBmbHVpZDwv

a2V5d29yZD48a2V5d29yZD5CcmFpbi9kaWFnbm9zdGljIGltYWdpbmcvZHJ1ZyBlZmZlY3RzPC9r

ZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbi8qZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3Jk

PkRvdWJsZS1CbGluZCBNZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxr

ZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbnN1bGlucy8qdGhlcmFwZXV0aWMgdXNl

PC9rZXl3b3JkPjxrZXl3b3JkPk1hZ25ldGljIFJlc29uYW5jZSBJbWFnaW5nPC9rZXl3b3JkPjxr

ZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+Tm9vdHJvcGljIEFnZW50cy8qdGhlcmFwZXV0

aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPk9yZ2FuIFNpemU8L2tleXdvcmQ+PGtleXdvcmQ+UGVw

dGlkZSBGcmFnbWVudHMvY2VyZWJyb3NwaW5hbCBmbHVpZDwva2V5d29yZD48a2V5d29yZD5UcmVh

dG1lbnQgT3V0Y29tZTwva2V5d29yZD48a2V5d29yZD50YXUgUHJvdGVpbnMvY2VyZWJyb3NwaW5h

bCBmbHVpZDwva2V5d29yZD48a2V5d29yZD4qQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3

b3JkPjxrZXl3b3JkPipjbGluaWNhbCB0cmlhbDwva2V5d29yZD48a2V5d29yZD4qaW5zdWxpbjwv

a2V5d29yZD48a2V5d29yZD4qaW50cmFuYXNhbDwva2V5d29yZD48a2V5d29yZD4qbWFnbmV0aWMg

cmVzb25hbmNlIGltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+Km1lbW9yeTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDE3PC95ZWFyPjwvZGF0ZXM+PGlzYm4+MTg3NS04OTA4IChF

bGVjdHJvbmljKSYjeEQ7MTM4Ny0yODc3IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4y

ODM3MjMzNTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3

dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yODM3MjMzNTwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48Y3VzdG9tMj5QTUM1NDA5MDUwPC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4zMjMzL0pBRC0xNjEyNTY8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 347,358,359. According to , results are awaited from two recently completed Phase II/III and II clinical trials on insulin (SNIFF; NCT01767909) and Glulisine (a rapid-action insulin analog that regulates glucose metabolism and counteracts Aβ) (NCT02503501), involving middle-aged and aged MCI or mild AD individuals. Possible limitations to the use of intranasal insulin for AD treatment could be the generalized increase in brain insulin levels and its possible adverse consequences on brain regions (like hypothalamus) that control, e.g., water and food intake ADDIN EN.CITE <EndNote><Cite><Author>Reger</Author><Year>2007</Year><RecNum>3791</RecNum><DisplayText><style face="superscript">360</style></DisplayText><record><rec-number>3791</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535919119">3791</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Reger, M. A.</author><author>Watson, G. S.</author><author>Green, P. S.</author><author>Wilkinson, C. W.</author><author>Baker, L. D.</author><author>Cholerton, B.</author><author>Fishel, M. A.</author><author>Plymate, S. R.</author><author>Breitner, J. C. S.</author><author>DeGroodt, W.</author><author>Mehta, P.</author><author>Craft, S.</author></authors></contributors><titles><title>Intranasal insulin improves cognition and modulates ?-amyloid in early AD</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title></periodical><pages>440-448</pages><volume>70</volume><number>6</number><dates><year>2007</year><pub-dates><date>2007/10/17</date></pub-dates></dates><publisher>Ovid Technologies (Wolters Kluwer Health)</publisher><isbn>0028-3878&#xD;1526-632X</isbn><urls><related-urls><url> increasing therapeutic potential of incretin drugs in AD-Dipeptidyl peptidase-IV inhibitorsSitagliptin, Saxagliptin, Linagliptin, Vildagliptin, Alogliptin, Tenegliptin, Dutogliptin, Gemigliptin are the main dipeptidyl peptidase-IV (DPP-IV) inhibitors used to treat T2D PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMsMzI0LDM2MTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM3

NDk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1

MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzUwNyI+Mzc0

OTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3

PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Q29yYmV0dCwgQS48L2F1

dGhvcj48YXV0aG9yPkJhbGxhcmQsIEMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

Pjx0aXRsZXM+PHRpdGxlPklzIGEgcG90ZW50aWFsIEFsemhlaW1lciZhcG9zO3MgdGhlcmFweSBh

bHJlYWR5IGluIHVzZSBmb3Igb3RoZXIgY29uZGl0aW9ucz8gQ2FuIG1lZGljYXRpb25zIGZvciBo

eXBlcnRlbnNpb24sIGRpYWJldGVzIGFuZCBhY25lIGhlbHAgd2l0aCB0aGUgc3ltcHRvbXM/PC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkV4cGVydCBPcGluIEludmVzdGlnIERydWdzPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjk0MS0zPC9wYWdlcz48dm9sdW1lPjIyPC92b2x1bWU+

PG51bWJlcj44PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypk

cnVnIHRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QW5naW90ZW5zaW4gUmVjZXB0b3IgQW50YWdv

bmlzdHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFudGktQmFjdGVyaWFsIEFn

ZW50cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+Q2FsY2l1bSBDaGFubmVsIEJs

b2NrZXJzL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD4qRHJ1ZyBSZXBvc2l0aW9u

aW5nPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IeXBvZ2x5Y2Vt

aWMgQWdlbnRzL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVh

cj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXVnPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0

ZXM+PGlzYm4+MTc0NC03NjU4IChFbGVjdHJvbmljKSYjeEQ7MTM1NC0zNzg0IChMaW5raW5nKTwv

aXNibj48YWNjZXNzaW9uLW51bT4yMzgwODcwODwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRl

ZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMzgwODcwODwv

dXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTUx

Ny8xMzU0Mzc4NC4yMDEzLjgxNTcyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+

PC9DaXRlPjxDaXRlPjxBdXRob3I+U2FuZGhpcjwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl

Y051bT4zNzUwPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zNzUwPC9yZWMtbnVtYmVyPjxm

b3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5

enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTc1NjUiPjM3NTA8L2tleT48L2ZvcmVpZ24t

a2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRy

aWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNhbmRoaXIsIFIuPC9hdXRob3I+PGF1dGhvcj5HdXB0

YSwgUy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5SYWph

dCBTYW5kaGlyLCBTbXJpdGkgR3VwdGEsIERlcGFydG1lbnQgb2YgQmlvY2hlbWlzdHJ5LCBQYW5q

YWIgVW5pdmVyc2l0eSwgQ2hhbmRpZ2FyaCAxNjAwMTQsIEluZGlhLjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPk1vbGVjdWxhciBhbmQgYmlvY2hlbWljYWwgdHJhamVjdG9yaWVzIGZyb20g

ZGlhYmV0ZXMgdG8gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlOiBBIGNyaXRpY2FsIGFwcHJhaXNh

bDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Xb3JsZCBKIERpYWJldGVzPC9zZWNvbmRhcnktdGl0

bGU+PC90aXRsZXM+PHBhZ2VzPjEyMjMtNDI8L3BhZ2VzPjx2b2x1bWU+Njwvdm9sdW1lPjxudW1i

ZXI+MTI8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNl

PC9rZXl3b3JkPjxrZXl3b3JkPkRpYWJldGVzIG1lbGxpdHVzPC9rZXl3b3JkPjxrZXl3b3JkPklu

c3VsaW48L2tleXdvcmQ+PGtleXdvcmQ+VHlwZSAyIGRpYWJldGVzPC9rZXl3b3JkPjxrZXl3b3Jk

PlR5cGUgMyBkaWFiZXRlczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE1PC95

ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwIDI1PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlz

Ym4+MTk0OC05MzU4IChQcmludCkmI3hEOzE5NDgtOTM1OCAoTGlua2luZyk8L2lzYm4+PGFjY2Vz

c2lvbi1udW0+MjY0NjQ3NjA8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJs

Pmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjY0NjQ3NjA8L3VybD48L3JlbGF0

ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNDU5ODYwNTwvY3VzdG9tMj48ZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+MTAuNDIzOS93amQudjYuaTEyLjEyMjM8L2VsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkdoYXNlbWk8L0F1dGhvcj48WWVhcj4y

MDEzPC9ZZWFyPjxSZWNOdW0+Mzc5MjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc5Mjwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5Ij4zNzkyPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5HaGFzZW1pLCBSYXNvdWw8L2F1

dGhvcj48YXV0aG9yPkRhcmdhaGksIExlaWxhPC9hdXRob3I+PGF1dGhvcj5IYWVyaSwgQWxpPC9h

dXRob3I+PGF1dGhvcj5Nb29zYXZpLCBNYXJ5YW08L2F1dGhvcj48YXV0aG9yPk1vaGFtZWQsIFph

aHVyaW48L2F1dGhvcj48YXV0aG9yPkFobWFkaWFuaSwgQWJvbGhhc3NhbjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5CcmFpbiBJbnN1bGluIER5c3JlZ3Vs

YXRpb246IEltcGxpY2F0aW9uIGZvciBOZXVyb2xvZ2ljYWwgYW5kIE5ldXJvcHN5Y2hpYXRyaWMg

RGlzb3JkZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk1vbGVjdWxhciBOZXVyb2Jpb2xvZ3k8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTA0NS0xMDY1PC9wYWdlcz48dm9sdW1l

PjQ3PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT4yMDEzLzAxLzIwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxp

c2hlcj5TcHJpbmdlciBOYXR1cmU8L3B1Ymxpc2hlcj48aXNibj4wODkzLTc2NDgmI3hEOzE1NTkt

MTE4MjwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAu

MTAwNy9zMTIwMzUtMDEzLTg0MDQtejwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMTIwMzUtMDEzLTg0MDQtejwvZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMsMzI0LDM2MTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM3

NDk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1

MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzUwNyI+Mzc0

OTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3

PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Q29yYmV0dCwgQS48L2F1

dGhvcj48YXV0aG9yPkJhbGxhcmQsIEMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

Pjx0aXRsZXM+PHRpdGxlPklzIGEgcG90ZW50aWFsIEFsemhlaW1lciZhcG9zO3MgdGhlcmFweSBh

bHJlYWR5IGluIHVzZSBmb3Igb3RoZXIgY29uZGl0aW9ucz8gQ2FuIG1lZGljYXRpb25zIGZvciBo

eXBlcnRlbnNpb24sIGRpYWJldGVzIGFuZCBhY25lIGhlbHAgd2l0aCB0aGUgc3ltcHRvbXM/PC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkV4cGVydCBPcGluIEludmVzdGlnIERydWdzPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjk0MS0zPC9wYWdlcz48dm9sdW1lPjIyPC92b2x1bWU+

PG51bWJlcj44PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypk

cnVnIHRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QW5naW90ZW5zaW4gUmVjZXB0b3IgQW50YWdv

bmlzdHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFudGktQmFjdGVyaWFsIEFn

ZW50cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+Q2FsY2l1bSBDaGFubmVsIEJs

b2NrZXJzL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD4qRHJ1ZyBSZXBvc2l0aW9u

aW5nPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IeXBvZ2x5Y2Vt

aWMgQWdlbnRzL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVh

cj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXVnPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0

ZXM+PGlzYm4+MTc0NC03NjU4IChFbGVjdHJvbmljKSYjeEQ7MTM1NC0zNzg0IChMaW5raW5nKTwv

aXNibj48YWNjZXNzaW9uLW51bT4yMzgwODcwODwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRl

ZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMzgwODcwODwv

dXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTUx

Ny8xMzU0Mzc4NC4yMDEzLjgxNTcyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+

PC9DaXRlPjxDaXRlPjxBdXRob3I+U2FuZGhpcjwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl

Y051bT4zNzUwPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zNzUwPC9yZWMtbnVtYmVyPjxm

b3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5

enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTc1NjUiPjM3NTA8L2tleT48L2ZvcmVpZ24t

a2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRy

aWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNhbmRoaXIsIFIuPC9hdXRob3I+PGF1dGhvcj5HdXB0

YSwgUy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5SYWph

dCBTYW5kaGlyLCBTbXJpdGkgR3VwdGEsIERlcGFydG1lbnQgb2YgQmlvY2hlbWlzdHJ5LCBQYW5q

YWIgVW5pdmVyc2l0eSwgQ2hhbmRpZ2FyaCAxNjAwMTQsIEluZGlhLjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPk1vbGVjdWxhciBhbmQgYmlvY2hlbWljYWwgdHJhamVjdG9yaWVzIGZyb20g

ZGlhYmV0ZXMgdG8gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlOiBBIGNyaXRpY2FsIGFwcHJhaXNh

bDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Xb3JsZCBKIERpYWJldGVzPC9zZWNvbmRhcnktdGl0

bGU+PC90aXRsZXM+PHBhZ2VzPjEyMjMtNDI8L3BhZ2VzPjx2b2x1bWU+Njwvdm9sdW1lPjxudW1i

ZXI+MTI8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNl

PC9rZXl3b3JkPjxrZXl3b3JkPkRpYWJldGVzIG1lbGxpdHVzPC9rZXl3b3JkPjxrZXl3b3JkPklu

c3VsaW48L2tleXdvcmQ+PGtleXdvcmQ+VHlwZSAyIGRpYWJldGVzPC9rZXl3b3JkPjxrZXl3b3Jk

PlR5cGUgMyBkaWFiZXRlczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE1PC95

ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwIDI1PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlz

Ym4+MTk0OC05MzU4IChQcmludCkmI3hEOzE5NDgtOTM1OCAoTGlua2luZyk8L2lzYm4+PGFjY2Vz

c2lvbi1udW0+MjY0NjQ3NjA8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJs

Pmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjY0NjQ3NjA8L3VybD48L3JlbGF0

ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNDU5ODYwNTwvY3VzdG9tMj48ZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+MTAuNDIzOS93amQudjYuaTEyLjEyMjM8L2VsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkdoYXNlbWk8L0F1dGhvcj48WWVhcj4y

MDEzPC9ZZWFyPjxSZWNOdW0+Mzc5MjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc5Mjwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5Ij4zNzkyPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5HaGFzZW1pLCBSYXNvdWw8L2F1

dGhvcj48YXV0aG9yPkRhcmdhaGksIExlaWxhPC9hdXRob3I+PGF1dGhvcj5IYWVyaSwgQWxpPC9h

dXRob3I+PGF1dGhvcj5Nb29zYXZpLCBNYXJ5YW08L2F1dGhvcj48YXV0aG9yPk1vaGFtZWQsIFph

aHVyaW48L2F1dGhvcj48YXV0aG9yPkFobWFkaWFuaSwgQWJvbGhhc3NhbjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5CcmFpbiBJbnN1bGluIER5c3JlZ3Vs

YXRpb246IEltcGxpY2F0aW9uIGZvciBOZXVyb2xvZ2ljYWwgYW5kIE5ldXJvcHN5Y2hpYXRyaWMg

RGlzb3JkZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk1vbGVjdWxhciBOZXVyb2Jpb2xvZ3k8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTA0NS0xMDY1PC9wYWdlcz48dm9sdW1l

PjQ3PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT4yMDEzLzAxLzIwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxp

c2hlcj5TcHJpbmdlciBOYXR1cmU8L3B1Ymxpc2hlcj48aXNibj4wODkzLTc2NDgmI3hEOzE1NTkt

MTE4MjwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAu

MTAwNy9zMTIwMzUtMDEzLTg0MDQtejwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMTIwMzUtMDEzLTg0MDQtejwvZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 323,324,361. DPP-IV inhibitors are oral small molecules that blunt the degradation of native GLP-1 by the aminopeptidase DPP-IV, increasing its half-time and circulating levels, together with the attenuation of glucagon effects PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HaGFzZW1pPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3OTI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zNjEtMzYzPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc5Mjwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5Ij4zNzkyPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5HaGFzZW1pLCBSYXNvdWw8L2F1

dGhvcj48YXV0aG9yPkRhcmdhaGksIExlaWxhPC9hdXRob3I+PGF1dGhvcj5IYWVyaSwgQWxpPC9h

dXRob3I+PGF1dGhvcj5Nb29zYXZpLCBNYXJ5YW08L2F1dGhvcj48YXV0aG9yPk1vaGFtZWQsIFph

aHVyaW48L2F1dGhvcj48YXV0aG9yPkFobWFkaWFuaSwgQWJvbGhhc3NhbjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5CcmFpbiBJbnN1bGluIER5c3JlZ3Vs

YXRpb246IEltcGxpY2F0aW9uIGZvciBOZXVyb2xvZ2ljYWwgYW5kIE5ldXJvcHN5Y2hpYXRyaWMg

RGlzb3JkZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk1vbGVjdWxhciBOZXVyb2Jpb2xvZ3k8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTA0NS0xMDY1PC9wYWdlcz48dm9sdW1l

PjQ3PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT4yMDEzLzAxLzIwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxp

c2hlcj5TcHJpbmdlciBOYXR1cmU8L3B1Ymxpc2hlcj48aXNibj4wODkzLTc2NDgmI3hEOzE1NTkt

MTE4MjwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAu

MTAwNy9zMTIwMzUtMDEzLTg0MDQtejwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMTIwMzUtMDEzLTg0MDQtejwvZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Q2FuZGVpYXM8L0F1dGhv

cj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNOdW0+Mzc5MzwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1i

ZXI+Mzc5MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3

YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5

Ij4zNzkzPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs

ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DYW5kZWlhcywg

RW1hbnVlbCBNb250ZWlybzwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVz

Pjx0aXRsZT5HdXQtYnJhaW4gY29ubmVjdGlvbjogVGhlIG5ldXJvcHJvdGVjdGl2ZSBlZmZlY3Rz

IG9mIHRoZSBhbnRpLWRpYWJldGljIGRydWcgbGlyYWdsdXRpZGU8L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+V29ybGQgSm91cm5hbCBvZiBEaWFiZXRlczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwYWdlcz44MDc8L3BhZ2VzPjx2b2x1bWU+Njwvdm9sdW1lPjxudW1iZXI+NjwvbnVtYmVyPjxk

YXRlcz48eWVhcj4yMDE1PC95ZWFyPjwvZGF0ZXM+PHB1Ymxpc2hlcj5CYWlzaGlkZW5nIFB1Ymxp

c2hpbmcgR3JvdXAgSW5jLjwvcHVibGlzaGVyPjxpc2JuPjE5NDgtOTM1ODwvaXNibj48dXJscz48

cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuNDIzOS93amQudjYuaTYuODA3

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC40

MjM5L3dqZC52Ni5pNi44MDc8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0

ZT48Q2l0ZT48QXV0aG9yPlN0b2xhcjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJlY051bT4z

ODU0PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zODU0PC9yZWMtbnVtYmVyPjxmb3JlaWdu

LWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpw

cnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MjIzNDYiPjM4NTQ8L2tleT48L2ZvcmVpZ24ta2V5cz48

cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9y

cz48YXV0aG9ycz48YXV0aG9yPlN0b2xhciwgTS4gVy48L2F1dGhvcj48YXV0aG9yPkdyaW1tLCBN

LjwvYXV0aG9yPjxhdXRob3I+Q2hlbiwgUy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5DbGluaWNhbCBNZWRpY2luZSwgTm9ydGh3ZXN0ZXJuIFVuaXZlcnNp

dHkgRmVpbmJlcmcgU2Nob29sIG9mIE1lZGljaW5lLCBDaGljYWdvLCBJTCwgVVNBLjwvYXV0aC1h

ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNvbXBhcmlzb24gb2YgZXh0ZW5kZWQgcmVsZWFzZSBHTFAt

MSByZWNlcHRvciBhZ29uaXN0IHRoZXJhcHkgdmVyc3VzIHNpdGFnbGlwdGluIGluIHRoZSBtYW5h

Z2VtZW50IG9mIHR5cGUgMiBkaWFiZXRlczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5EaWFiZXRl

cyBNZXRhYiBTeW5kciBPYmVzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjQzNS00

NDwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PGtleXdvcmRzPjxrZXl3b3JkPmRpcGVwdGlkeWwg

cGVwdGlkYXNlLTQgaW5oaWJpdG9yczwva2V5d29yZD48a2V5d29yZD5leGVuYXRpZGU8L2tleXdv

cmQ+PGtleXdvcmQ+Z2x1Y2Fnb24tbGlrZSBwZXB0aWRlIDE8L2tleXdvcmQ+PC9rZXl3b3Jkcz48

ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48L2RhdGVzPjxpc2JuPjExNzgtNzAwNyAoUHJpbnQpJiN4

RDsxMTc4LTcwMDcgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI0Mjg1OTI3PC9hY2Nl

c3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5p

aC5nb3YvcHVibWVkLzI0Mjg1OTI3PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20y

PlBNQzM4NDA3NzY8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjIxNDcvRE1T

Ty5TNDg4Mzc8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5v

dGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HaGFzZW1pPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3OTI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zNjEtMzYzPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc5Mjwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5Ij4zNzkyPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5HaGFzZW1pLCBSYXNvdWw8L2F1

dGhvcj48YXV0aG9yPkRhcmdhaGksIExlaWxhPC9hdXRob3I+PGF1dGhvcj5IYWVyaSwgQWxpPC9h

dXRob3I+PGF1dGhvcj5Nb29zYXZpLCBNYXJ5YW08L2F1dGhvcj48YXV0aG9yPk1vaGFtZWQsIFph

aHVyaW48L2F1dGhvcj48YXV0aG9yPkFobWFkaWFuaSwgQWJvbGhhc3NhbjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5CcmFpbiBJbnN1bGluIER5c3JlZ3Vs

YXRpb246IEltcGxpY2F0aW9uIGZvciBOZXVyb2xvZ2ljYWwgYW5kIE5ldXJvcHN5Y2hpYXRyaWMg

RGlzb3JkZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk1vbGVjdWxhciBOZXVyb2Jpb2xvZ3k8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTA0NS0xMDY1PC9wYWdlcz48dm9sdW1l

PjQ3PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT4yMDEzLzAxLzIwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxp

c2hlcj5TcHJpbmdlciBOYXR1cmU8L3B1Ymxpc2hlcj48aXNibj4wODkzLTc2NDgmI3hEOzE1NTkt

MTE4MjwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAu

MTAwNy9zMTIwMzUtMDEzLTg0MDQtejwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMTIwMzUtMDEzLTg0MDQtejwvZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Q2FuZGVpYXM8L0F1dGhv

cj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNOdW0+Mzc5MzwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1i

ZXI+Mzc5MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3

YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5

Ij4zNzkzPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs

ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DYW5kZWlhcywg

RW1hbnVlbCBNb250ZWlybzwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVz

Pjx0aXRsZT5HdXQtYnJhaW4gY29ubmVjdGlvbjogVGhlIG5ldXJvcHJvdGVjdGl2ZSBlZmZlY3Rz

IG9mIHRoZSBhbnRpLWRpYWJldGljIGRydWcgbGlyYWdsdXRpZGU8L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+V29ybGQgSm91cm5hbCBvZiBEaWFiZXRlczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwYWdlcz44MDc8L3BhZ2VzPjx2b2x1bWU+Njwvdm9sdW1lPjxudW1iZXI+NjwvbnVtYmVyPjxk

YXRlcz48eWVhcj4yMDE1PC95ZWFyPjwvZGF0ZXM+PHB1Ymxpc2hlcj5CYWlzaGlkZW5nIFB1Ymxp

c2hpbmcgR3JvdXAgSW5jLjwvcHVibGlzaGVyPjxpc2JuPjE5NDgtOTM1ODwvaXNibj48dXJscz48

cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuNDIzOS93amQudjYuaTYuODA3

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC40

MjM5L3dqZC52Ni5pNi44MDc8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0

ZT48Q2l0ZT48QXV0aG9yPlN0b2xhcjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJlY051bT4z

ODU0PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zODU0PC9yZWMtbnVtYmVyPjxmb3JlaWdu

LWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpw

cnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MjIzNDYiPjM4NTQ8L2tleT48L2ZvcmVpZ24ta2V5cz48

cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9y

cz48YXV0aG9ycz48YXV0aG9yPlN0b2xhciwgTS4gVy48L2F1dGhvcj48YXV0aG9yPkdyaW1tLCBN

LjwvYXV0aG9yPjxhdXRob3I+Q2hlbiwgUy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5DbGluaWNhbCBNZWRpY2luZSwgTm9ydGh3ZXN0ZXJuIFVuaXZlcnNp

dHkgRmVpbmJlcmcgU2Nob29sIG9mIE1lZGljaW5lLCBDaGljYWdvLCBJTCwgVVNBLjwvYXV0aC1h

ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNvbXBhcmlzb24gb2YgZXh0ZW5kZWQgcmVsZWFzZSBHTFAt

MSByZWNlcHRvciBhZ29uaXN0IHRoZXJhcHkgdmVyc3VzIHNpdGFnbGlwdGluIGluIHRoZSBtYW5h

Z2VtZW50IG9mIHR5cGUgMiBkaWFiZXRlczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5EaWFiZXRl

cyBNZXRhYiBTeW5kciBPYmVzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjQzNS00

NDwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PGtleXdvcmRzPjxrZXl3b3JkPmRpcGVwdGlkeWwg

cGVwdGlkYXNlLTQgaW5oaWJpdG9yczwva2V5d29yZD48a2V5d29yZD5leGVuYXRpZGU8L2tleXdv

cmQ+PGtleXdvcmQ+Z2x1Y2Fnb24tbGlrZSBwZXB0aWRlIDE8L2tleXdvcmQ+PC9rZXl3b3Jkcz48

ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48L2RhdGVzPjxpc2JuPjExNzgtNzAwNyAoUHJpbnQpJiN4

RDsxMTc4LTcwMDcgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI0Mjg1OTI3PC9hY2Nl

c3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5p

aC5nb3YvcHVibWVkLzI0Mjg1OTI3PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20y

PlBNQzM4NDA3NzY8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjIxNDcvRE1T

Ty5TNDg4Mzc8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5v

dGU+AG==

ADDIN EN.CITE.DATA 361-363. DPP-IV inhibitors are well tolerated and can be used either as mono- or multi-therapy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

UmVjTnVtPjM3NTA8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjQsMzYxPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc1MDwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTY1Ij4zNzUwPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TYW5kaGlyLCBSLjwvYXV0aG9y

PjxhdXRob3I+R3VwdGEsIFMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo

LWFkZHJlc3M+UmFqYXQgU2FuZGhpciwgU21yaXRpIEd1cHRhLCBEZXBhcnRtZW50IG9mIEJpb2No

ZW1pc3RyeSwgUGFuamFiIFVuaXZlcnNpdHksIENoYW5kaWdhcmggMTYwMDE0LCBJbmRpYS48L2F1

dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Nb2xlY3VsYXIgYW5kIGJpb2NoZW1pY2FsIHRyYWpl

Y3RvcmllcyBmcm9tIGRpYWJldGVzIHRvIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogQSBjcml0

aWNhbCBhcHByYWlzYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+V29ybGQgSiBEaWFiZXRlczwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMjIzLTQyPC9wYWdlcz48dm9sdW1lPjY8

L3ZvbHVtZT48bnVtYmVyPjEyPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciZh

cG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBtZWxsaXR1czwva2V5d29y

ZD48a2V5d29yZD5JbnN1bGluPC9rZXl3b3JkPjxrZXl3b3JkPlR5cGUgMiBkaWFiZXRlczwva2V5

d29yZD48a2V5d29yZD5UeXBlIDMgZGlhYmV0ZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPlNlcCAyNTwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxpc2JuPjE5NDgtOTM1OCAoUHJpbnQpJiN4RDsxOTQ4LTkzNTggKExpbmtpbmcp

PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2NDY0NzYwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh

dGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI2NDY0NzYw

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQ1OTg2MDU8L2N1c3RvbTI+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjQyMzkvd2pkLnY2LmkxMi4xMjIzPC9lbGVjdHJv

bmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5HaGFzZW1pPC9B

dXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVtPjM3OTI8L1JlY051bT48cmVjb3JkPjxyZWMt

bnVtYmVyPjM3OTI8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk

PSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkx

OTExOSI+Mzc5Mjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFy

dGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+R2hhc2Vt

aSwgUmFzb3VsPC9hdXRob3I+PGF1dGhvcj5EYXJnYWhpLCBMZWlsYTwvYXV0aG9yPjxhdXRob3I+

SGFlcmksIEFsaTwvYXV0aG9yPjxhdXRob3I+TW9vc2F2aSwgTWFyeWFtPC9hdXRob3I+PGF1dGhv

cj5Nb2hhbWVkLCBaYWh1cmluPC9hdXRob3I+PGF1dGhvcj5BaG1hZGlhbmksIEFib2xoYXNzYW48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QnJhaW4gSW5z

dWxpbiBEeXNyZWd1bGF0aW9uOiBJbXBsaWNhdGlvbiBmb3IgTmV1cm9sb2dpY2FsIGFuZCBOZXVy

b3BzeWNoaWF0cmljIERpc29yZGVyczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Nb2xlY3VsYXIg

TmV1cm9iaW9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEwNDUtMTA2NTwv

cGFnZXM+PHZvbHVtZT40Nzwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxkYXRlcz48eWVhcj4y

MDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxMy8wMS8yMDwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxwdWJsaXNoZXI+U3ByaW5nZXIgTmF0dXJlPC9wdWJsaXNoZXI+PGlzYm4+MDg5My03

NjQ4JiN4RDsxNTU5LTExODI8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9k

eC5kb2kub3JnLzEwLjEwMDcvczEyMDM1LTAxMy04NDA0LXo8L3VybD48L3JlbGF0ZWQtdXJscz48

L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDcvczEyMDM1LTAxMy04NDA0LXo8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

UmVjTnVtPjM3NTA8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjQsMzYxPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc1MDwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTY1Ij4zNzUwPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TYW5kaGlyLCBSLjwvYXV0aG9y

PjxhdXRob3I+R3VwdGEsIFMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo

LWFkZHJlc3M+UmFqYXQgU2FuZGhpciwgU21yaXRpIEd1cHRhLCBEZXBhcnRtZW50IG9mIEJpb2No

ZW1pc3RyeSwgUGFuamFiIFVuaXZlcnNpdHksIENoYW5kaWdhcmggMTYwMDE0LCBJbmRpYS48L2F1

dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Nb2xlY3VsYXIgYW5kIGJpb2NoZW1pY2FsIHRyYWpl

Y3RvcmllcyBmcm9tIGRpYWJldGVzIHRvIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogQSBjcml0

aWNhbCBhcHByYWlzYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+V29ybGQgSiBEaWFiZXRlczwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMjIzLTQyPC9wYWdlcz48dm9sdW1lPjY8

L3ZvbHVtZT48bnVtYmVyPjEyPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciZh

cG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBtZWxsaXR1czwva2V5d29y

ZD48a2V5d29yZD5JbnN1bGluPC9rZXl3b3JkPjxrZXl3b3JkPlR5cGUgMiBkaWFiZXRlczwva2V5

d29yZD48a2V5d29yZD5UeXBlIDMgZGlhYmV0ZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPlNlcCAyNTwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxpc2JuPjE5NDgtOTM1OCAoUHJpbnQpJiN4RDsxOTQ4LTkzNTggKExpbmtpbmcp

PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2NDY0NzYwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh

dGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI2NDY0NzYw

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQ1OTg2MDU8L2N1c3RvbTI+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjQyMzkvd2pkLnY2LmkxMi4xMjIzPC9lbGVjdHJv

bmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5HaGFzZW1pPC9B

dXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVtPjM3OTI8L1JlY051bT48cmVjb3JkPjxyZWMt

bnVtYmVyPjM3OTI8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk

PSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkx

OTExOSI+Mzc5Mjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFy

dGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+R2hhc2Vt

aSwgUmFzb3VsPC9hdXRob3I+PGF1dGhvcj5EYXJnYWhpLCBMZWlsYTwvYXV0aG9yPjxhdXRob3I+

SGFlcmksIEFsaTwvYXV0aG9yPjxhdXRob3I+TW9vc2F2aSwgTWFyeWFtPC9hdXRob3I+PGF1dGhv

cj5Nb2hhbWVkLCBaYWh1cmluPC9hdXRob3I+PGF1dGhvcj5BaG1hZGlhbmksIEFib2xoYXNzYW48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QnJhaW4gSW5z

dWxpbiBEeXNyZWd1bGF0aW9uOiBJbXBsaWNhdGlvbiBmb3IgTmV1cm9sb2dpY2FsIGFuZCBOZXVy

b3BzeWNoaWF0cmljIERpc29yZGVyczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Nb2xlY3VsYXIg

TmV1cm9iaW9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEwNDUtMTA2NTwv

cGFnZXM+PHZvbHVtZT40Nzwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxkYXRlcz48eWVhcj4y

MDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxMy8wMS8yMDwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxwdWJsaXNoZXI+U3ByaW5nZXIgTmF0dXJlPC9wdWJsaXNoZXI+PGlzYm4+MDg5My03

NjQ4JiN4RDsxNTU5LTExODI8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9k

eC5kb2kub3JnLzEwLjEwMDcvczEyMDM1LTAxMy04NDA0LXo8L3VybD48L3JlbGF0ZWQtdXJscz48

L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDcvczEyMDM1LTAxMy04NDA0LXo8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 324,361. Apparently, these drugs do not affect gastric emptying, body weight or cardiovascular function and present a low risk of hypoglycemia PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

UmVjTnVtPjM3NTA8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjQsMzYxPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc1MDwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTY1Ij4zNzUwPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TYW5kaGlyLCBSLjwvYXV0aG9y

PjxhdXRob3I+R3VwdGEsIFMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo

LWFkZHJlc3M+UmFqYXQgU2FuZGhpciwgU21yaXRpIEd1cHRhLCBEZXBhcnRtZW50IG9mIEJpb2No

ZW1pc3RyeSwgUGFuamFiIFVuaXZlcnNpdHksIENoYW5kaWdhcmggMTYwMDE0LCBJbmRpYS48L2F1

dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Nb2xlY3VsYXIgYW5kIGJpb2NoZW1pY2FsIHRyYWpl

Y3RvcmllcyBmcm9tIGRpYWJldGVzIHRvIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogQSBjcml0

aWNhbCBhcHByYWlzYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+V29ybGQgSiBEaWFiZXRlczwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMjIzLTQyPC9wYWdlcz48dm9sdW1lPjY8

L3ZvbHVtZT48bnVtYmVyPjEyPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciZh

cG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBtZWxsaXR1czwva2V5d29y

ZD48a2V5d29yZD5JbnN1bGluPC9rZXl3b3JkPjxrZXl3b3JkPlR5cGUgMiBkaWFiZXRlczwva2V5

d29yZD48a2V5d29yZD5UeXBlIDMgZGlhYmV0ZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPlNlcCAyNTwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxpc2JuPjE5NDgtOTM1OCAoUHJpbnQpJiN4RDsxOTQ4LTkzNTggKExpbmtpbmcp

PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2NDY0NzYwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh

dGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI2NDY0NzYw

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQ1OTg2MDU8L2N1c3RvbTI+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjQyMzkvd2pkLnY2LmkxMi4xMjIzPC9lbGVjdHJv

bmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5HaGFzZW1pPC9B

dXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVtPjM3OTI8L1JlY051bT48cmVjb3JkPjxyZWMt

bnVtYmVyPjM3OTI8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk

PSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkx

OTExOSI+Mzc5Mjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFy

dGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+R2hhc2Vt

aSwgUmFzb3VsPC9hdXRob3I+PGF1dGhvcj5EYXJnYWhpLCBMZWlsYTwvYXV0aG9yPjxhdXRob3I+

SGFlcmksIEFsaTwvYXV0aG9yPjxhdXRob3I+TW9vc2F2aSwgTWFyeWFtPC9hdXRob3I+PGF1dGhv

cj5Nb2hhbWVkLCBaYWh1cmluPC9hdXRob3I+PGF1dGhvcj5BaG1hZGlhbmksIEFib2xoYXNzYW48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QnJhaW4gSW5z

dWxpbiBEeXNyZWd1bGF0aW9uOiBJbXBsaWNhdGlvbiBmb3IgTmV1cm9sb2dpY2FsIGFuZCBOZXVy

b3BzeWNoaWF0cmljIERpc29yZGVyczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Nb2xlY3VsYXIg

TmV1cm9iaW9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEwNDUtMTA2NTwv

cGFnZXM+PHZvbHVtZT40Nzwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxkYXRlcz48eWVhcj4y

MDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxMy8wMS8yMDwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxwdWJsaXNoZXI+U3ByaW5nZXIgTmF0dXJlPC9wdWJsaXNoZXI+PGlzYm4+MDg5My03

NjQ4JiN4RDsxNTU5LTExODI8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9k

eC5kb2kub3JnLzEwLjEwMDcvczEyMDM1LTAxMy04NDA0LXo8L3VybD48L3JlbGF0ZWQtdXJscz48

L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDcvczEyMDM1LTAxMy04NDA0LXo8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

UmVjTnVtPjM3NTA8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjQsMzYxPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc1MDwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTY1Ij4zNzUwPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TYW5kaGlyLCBSLjwvYXV0aG9y

PjxhdXRob3I+R3VwdGEsIFMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo

LWFkZHJlc3M+UmFqYXQgU2FuZGhpciwgU21yaXRpIEd1cHRhLCBEZXBhcnRtZW50IG9mIEJpb2No

ZW1pc3RyeSwgUGFuamFiIFVuaXZlcnNpdHksIENoYW5kaWdhcmggMTYwMDE0LCBJbmRpYS48L2F1

dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Nb2xlY3VsYXIgYW5kIGJpb2NoZW1pY2FsIHRyYWpl

Y3RvcmllcyBmcm9tIGRpYWJldGVzIHRvIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogQSBjcml0

aWNhbCBhcHByYWlzYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+V29ybGQgSiBEaWFiZXRlczwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMjIzLTQyPC9wYWdlcz48dm9sdW1lPjY8

L3ZvbHVtZT48bnVtYmVyPjEyPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciZh

cG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBtZWxsaXR1czwva2V5d29y

ZD48a2V5d29yZD5JbnN1bGluPC9rZXl3b3JkPjxrZXl3b3JkPlR5cGUgMiBkaWFiZXRlczwva2V5

d29yZD48a2V5d29yZD5UeXBlIDMgZGlhYmV0ZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPlNlcCAyNTwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxpc2JuPjE5NDgtOTM1OCAoUHJpbnQpJiN4RDsxOTQ4LTkzNTggKExpbmtpbmcp

PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2NDY0NzYwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh

dGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI2NDY0NzYw

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQ1OTg2MDU8L2N1c3RvbTI+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjQyMzkvd2pkLnY2LmkxMi4xMjIzPC9lbGVjdHJv

bmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5HaGFzZW1pPC9B

dXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVtPjM3OTI8L1JlY051bT48cmVjb3JkPjxyZWMt

bnVtYmVyPjM3OTI8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk

PSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkx

OTExOSI+Mzc5Mjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFy

dGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+R2hhc2Vt

aSwgUmFzb3VsPC9hdXRob3I+PGF1dGhvcj5EYXJnYWhpLCBMZWlsYTwvYXV0aG9yPjxhdXRob3I+

SGFlcmksIEFsaTwvYXV0aG9yPjxhdXRob3I+TW9vc2F2aSwgTWFyeWFtPC9hdXRob3I+PGF1dGhv

cj5Nb2hhbWVkLCBaYWh1cmluPC9hdXRob3I+PGF1dGhvcj5BaG1hZGlhbmksIEFib2xoYXNzYW48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QnJhaW4gSW5z

dWxpbiBEeXNyZWd1bGF0aW9uOiBJbXBsaWNhdGlvbiBmb3IgTmV1cm9sb2dpY2FsIGFuZCBOZXVy

b3BzeWNoaWF0cmljIERpc29yZGVyczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Nb2xlY3VsYXIg

TmV1cm9iaW9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEwNDUtMTA2NTwv

cGFnZXM+PHZvbHVtZT40Nzwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxkYXRlcz48eWVhcj4y

MDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxMy8wMS8yMDwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxwdWJsaXNoZXI+U3ByaW5nZXIgTmF0dXJlPC9wdWJsaXNoZXI+PGlzYm4+MDg5My03

NjQ4JiN4RDsxNTU5LTExODI8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9k

eC5kb2kub3JnLzEwLjEwMDcvczEyMDM1LTAxMy04NDA0LXo8L3VybD48L3JlbGF0ZWQtdXJscz48

L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDcvczEyMDM1LTAxMy04NDA0LXo8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 324,361. However, their efficacy may be lost upon T2D progression ADDIN EN.CITE <EndNote><Cite><Author>Montanya</Author><Year>2012</Year><RecNum>3795</RecNum><DisplayText><style face="superscript">364</style></DisplayText><record><rec-number>3795</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535919119">3795</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Montanya, Eduard</author></authors></contributors><titles><title>A comparison of currently available GLP-1 receptor agonists for the treatment of type 2 diabetes</title><secondary-title>Expert Opinion on Pharmacotherapy</secondary-title></titles><pages>1451-1467</pages><volume>13</volume><number>10</number><dates><year>2012</year><pub-dates><date>2012/06/23</date></pub-dates></dates><publisher>Informa Healthcare</publisher><isbn>1465-6566&#xD;1744-7666</isbn><urls><related-urls><url> attenuated mouse hippocampal AD neuropathological hallmarks, improving also acetylcholine and adiponectin receptor levels in T2D rat brains PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYW1pbHRvbjwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

PFJlY051bT4zNzk2PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MzY1LDM2Njwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM3OTY8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxOTExOSI+Mzc5Njwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SGFtaWx0b24sIEEuPC9hdXRo

b3I+PGF1dGhvcj5QYXR0ZXJzb24sIFMuPC9hdXRob3I+PGF1dGhvcj5Qb3J0ZXIsIEQuPC9hdXRo

b3I+PGF1dGhvcj5HYXVsdCwgVi4gQS48L2F1dGhvcj48YXV0aG9yPkhvbHNjaGVyLCBDLjwvYXV0

aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5Ob3ZlbCBHTFAtMSBt

aW1ldGljcyBkZXZlbG9wZWQgdG8gdHJlYXQgdHlwZSAyIGRpYWJldGVzIHByb21vdGUgcHJvZ2Vu

aXRvciBjZWxsIHByb2xpZmVyYXRpb24gaW4gdGhlIGJyYWluPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPkpvdXJuYWwgb2YgTmV1cm9zY2llbmNlIFJlc2VhcmNoPC9zZWNvbmRhcnktdGl0bGU+PC90

aXRsZXM+PHBhZ2VzPjQ4MS00ODk8L3BhZ2VzPjx2b2x1bWU+ODk8L3ZvbHVtZT48bnVtYmVyPjQ8

L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTEvMDEv

MTA8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPldpbGV5PC9wdWJsaXNoZXI+

PGlzYm4+MDM2MC00MDEyPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHgu

ZG9pLm9yZy8xMC4xMDAyL2puci4yMjU2NTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwMi9qbnIuMjI1NjU8L2VsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkQmYXBvcztBbWljbzwvQXV0aG9y

PjxZZWFyPjIwMTM8L1llYXI+PFJlY051bT4zNzk4PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJl

cj4zNzk4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndh

MHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTkxMTki

PjM3OTg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xl

Ij4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkQmYXBvcztBbWlj

bywgTWljaGVsZTwvYXV0aG9yPjxhdXRob3I+RGkgRmlsaXBwbywgQ2xhcmE8L2F1dGhvcj48YXV0

aG9yPk1hcmZlbGxhLCBSYWZmYWVsZTwvYXV0aG9yPjxhdXRob3I+QWJiYXRlY29sYSwgQW5nZWxh

IE1hcmlhPC9hdXRob3I+PGF1dGhvcj5GZXJyYXJhY2NpbywgRnJhbmNhPC9hdXRob3I+PGF1dGhv

cj5Sb3NzaSwgRnJhbmNlc2NvPC9hdXRob3I+PGF1dGhvcj5QYW9saXNzbywgR2l1c2VwcGU8L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+Q29ycmlnZW5kdW0g

dG8g4oCcTE9ORy1URVJNIGluaGliaXRpb24gb2YgZGlwZXB0aWR5bCBwZXB0aWRhc2UtNCBpbiBB

bHpoZWltZXImYXBvcztzIHByb25lIG1pY2XigJ0gW0V4cC4gR2Vyb250b2wuICgyMDEwKSAyMDLi

gJMyMDddPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkV4cGVyaW1lbnRhbCBHZXJvbnRvbG9neTwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMDAyPC9wYWdlcz48dm9sdW1lPjQ4PC92

b2x1bWU+PG51bWJlcj45PC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT4yMDEzLzA5PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5FbHNl

dmllciBCVjwvcHVibGlzaGVyPjxpc2JuPjA1MzEtNTU2NTwvaXNibj48dXJscz48cmVsYXRlZC11

cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAxNi9qLmV4Z2VyLjIwMTMuMDIuMDA2PC91

cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2

L2ouZXhnZXIuMjAxMy4wMi4wMDY8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYW1pbHRvbjwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

PFJlY051bT4zNzk2PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MzY1LDM2Njwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM3OTY8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxOTExOSI+Mzc5Njwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SGFtaWx0b24sIEEuPC9hdXRo

b3I+PGF1dGhvcj5QYXR0ZXJzb24sIFMuPC9hdXRob3I+PGF1dGhvcj5Qb3J0ZXIsIEQuPC9hdXRo

b3I+PGF1dGhvcj5HYXVsdCwgVi4gQS48L2F1dGhvcj48YXV0aG9yPkhvbHNjaGVyLCBDLjwvYXV0

aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5Ob3ZlbCBHTFAtMSBt

aW1ldGljcyBkZXZlbG9wZWQgdG8gdHJlYXQgdHlwZSAyIGRpYWJldGVzIHByb21vdGUgcHJvZ2Vu

aXRvciBjZWxsIHByb2xpZmVyYXRpb24gaW4gdGhlIGJyYWluPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPkpvdXJuYWwgb2YgTmV1cm9zY2llbmNlIFJlc2VhcmNoPC9zZWNvbmRhcnktdGl0bGU+PC90

aXRsZXM+PHBhZ2VzPjQ4MS00ODk8L3BhZ2VzPjx2b2x1bWU+ODk8L3ZvbHVtZT48bnVtYmVyPjQ8

L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTEvMDEv

MTA8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPldpbGV5PC9wdWJsaXNoZXI+

PGlzYm4+MDM2MC00MDEyPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHgu

ZG9pLm9yZy8xMC4xMDAyL2puci4yMjU2NTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwMi9qbnIuMjI1NjU8L2VsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkQmYXBvcztBbWljbzwvQXV0aG9y

PjxZZWFyPjIwMTM8L1llYXI+PFJlY051bT4zNzk4PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJl

cj4zNzk4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndh

MHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTkxMTki

PjM3OTg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xl

Ij4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkQmYXBvcztBbWlj

bywgTWljaGVsZTwvYXV0aG9yPjxhdXRob3I+RGkgRmlsaXBwbywgQ2xhcmE8L2F1dGhvcj48YXV0

aG9yPk1hcmZlbGxhLCBSYWZmYWVsZTwvYXV0aG9yPjxhdXRob3I+QWJiYXRlY29sYSwgQW5nZWxh

IE1hcmlhPC9hdXRob3I+PGF1dGhvcj5GZXJyYXJhY2NpbywgRnJhbmNhPC9hdXRob3I+PGF1dGhv

cj5Sb3NzaSwgRnJhbmNlc2NvPC9hdXRob3I+PGF1dGhvcj5QYW9saXNzbywgR2l1c2VwcGU8L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+Q29ycmlnZW5kdW0g

dG8g4oCcTE9ORy1URVJNIGluaGliaXRpb24gb2YgZGlwZXB0aWR5bCBwZXB0aWRhc2UtNCBpbiBB

bHpoZWltZXImYXBvcztzIHByb25lIG1pY2XigJ0gW0V4cC4gR2Vyb250b2wuICgyMDEwKSAyMDLi

gJMyMDddPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkV4cGVyaW1lbnRhbCBHZXJvbnRvbG9neTwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMDAyPC9wYWdlcz48dm9sdW1lPjQ4PC92

b2x1bWU+PG51bWJlcj45PC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT4yMDEzLzA5PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5FbHNl

dmllciBCVjwvcHVibGlzaGVyPjxpc2JuPjA1MzEtNTU2NTwvaXNibj48dXJscz48cmVsYXRlZC11

cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAxNi9qLmV4Z2VyLjIwMTMuMDIuMDA2PC91

cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2

L2ouZXhnZXIuMjAxMy4wMi4wMDY8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 365,366. Sitagliptin and Vildagliptin also decreased peripheral T2D and oxidative stress markers and rescued learning and memory deficits in insulin resistant and T2D rats PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYW1pbHRvbjwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

PFJlY051bT4zNzk2PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MzY1LDM2NywzNjg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4z

Nzk2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4

NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTkxMTkiPjM3

OTY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x

NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhhbWlsdG9uLCBBLjwv

YXV0aG9yPjxhdXRob3I+UGF0dGVyc29uLCBTLjwvYXV0aG9yPjxhdXRob3I+UG9ydGVyLCBELjwv

YXV0aG9yPjxhdXRob3I+R2F1bHQsIFYuIEEuPC9hdXRob3I+PGF1dGhvcj5Ib2xzY2hlciwgQy48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+Tm92ZWwgR0xQ

LTEgbWltZXRpY3MgZGV2ZWxvcGVkIHRvIHRyZWF0IHR5cGUgMiBkaWFiZXRlcyBwcm9tb3RlIHBy

b2dlbml0b3IgY2VsbCBwcm9saWZlcmF0aW9uIGluIHRoZSBicmFpbjwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5Kb3VybmFsIG9mIE5ldXJvc2NpZW5jZSBSZXNlYXJjaDwvc2Vjb25kYXJ5LXRpdGxl

PjwvdGl0bGVzPjxwYWdlcz40ODEtNDg5PC9wYWdlcz48dm9sdW1lPjg5PC92b2x1bWU+PG51bWJl

cj40PC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDEx

LzAxLzEwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5XaWxleTwvcHVibGlz

aGVyPjxpc2JuPjAzNjAtNDAxMjwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDov

L2R4LmRvaS5vcmcvMTAuMTAwMi9qbnIuMjI1NjU8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDIvam5yLjIyNTY1PC9lbGVjdHJvbmljLXJl

c291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5CZWVyaTwvQXV0aG9yPjxZ

ZWFyPjIwMDg8L1llYXI+PFJlY051bT4zNzk5PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4z

Nzk5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4

NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTkxMTkiPjM3

OTk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x

NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJlZXJpLCBNLiBTLjwv

YXV0aG9yPjxhdXRob3I+U2NobWVpZGxlciwgSi48L2F1dGhvcj48YXV0aG9yPlNpbHZlcm1hbiwg

Si4gTS48L2F1dGhvcj48YXV0aG9yPkdhbmR5LCBTLjwvYXV0aG9yPjxhdXRob3I+V3lzb2NraSwg

TS48L2F1dGhvcj48YXV0aG9yPkhhbm5pZ2FuLCBDLiBNLjwvYXV0aG9yPjxhdXRob3I+UHVyb2hp

dCwgRC4gUC48L2F1dGhvcj48YXV0aG9yPkxlc3NlciwgRy48L2F1dGhvcj48YXV0aG9yPkdyb3Nz

bWFuLCBILiBULjwvYXV0aG9yPjxhdXRob3I+SGFyb3V0dW5pYW4sIFYuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkluc3VsaW4gaW4gY29tYmluYXRpb24g

d2l0aCBvdGhlciBkaWFiZXRlcyBtZWRpY2F0aW9uIGlzIGFzc29jaWF0ZWQgd2l0aCBsZXNzIEFs

emhlaW1lciBuZXVyb3BhdGhvbG9neTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb2xvZ3k8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb2xv

Z3k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz43NTAtNzU3PC9wYWdlcz48dm9sdW1l

PjcxPC92b2x1bWU+PG51bWJlcj4xMDwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDA4PC95ZWFyPjxw

dWItZGF0ZXM+PGRhdGU+MjAwOC8wOS8wMjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxwdWJs

aXNoZXI+T3ZpZCBUZWNobm9sb2dpZXMgKFdvbHRlcnMgS2x1d2VyIEhlYWx0aCk8L3B1Ymxpc2hl

cj48aXNibj4wMDI4LTM4NzgmI3hEOzE1MjYtNjMyWDwvaXNibj48dXJscz48cmVsYXRlZC11cmxz

Pjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTIxMi8wMS53bmwuMDAwMDMyNDkyNS45NTIxMC42

ZDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu

MTIxMi8wMS53bmwuMDAwMDMyNDkyNS45NTIxMC42ZDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+UGludGFuYTwvQXV0aG9yPjxZZWFyPjIwMTM8

L1llYXI+PFJlY051bT4zODAwPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zODAwPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTkxMTkiPjM4MDA8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlBpbnRhbmEsIEhpcmFueWE8L2F1dGhv

cj48YXV0aG9yPkFwYWlqYWksIE5hdHRheWFwb3JuPC9hdXRob3I+PGF1dGhvcj5DaGF0dGlwYWtv

cm4sIE5pcG9uPC9hdXRob3I+PGF1dGhvcj5DaGF0dGlwYWtvcm4sIFNpcmlwb3JuIEMuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkRQUC00IGluaGliaXRv

cnMgaW1wcm92ZSBjb2duaXRpb24gYW5kIGJyYWluIG1pdG9jaG9uZHJpYWwgZnVuY3Rpb24gb2Yg

aW5zdWxpbi1yZXNpc3RhbnQgcmF0czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Kb3VybmFsIG9m

IEVuZG9jcmlub2xvZ3k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MS0xMTwvcGFn

ZXM+PHZvbHVtZT4yMTg8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAx

MzwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTMvMDQvMTY8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48cHVibGlzaGVyPkJpb3NjaWVudGlmaWNhPC9wdWJsaXNoZXI+PGlzYm4+MDAyMi0wNzk1

JiN4RDsxNDc5LTY4MDU8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5k

b2kub3JnLzEwLjE1MzAvam9lLTEyLTA1MjE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjE1MzAvam9lLTEyLTA1MjE8L2VsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYW1pbHRvbjwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

PFJlY051bT4zNzk2PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MzY1LDM2NywzNjg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4z

Nzk2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4

NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTkxMTkiPjM3

OTY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x

NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhhbWlsdG9uLCBBLjwv

YXV0aG9yPjxhdXRob3I+UGF0dGVyc29uLCBTLjwvYXV0aG9yPjxhdXRob3I+UG9ydGVyLCBELjwv

YXV0aG9yPjxhdXRob3I+R2F1bHQsIFYuIEEuPC9hdXRob3I+PGF1dGhvcj5Ib2xzY2hlciwgQy48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+Tm92ZWwgR0xQ

LTEgbWltZXRpY3MgZGV2ZWxvcGVkIHRvIHRyZWF0IHR5cGUgMiBkaWFiZXRlcyBwcm9tb3RlIHBy

b2dlbml0b3IgY2VsbCBwcm9saWZlcmF0aW9uIGluIHRoZSBicmFpbjwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5Kb3VybmFsIG9mIE5ldXJvc2NpZW5jZSBSZXNlYXJjaDwvc2Vjb25kYXJ5LXRpdGxl

PjwvdGl0bGVzPjxwYWdlcz40ODEtNDg5PC9wYWdlcz48dm9sdW1lPjg5PC92b2x1bWU+PG51bWJl

cj40PC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDEx

LzAxLzEwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5XaWxleTwvcHVibGlz

aGVyPjxpc2JuPjAzNjAtNDAxMjwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDov

L2R4LmRvaS5vcmcvMTAuMTAwMi9qbnIuMjI1NjU8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDIvam5yLjIyNTY1PC9lbGVjdHJvbmljLXJl

c291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5CZWVyaTwvQXV0aG9yPjxZ

ZWFyPjIwMDg8L1llYXI+PFJlY051bT4zNzk5PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4z

Nzk5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4

NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTkxMTkiPjM3

OTk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x

NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJlZXJpLCBNLiBTLjwv

YXV0aG9yPjxhdXRob3I+U2NobWVpZGxlciwgSi48L2F1dGhvcj48YXV0aG9yPlNpbHZlcm1hbiwg

Si4gTS48L2F1dGhvcj48YXV0aG9yPkdhbmR5LCBTLjwvYXV0aG9yPjxhdXRob3I+V3lzb2NraSwg

TS48L2F1dGhvcj48YXV0aG9yPkhhbm5pZ2FuLCBDLiBNLjwvYXV0aG9yPjxhdXRob3I+UHVyb2hp

dCwgRC4gUC48L2F1dGhvcj48YXV0aG9yPkxlc3NlciwgRy48L2F1dGhvcj48YXV0aG9yPkdyb3Nz

bWFuLCBILiBULjwvYXV0aG9yPjxhdXRob3I+SGFyb3V0dW5pYW4sIFYuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkluc3VsaW4gaW4gY29tYmluYXRpb24g

d2l0aCBvdGhlciBkaWFiZXRlcyBtZWRpY2F0aW9uIGlzIGFzc29jaWF0ZWQgd2l0aCBsZXNzIEFs

emhlaW1lciBuZXVyb3BhdGhvbG9neTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb2xvZ3k8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb2xv

Z3k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz43NTAtNzU3PC9wYWdlcz48dm9sdW1l

PjcxPC92b2x1bWU+PG51bWJlcj4xMDwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDA4PC95ZWFyPjxw

dWItZGF0ZXM+PGRhdGU+MjAwOC8wOS8wMjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxwdWJs

aXNoZXI+T3ZpZCBUZWNobm9sb2dpZXMgKFdvbHRlcnMgS2x1d2VyIEhlYWx0aCk8L3B1Ymxpc2hl

cj48aXNibj4wMDI4LTM4NzgmI3hEOzE1MjYtNjMyWDwvaXNibj48dXJscz48cmVsYXRlZC11cmxz

Pjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTIxMi8wMS53bmwuMDAwMDMyNDkyNS45NTIxMC42

ZDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu

MTIxMi8wMS53bmwuMDAwMDMyNDkyNS45NTIxMC42ZDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+UGludGFuYTwvQXV0aG9yPjxZZWFyPjIwMTM8

L1llYXI+PFJlY051bT4zODAwPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zODAwPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTkxMTkiPjM4MDA8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlBpbnRhbmEsIEhpcmFueWE8L2F1dGhv

cj48YXV0aG9yPkFwYWlqYWksIE5hdHRheWFwb3JuPC9hdXRob3I+PGF1dGhvcj5DaGF0dGlwYWtv

cm4sIE5pcG9uPC9hdXRob3I+PGF1dGhvcj5DaGF0dGlwYWtvcm4sIFNpcmlwb3JuIEMuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkRQUC00IGluaGliaXRv

cnMgaW1wcm92ZSBjb2duaXRpb24gYW5kIGJyYWluIG1pdG9jaG9uZHJpYWwgZnVuY3Rpb24gb2Yg

aW5zdWxpbi1yZXNpc3RhbnQgcmF0czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Kb3VybmFsIG9m

IEVuZG9jcmlub2xvZ3k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MS0xMTwvcGFn

ZXM+PHZvbHVtZT4yMTg8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAx

MzwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTMvMDQvMTY8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48cHVibGlzaGVyPkJpb3NjaWVudGlmaWNhPC9wdWJsaXNoZXI+PGlzYm4+MDAyMi0wNzk1

JiN4RDsxNDc5LTY4MDU8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5k

b2kub3JnLzEwLjE1MzAvam9lLTEyLTA1MjE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjE1MzAvam9lLTEyLTA1MjE8L2VsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 365,367,368. Vildagliptin also decreased the levels of Aβ, hyperphosphorylated Tau and neuroinflammatory markers, and rescued memory deficits upon AD ADDIN EN.CITE <EndNote><Cite><Author>Darsalia</Author><Year>2018</Year><RecNum>3855</RecNum><DisplayText><style face="superscript">369</style></DisplayText><record><rec-number>3855</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535922664">3855</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Darsalia, V.</author><author>Klein, T.</author><author>Nystrom, T.</author><author>Patrone, C.</author></authors></contributors><auth-address>Karolinska Institutet, Department of Clinical Science and Education, Sodersjukhuset, Internal Medicine, Stockholm, Sweden.&#xD;Boehringer Ingelheim Pharma GmbH &amp; Co. KG, Biberach, Germany.&#xD;Karolinska Institutet, Department of Clinical Science and Education, Sodersjukhuset, Internal Medicine, Stockholm, Sweden. Electronic address: cesare.patrone@ki.se.</auth-address><titles><title>Glucagon-like receptor 1 agonists and DPP-4 inhibitors: Anti-diabetic drugs with anti-stroke potential</title><secondary-title>Neuropharmacology</secondary-title></titles><periodical><full-title>Neuropharmacology</full-title></periodical><pages>280-286</pages><volume>136</volume><number>Pt B</number><keywords><keyword>DPP-4 inhibitors</keyword><keyword>Diabetes</keyword><keyword>Glp-1</keyword><keyword>GLP-1R agonists</keyword><keyword>Neuroprotection</keyword><keyword>Stroke</keyword></keywords><dates><year>2018</year><pub-dates><date>Jul 1</date></pub-dates></dates><isbn>1873-7064 (Electronic)&#xD;0028-3908 (Linking)</isbn><accession-num>28823610</accession-num><urls><related-urls><url>. However, it is still debated whether DPP-IV inhibitors can cross the blood-brain barrier and exert direct effects in the brain or if their effects are mostly peripheral PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

UmVjTnVtPjM3NTA8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjQsMzYxPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc1MDwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTY1Ij4zNzUwPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TYW5kaGlyLCBSLjwvYXV0aG9y

PjxhdXRob3I+R3VwdGEsIFMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo

LWFkZHJlc3M+UmFqYXQgU2FuZGhpciwgU21yaXRpIEd1cHRhLCBEZXBhcnRtZW50IG9mIEJpb2No

ZW1pc3RyeSwgUGFuamFiIFVuaXZlcnNpdHksIENoYW5kaWdhcmggMTYwMDE0LCBJbmRpYS48L2F1

dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Nb2xlY3VsYXIgYW5kIGJpb2NoZW1pY2FsIHRyYWpl

Y3RvcmllcyBmcm9tIGRpYWJldGVzIHRvIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogQSBjcml0

aWNhbCBhcHByYWlzYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+V29ybGQgSiBEaWFiZXRlczwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMjIzLTQyPC9wYWdlcz48dm9sdW1lPjY8

L3ZvbHVtZT48bnVtYmVyPjEyPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciZh

cG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBtZWxsaXR1czwva2V5d29y

ZD48a2V5d29yZD5JbnN1bGluPC9rZXl3b3JkPjxrZXl3b3JkPlR5cGUgMiBkaWFiZXRlczwva2V5

d29yZD48a2V5d29yZD5UeXBlIDMgZGlhYmV0ZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPlNlcCAyNTwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxpc2JuPjE5NDgtOTM1OCAoUHJpbnQpJiN4RDsxOTQ4LTkzNTggKExpbmtpbmcp

PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2NDY0NzYwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh

dGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI2NDY0NzYw

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQ1OTg2MDU8L2N1c3RvbTI+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjQyMzkvd2pkLnY2LmkxMi4xMjIzPC9lbGVjdHJv

bmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5HaGFzZW1pPC9B

dXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVtPjM3OTI8L1JlY051bT48cmVjb3JkPjxyZWMt

bnVtYmVyPjM3OTI8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk

PSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkx

OTExOSI+Mzc5Mjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFy

dGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+R2hhc2Vt

aSwgUmFzb3VsPC9hdXRob3I+PGF1dGhvcj5EYXJnYWhpLCBMZWlsYTwvYXV0aG9yPjxhdXRob3I+

SGFlcmksIEFsaTwvYXV0aG9yPjxhdXRob3I+TW9vc2F2aSwgTWFyeWFtPC9hdXRob3I+PGF1dGhv

cj5Nb2hhbWVkLCBaYWh1cmluPC9hdXRob3I+PGF1dGhvcj5BaG1hZGlhbmksIEFib2xoYXNzYW48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QnJhaW4gSW5z

dWxpbiBEeXNyZWd1bGF0aW9uOiBJbXBsaWNhdGlvbiBmb3IgTmV1cm9sb2dpY2FsIGFuZCBOZXVy

b3BzeWNoaWF0cmljIERpc29yZGVyczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Nb2xlY3VsYXIg

TmV1cm9iaW9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEwNDUtMTA2NTwv

cGFnZXM+PHZvbHVtZT40Nzwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxkYXRlcz48eWVhcj4y

MDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxMy8wMS8yMDwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxwdWJsaXNoZXI+U3ByaW5nZXIgTmF0dXJlPC9wdWJsaXNoZXI+PGlzYm4+MDg5My03

NjQ4JiN4RDsxNTU5LTExODI8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9k

eC5kb2kub3JnLzEwLjEwMDcvczEyMDM1LTAxMy04NDA0LXo8L3VybD48L3JlbGF0ZWQtdXJscz48

L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDcvczEyMDM1LTAxMy04NDA0LXo8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

UmVjTnVtPjM3NTA8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjQsMzYxPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc1MDwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTY1Ij4zNzUwPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TYW5kaGlyLCBSLjwvYXV0aG9y

PjxhdXRob3I+R3VwdGEsIFMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo

LWFkZHJlc3M+UmFqYXQgU2FuZGhpciwgU21yaXRpIEd1cHRhLCBEZXBhcnRtZW50IG9mIEJpb2No

ZW1pc3RyeSwgUGFuamFiIFVuaXZlcnNpdHksIENoYW5kaWdhcmggMTYwMDE0LCBJbmRpYS48L2F1

dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Nb2xlY3VsYXIgYW5kIGJpb2NoZW1pY2FsIHRyYWpl

Y3RvcmllcyBmcm9tIGRpYWJldGVzIHRvIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogQSBjcml0

aWNhbCBhcHByYWlzYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+V29ybGQgSiBEaWFiZXRlczwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMjIzLTQyPC9wYWdlcz48dm9sdW1lPjY8

L3ZvbHVtZT48bnVtYmVyPjEyPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciZh

cG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBtZWxsaXR1czwva2V5d29y

ZD48a2V5d29yZD5JbnN1bGluPC9rZXl3b3JkPjxrZXl3b3JkPlR5cGUgMiBkaWFiZXRlczwva2V5

d29yZD48a2V5d29yZD5UeXBlIDMgZGlhYmV0ZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPlNlcCAyNTwvZGF0ZT48L3B1Yi1kYXRl

cz48L2RhdGVzPjxpc2JuPjE5NDgtOTM1OCAoUHJpbnQpJiN4RDsxOTQ4LTkzNTggKExpbmtpbmcp

PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2NDY0NzYwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh

dGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI2NDY0NzYw

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQ1OTg2MDU8L2N1c3RvbTI+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjQyMzkvd2pkLnY2LmkxMi4xMjIzPC9lbGVjdHJv

bmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5HaGFzZW1pPC9B

dXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVtPjM3OTI8L1JlY051bT48cmVjb3JkPjxyZWMt

bnVtYmVyPjM3OTI8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk

PSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkx

OTExOSI+Mzc5Mjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFy

dGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+R2hhc2Vt

aSwgUmFzb3VsPC9hdXRob3I+PGF1dGhvcj5EYXJnYWhpLCBMZWlsYTwvYXV0aG9yPjxhdXRob3I+

SGFlcmksIEFsaTwvYXV0aG9yPjxhdXRob3I+TW9vc2F2aSwgTWFyeWFtPC9hdXRob3I+PGF1dGhv

cj5Nb2hhbWVkLCBaYWh1cmluPC9hdXRob3I+PGF1dGhvcj5BaG1hZGlhbmksIEFib2xoYXNzYW48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QnJhaW4gSW5z

dWxpbiBEeXNyZWd1bGF0aW9uOiBJbXBsaWNhdGlvbiBmb3IgTmV1cm9sb2dpY2FsIGFuZCBOZXVy

b3BzeWNoaWF0cmljIERpc29yZGVyczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Nb2xlY3VsYXIg

TmV1cm9iaW9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEwNDUtMTA2NTwv

cGFnZXM+PHZvbHVtZT40Nzwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxkYXRlcz48eWVhcj4y

MDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxMy8wMS8yMDwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxwdWJsaXNoZXI+U3ByaW5nZXIgTmF0dXJlPC9wdWJsaXNoZXI+PGlzYm4+MDg5My03

NjQ4JiN4RDsxNTU5LTExODI8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9k

eC5kb2kub3JnLzEwLjEwMDcvczEyMDM1LTAxMy04NDA0LXo8L3VybD48L3JlbGF0ZWQtdXJscz48

L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDcvczEyMDM1LTAxMy04NDA0LXo8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 324,361. Further research is needed before including DPP-IV inhibitors into clinical trials in AD.-GLP-1 receptor agonistsExendin-4, Liraglutide, and Lixisenatide are the most used GLP-1 receptor (GLP-1R) agonists in T2D PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMsMzI0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMsMzI0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc0OTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE3NTA3Ij4zNzQ5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db3JiZXR0LCBBLjwvYXV0aG9y

PjxhdXRob3I+QmFsbGFyZCwgQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+SXMgYSBwb3RlbnRpYWwgQWx6aGVpbWVyJmFwb3M7cyB0aGVyYXB5IGFscmVh

ZHkgaW4gdXNlIGZvciBvdGhlciBjb25kaXRpb25zPyBDYW4gbWVkaWNhdGlvbnMgZm9yIGh5cGVy

dGVuc2lvbiwgZGlhYmV0ZXMgYW5kIGFjbmUgaGVscCB3aXRoIHRoZSBzeW1wdG9tcz88L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+RXhwZXJ0IE9waW4gSW52ZXN0aWcgRHJ1Z3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+OTQxLTM8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVt

YmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRydWcg

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNpbiBSZWNlcHRvciBBbnRhZ29uaXN0

cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1CYWN0ZXJpYWwgQWdlbnRz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtIENoYW5uZWwgQmxvY2tl

cnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPipEcnVnIFJlcG9zaXRpb25pbmc8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNzQ0LTc2NTggKEVsZWN0cm9uaWMpJiN4RDsxMzU0LTM3ODQgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjIzODA4NzA4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzODA4NzA4PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTE3LzEz

NTQzNzg0LjIwMTMuODE1NzIzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TYW5kaGlyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjM3NTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3NTA8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzU2NSI+Mzc1MDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2FuZGhpciwgUi48L2F1dGhvcj48YXV0aG9yPkd1cHRhLCBT

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlJhamF0IFNh

bmRoaXIsIFNtcml0aSBHdXB0YSwgRGVwYXJ0bWVudCBvZiBCaW9jaGVtaXN0cnksIFBhbmphYiBV

bml2ZXJzaXR5LCBDaGFuZGlnYXJoIDE2MDAxNCwgSW5kaWEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+TW9sZWN1bGFyIGFuZCBiaW9jaGVtaWNhbCB0cmFqZWN0b3JpZXMgZnJvbSBkaWFi

ZXRlcyB0byBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IEEgY3JpdGljYWwgYXBwcmFpc2FsPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPldvcmxkIEogRGlhYmV0ZXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTIyMy00MjwvcGFnZXM+PHZvbHVtZT42PC92b2x1bWU+PG51bWJlcj4x

MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgbWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bjwva2V5d29yZD48a2V5d29yZD5UeXBlIDIgZGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+VHlw

ZSAzIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

OTQ4LTkzNTggKFByaW50KSYjeEQ7MTk0OC05MzU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yNjQ2NDc2MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjQ2NDc2MDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NTk4NjA1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC40MjM5L3dqZC52Ni5pMTIuMTIyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 323,324 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HaGFzZW1pPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3OTI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zNjEsMzcwPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc5Mjwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5Ij4zNzkyPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5HaGFzZW1pLCBSYXNvdWw8L2F1

dGhvcj48YXV0aG9yPkRhcmdhaGksIExlaWxhPC9hdXRob3I+PGF1dGhvcj5IYWVyaSwgQWxpPC9h

dXRob3I+PGF1dGhvcj5Nb29zYXZpLCBNYXJ5YW08L2F1dGhvcj48YXV0aG9yPk1vaGFtZWQsIFph

aHVyaW48L2F1dGhvcj48YXV0aG9yPkFobWFkaWFuaSwgQWJvbGhhc3NhbjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5CcmFpbiBJbnN1bGluIER5c3JlZ3Vs

YXRpb246IEltcGxpY2F0aW9uIGZvciBOZXVyb2xvZ2ljYWwgYW5kIE5ldXJvcHN5Y2hpYXRyaWMg

RGlzb3JkZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk1vbGVjdWxhciBOZXVyb2Jpb2xvZ3k8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTA0NS0xMDY1PC9wYWdlcz48dm9sdW1l

PjQ3PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT4yMDEzLzAxLzIwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxp

c2hlcj5TcHJpbmdlciBOYXR1cmU8L3B1Ymxpc2hlcj48aXNibj4wODkzLTc2NDgmI3hEOzE1NTkt

MTE4MjwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAu

MTAwNy9zMTIwMzUtMDEzLTg0MDQtejwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMTIwMzUtMDEzLTg0MDQtejwvZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+S29zYXJhanU8L0F1dGhv

cj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNOdW0+MzgwMjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1i

ZXI+MzgwMjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3

YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5

Ij4zODAyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs

ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Lb3NhcmFqdSwg

SmF5YXNhbmthcjwvYXV0aG9yPjxhdXRob3I+TXVydGh5LCBWaXNoYWthbnRoYTwvYXV0aG9yPjxh

dXRob3I+S2hhdHdhbCwgUml6d2FuIEJhc2hhPC9hdXRob3I+PGF1dGhvcj5EdWJhbGEsIEFuaWw8

L2F1dGhvcj48YXV0aG9yPkNoaW5uaSwgU2FudGhpdmFyZGhhbjwvYXV0aG9yPjxhdXRob3I+TXV0

aHVyZWRkeSBOYXRhcmFqLCBTYXRpc2ggS3VtYXI8L2F1dGhvcj48YXV0aG9yPkJhc2F2YW4sIER1

cmFpc3dhbXk8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+

VmlsZGFnbGlwdGluOiBhbiBhbnRpLWRpYWJldGVzIGFnZW50IGFtZWxpb3JhdGVzIGNvZ25pdGl2

ZSBkZWZpY2l0cyBhbmQgcGF0aG9sb2d5IG9ic2VydmVkIGluIHN0cmVwdG96b3RvY2luLWluZHVj

ZWQgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkpvdXJu

YWwgb2YgUGhhcm1hY3kgYW5kIFBoYXJtYWNvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwYWdlcz4xNzczLTE3ODQ8L3BhZ2VzPjx2b2x1bWU+NjU8L3ZvbHVtZT48bnVtYmVyPjEyPC9u

dW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDEzLzEwLzEw

PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5XaWxleTwvcHVibGlzaGVyPjxp

c2JuPjAwMjItMzU3MzwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRv

aS5vcmcvMTAuMTExMS9qcGhwLjEyMTQ4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVj

dHJvbmljLXJlc291cmNlLW51bT4xMC4xMTExL2pwaHAuMTIxNDg8L2VsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HaGFzZW1pPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3OTI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zNjEsMzcwPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc5Mjwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5Ij4zNzkyPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5HaGFzZW1pLCBSYXNvdWw8L2F1

dGhvcj48YXV0aG9yPkRhcmdhaGksIExlaWxhPC9hdXRob3I+PGF1dGhvcj5IYWVyaSwgQWxpPC9h

dXRob3I+PGF1dGhvcj5Nb29zYXZpLCBNYXJ5YW08L2F1dGhvcj48YXV0aG9yPk1vaGFtZWQsIFph

aHVyaW48L2F1dGhvcj48YXV0aG9yPkFobWFkaWFuaSwgQWJvbGhhc3NhbjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5CcmFpbiBJbnN1bGluIER5c3JlZ3Vs

YXRpb246IEltcGxpY2F0aW9uIGZvciBOZXVyb2xvZ2ljYWwgYW5kIE5ldXJvcHN5Y2hpYXRyaWMg

RGlzb3JkZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk1vbGVjdWxhciBOZXVyb2Jpb2xvZ3k8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTA0NS0xMDY1PC9wYWdlcz48dm9sdW1l

PjQ3PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT4yMDEzLzAxLzIwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxp

c2hlcj5TcHJpbmdlciBOYXR1cmU8L3B1Ymxpc2hlcj48aXNibj4wODkzLTc2NDgmI3hEOzE1NTkt

MTE4MjwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAu

MTAwNy9zMTIwMzUtMDEzLTg0MDQtejwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMTIwMzUtMDEzLTg0MDQtejwvZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+S29zYXJhanU8L0F1dGhv

cj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNOdW0+MzgwMjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1i

ZXI+MzgwMjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3

YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5

Ij4zODAyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs

ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Lb3NhcmFqdSwg

SmF5YXNhbmthcjwvYXV0aG9yPjxhdXRob3I+TXVydGh5LCBWaXNoYWthbnRoYTwvYXV0aG9yPjxh

dXRob3I+S2hhdHdhbCwgUml6d2FuIEJhc2hhPC9hdXRob3I+PGF1dGhvcj5EdWJhbGEsIEFuaWw8

L2F1dGhvcj48YXV0aG9yPkNoaW5uaSwgU2FudGhpdmFyZGhhbjwvYXV0aG9yPjxhdXRob3I+TXV0

aHVyZWRkeSBOYXRhcmFqLCBTYXRpc2ggS3VtYXI8L2F1dGhvcj48YXV0aG9yPkJhc2F2YW4sIER1

cmFpc3dhbXk8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+

VmlsZGFnbGlwdGluOiBhbiBhbnRpLWRpYWJldGVzIGFnZW50IGFtZWxpb3JhdGVzIGNvZ25pdGl2

ZSBkZWZpY2l0cyBhbmQgcGF0aG9sb2d5IG9ic2VydmVkIGluIHN0cmVwdG96b3RvY2luLWluZHVj

ZWQgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkpvdXJu

YWwgb2YgUGhhcm1hY3kgYW5kIFBoYXJtYWNvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwYWdlcz4xNzczLTE3ODQ8L3BhZ2VzPjx2b2x1bWU+NjU8L3ZvbHVtZT48bnVtYmVyPjEyPC9u

dW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDEzLzEwLzEw

PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5XaWxleTwvcHVibGlzaGVyPjxp

c2JuPjAwMjItMzU3MzwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRv

aS5vcmcvMTAuMTExMS9qcGhwLjEyMTQ4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVj

dHJvbmljLXJlc291cmNlLW51bT4xMC4xMTExL2pwaHAuMTIxNDg8L2VsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 361,370. They act as incretin mimetics, promoting insulin secretion in a glucose-dependent manner to overcome insulin resistance PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMsMzYxLDM3MDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM3

NDk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1

MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzUwNyI+Mzc0

OTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3

PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Q29yYmV0dCwgQS48L2F1

dGhvcj48YXV0aG9yPkJhbGxhcmQsIEMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

Pjx0aXRsZXM+PHRpdGxlPklzIGEgcG90ZW50aWFsIEFsemhlaW1lciZhcG9zO3MgdGhlcmFweSBh

bHJlYWR5IGluIHVzZSBmb3Igb3RoZXIgY29uZGl0aW9ucz8gQ2FuIG1lZGljYXRpb25zIGZvciBo

eXBlcnRlbnNpb24sIGRpYWJldGVzIGFuZCBhY25lIGhlbHAgd2l0aCB0aGUgc3ltcHRvbXM/PC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkV4cGVydCBPcGluIEludmVzdGlnIERydWdzPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjk0MS0zPC9wYWdlcz48dm9sdW1lPjIyPC92b2x1bWU+

PG51bWJlcj44PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypk

cnVnIHRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QW5naW90ZW5zaW4gUmVjZXB0b3IgQW50YWdv

bmlzdHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFudGktQmFjdGVyaWFsIEFn

ZW50cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+Q2FsY2l1bSBDaGFubmVsIEJs

b2NrZXJzL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD4qRHJ1ZyBSZXBvc2l0aW9u

aW5nPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IeXBvZ2x5Y2Vt

aWMgQWdlbnRzL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVh

cj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXVnPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0

ZXM+PGlzYm4+MTc0NC03NjU4IChFbGVjdHJvbmljKSYjeEQ7MTM1NC0zNzg0IChMaW5raW5nKTwv

aXNibj48YWNjZXNzaW9uLW51bT4yMzgwODcwODwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRl

ZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMzgwODcwODwv

dXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTUx

Ny8xMzU0Mzc4NC4yMDEzLjgxNTcyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+

PC9DaXRlPjxDaXRlPjxBdXRob3I+R2hhc2VtaTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl

Y051bT4zNzkyPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zNzkyPC9yZWMtbnVtYmVyPjxm

b3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5

enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTkxMTkiPjM3OTI8L2tleT48L2ZvcmVpZ24t

a2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRy

aWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkdoYXNlbWksIFJhc291bDwvYXV0aG9yPjxhdXRob3I+

RGFyZ2FoaSwgTGVpbGE8L2F1dGhvcj48YXV0aG9yPkhhZXJpLCBBbGk8L2F1dGhvcj48YXV0aG9y

Pk1vb3NhdmksIE1hcnlhbTwvYXV0aG9yPjxhdXRob3I+TW9oYW1lZCwgWmFodXJpbjwvYXV0aG9y

PjxhdXRob3I+QWhtYWRpYW5pLCBBYm9saGFzc2FuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp

YnV0b3JzPjx0aXRsZXM+PHRpdGxlPkJyYWluIEluc3VsaW4gRHlzcmVndWxhdGlvbjogSW1wbGlj

YXRpb24gZm9yIE5ldXJvbG9naWNhbCBhbmQgTmV1cm9wc3ljaGlhdHJpYyBEaXNvcmRlcnM8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+TW9sZWN1bGFyIE5ldXJvYmlvbG9neTwvc2Vjb25kYXJ5LXRp

dGxlPjwvdGl0bGVzPjxwYWdlcz4xMDQ1LTEwNjU8L3BhZ2VzPjx2b2x1bWU+NDc8L3ZvbHVtZT48

bnVtYmVyPjM8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRl

PjIwMTMvMDEvMjA8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPlNwcmluZ2Vy

IE5hdHVyZTwvcHVibGlzaGVyPjxpc2JuPjA4OTMtNzY0OCYjeEQ7MTU1OS0xMTgyPC9pc2JuPjx1

cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDA3L3MxMjAzNS0w

MTMtODQwNC16PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNl

LW51bT4xMC4xMDA3L3MxMjAzNS0wMTMtODQwNC16PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48

L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5Lb3NhcmFqdTwvQXV0aG9yPjxZZWFyPjIwMTM8

L1llYXI+PFJlY051bT4zODAyPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zODAyPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTkxMTkiPjM4MDI8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPktvc2FyYWp1LCBKYXlhc2Fua2FyPC9h

dXRob3I+PGF1dGhvcj5NdXJ0aHksIFZpc2hha2FudGhhPC9hdXRob3I+PGF1dGhvcj5LaGF0d2Fs

LCBSaXp3YW4gQmFzaGE8L2F1dGhvcj48YXV0aG9yPkR1YmFsYSwgQW5pbDwvYXV0aG9yPjxhdXRo

b3I+Q2hpbm5pLCBTYW50aGl2YXJkaGFuPC9hdXRob3I+PGF1dGhvcj5NdXRodXJlZGR5IE5hdGFy

YWosIFNhdGlzaCBLdW1hcjwvYXV0aG9yPjxhdXRob3I+QmFzYXZhbiwgRHVyYWlzd2FteTwvYXV0

aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5WaWxkYWdsaXB0aW46

IGFuIGFudGktZGlhYmV0ZXMgYWdlbnQgYW1lbGlvcmF0ZXMgY29nbml0aXZlIGRlZmljaXRzIGFu

ZCBwYXRob2xvZ3kgb2JzZXJ2ZWQgaW4gc3RyZXB0b3pvdG9jaW4taW5kdWNlZCBBbHpoZWltZXIm

YXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Sm91cm5hbCBvZiBQaGFybWFj

eSBhbmQgUGhhcm1hY29sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjE3NzMt

MTc4NDwvcGFnZXM+PHZvbHVtZT42NTwvdm9sdW1lPjxudW1iZXI+MTI8L251bWJlcj48ZGF0ZXM+

PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTMvMTAvMTA8L2RhdGU+PC9wdWIt

ZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPldpbGV5PC9wdWJsaXNoZXI+PGlzYm4+MDAyMi0zNTcz

PC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMTEx

L2pwaHAuMTIxNDg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjExMTEvanBocC4xMjE0ODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNv

cmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JiZXR0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3NDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMjMsMzYxLDM3MDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM3

NDk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1

MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxNzUwNyI+Mzc0

OTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3

PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Q29yYmV0dCwgQS48L2F1

dGhvcj48YXV0aG9yPkJhbGxhcmQsIEMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

Pjx0aXRsZXM+PHRpdGxlPklzIGEgcG90ZW50aWFsIEFsemhlaW1lciZhcG9zO3MgdGhlcmFweSBh

bHJlYWR5IGluIHVzZSBmb3Igb3RoZXIgY29uZGl0aW9ucz8gQ2FuIG1lZGljYXRpb25zIGZvciBo

eXBlcnRlbnNpb24sIGRpYWJldGVzIGFuZCBhY25lIGhlbHAgd2l0aCB0aGUgc3ltcHRvbXM/PC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkV4cGVydCBPcGluIEludmVzdGlnIERydWdzPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjk0MS0zPC9wYWdlcz48dm9sdW1lPjIyPC92b2x1bWU+

PG51bWJlcj44PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypk

cnVnIHRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QW5naW90ZW5zaW4gUmVjZXB0b3IgQW50YWdv

bmlzdHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFudGktQmFjdGVyaWFsIEFn

ZW50cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+Q2FsY2l1bSBDaGFubmVsIEJs

b2NrZXJzL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD4qRHJ1ZyBSZXBvc2l0aW9u

aW5nPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IeXBvZ2x5Y2Vt

aWMgQWdlbnRzL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVh

cj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXVnPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0

ZXM+PGlzYm4+MTc0NC03NjU4IChFbGVjdHJvbmljKSYjeEQ7MTM1NC0zNzg0IChMaW5raW5nKTwv

aXNibj48YWNjZXNzaW9uLW51bT4yMzgwODcwODwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRl

ZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMzgwODcwODwv

dXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTUx

Ny8xMzU0Mzc4NC4yMDEzLjgxNTcyMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+

PC9DaXRlPjxDaXRlPjxBdXRob3I+R2hhc2VtaTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl

Y051bT4zNzkyPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zNzkyPC9yZWMtbnVtYmVyPjxm

b3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5

enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTkxMTkiPjM3OTI8L2tleT48L2ZvcmVpZ24t

a2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRy

aWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkdoYXNlbWksIFJhc291bDwvYXV0aG9yPjxhdXRob3I+

RGFyZ2FoaSwgTGVpbGE8L2F1dGhvcj48YXV0aG9yPkhhZXJpLCBBbGk8L2F1dGhvcj48YXV0aG9y

Pk1vb3NhdmksIE1hcnlhbTwvYXV0aG9yPjxhdXRob3I+TW9oYW1lZCwgWmFodXJpbjwvYXV0aG9y

PjxhdXRob3I+QWhtYWRpYW5pLCBBYm9saGFzc2FuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp

YnV0b3JzPjx0aXRsZXM+PHRpdGxlPkJyYWluIEluc3VsaW4gRHlzcmVndWxhdGlvbjogSW1wbGlj

YXRpb24gZm9yIE5ldXJvbG9naWNhbCBhbmQgTmV1cm9wc3ljaGlhdHJpYyBEaXNvcmRlcnM8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+TW9sZWN1bGFyIE5ldXJvYmlvbG9neTwvc2Vjb25kYXJ5LXRp

dGxlPjwvdGl0bGVzPjxwYWdlcz4xMDQ1LTEwNjU8L3BhZ2VzPjx2b2x1bWU+NDc8L3ZvbHVtZT48

bnVtYmVyPjM8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRl

PjIwMTMvMDEvMjA8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPlNwcmluZ2Vy

IE5hdHVyZTwvcHVibGlzaGVyPjxpc2JuPjA4OTMtNzY0OCYjeEQ7MTU1OS0xMTgyPC9pc2JuPjx1

cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDA3L3MxMjAzNS0w

MTMtODQwNC16PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNl

LW51bT4xMC4xMDA3L3MxMjAzNS0wMTMtODQwNC16PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48

L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5Lb3NhcmFqdTwvQXV0aG9yPjxZZWFyPjIwMTM8

L1llYXI+PFJlY051bT4zODAyPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zODAyPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTkxMTkiPjM4MDI8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPktvc2FyYWp1LCBKYXlhc2Fua2FyPC9h

dXRob3I+PGF1dGhvcj5NdXJ0aHksIFZpc2hha2FudGhhPC9hdXRob3I+PGF1dGhvcj5LaGF0d2Fs

LCBSaXp3YW4gQmFzaGE8L2F1dGhvcj48YXV0aG9yPkR1YmFsYSwgQW5pbDwvYXV0aG9yPjxhdXRo

b3I+Q2hpbm5pLCBTYW50aGl2YXJkaGFuPC9hdXRob3I+PGF1dGhvcj5NdXRodXJlZGR5IE5hdGFy

YWosIFNhdGlzaCBLdW1hcjwvYXV0aG9yPjxhdXRob3I+QmFzYXZhbiwgRHVyYWlzd2FteTwvYXV0

aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5WaWxkYWdsaXB0aW46

IGFuIGFudGktZGlhYmV0ZXMgYWdlbnQgYW1lbGlvcmF0ZXMgY29nbml0aXZlIGRlZmljaXRzIGFu

ZCBwYXRob2xvZ3kgb2JzZXJ2ZWQgaW4gc3RyZXB0b3pvdG9jaW4taW5kdWNlZCBBbHpoZWltZXIm

YXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Sm91cm5hbCBvZiBQaGFybWFj

eSBhbmQgUGhhcm1hY29sb2d5PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjE3NzMt

MTc4NDwvcGFnZXM+PHZvbHVtZT42NTwvdm9sdW1lPjxudW1iZXI+MTI8L251bWJlcj48ZGF0ZXM+

PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTMvMTAvMTA8L2RhdGU+PC9wdWIt

ZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPldpbGV5PC9wdWJsaXNoZXI+PGlzYm4+MDAyMi0zNTcz

PC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMTEx

L2pwaHAuMTIxNDg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjExMTEvanBocC4xMjE0ODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNv

cmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 323,361,370. Besides their minimum risk of hypoglycemia, GLP-1R agonists have also potent, long-lasting anti-obesogenic effects, possibly via a hypothalamic-regulated decrease in appetite and food intake ADDIN EN.CITE <EndNote><Cite><Author>Ghasemi</Author><Year>2013</Year><RecNum>3792</RecNum><DisplayText><style face="superscript">361</style></DisplayText><record><rec-number>3792</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535919119">3792</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ghasemi, Rasoul</author><author>Dargahi, Leila</author><author>Haeri, Ali</author><author>Moosavi, Maryam</author><author>Mohamed, Zahurin</author><author>Ahmadiani, Abolhassan</author></authors></contributors><titles><title>Brain Insulin Dysregulation: Implication for Neurological and Neuropsychiatric Disorders</title><secondary-title>Molecular Neurobiology</secondary-title></titles><pages>1045-1065</pages><volume>47</volume><number>3</number><dates><year>2013</year><pub-dates><date>2013/01/20</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>0893-7648&#xD;1559-1182</isbn><urls><related-urls><url>. They also showed benefits in blood pressure, cholesterol and triglycerides levels, as well as in cardiac function upon T2D ADDIN EN.CITE <EndNote><Cite><Author>Ghasemi</Author><Year>2013</Year><RecNum>3792</RecNum><DisplayText><style face="superscript">361</style></DisplayText><record><rec-number>3792</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535919119">3792</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ghasemi, Rasoul</author><author>Dargahi, Leila</author><author>Haeri, Ali</author><author>Moosavi, Maryam</author><author>Mohamed, Zahurin</author><author>Ahmadiani, Abolhassan</author></authors></contributors><titles><title>Brain Insulin Dysregulation: Implication for Neurological and Neuropsychiatric Disorders</title><secondary-title>Molecular Neurobiology</secondary-title></titles><pages>1045-1065</pages><volume>47</volume><number>3</number><dates><year>2013</year><pub-dates><date>2013/01/20</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>0893-7648&#xD;1559-1182</isbn><urls><related-urls><url>. Though the mechanisms involved herein remain poorly known, they may rely on a decrement in markers for cardiovascular risk (as IL-6, TNFα), endothelial dysfunction, oxidative/endoplasmic reticulum (ER) stress and inflammatory pathways ADDIN EN.CITE <EndNote><Cite><Author>Ghasemi</Author><Year>2013</Year><RecNum>3792</RecNum><DisplayText><style face="superscript">361</style></DisplayText><record><rec-number>3792</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535919119">3792</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ghasemi, Rasoul</author><author>Dargahi, Leila</author><author>Haeri, Ali</author><author>Moosavi, Maryam</author><author>Mohamed, Zahurin</author><author>Ahmadiani, Abolhassan</author></authors></contributors><titles><title>Brain Insulin Dysregulation: Implication for Neurological and Neuropsychiatric Disorders</title><secondary-title>Molecular Neurobiology</secondary-title></titles><pages>1045-1065</pages><volume>47</volume><number>3</number><dates><year>2013</year><pub-dates><date>2013/01/20</date></pub-dates></dates><publisher>Springer Nature</publisher><isbn>0893-7648&#xD;1559-1182</isbn><urls><related-urls><url>. Interestingly, Liraglutide promoted GLUT4 translocation in mouse skeletal muscle via cAMP signaling and may thus affect glucose uptake and metabolism ADDIN EN.CITE <EndNote><Cite><Author>Bae</Author><Year>2017</Year><RecNum>3803</RecNum><DisplayText><style face="superscript">371</style></DisplayText><record><rec-number>3803</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535919119">3803</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bae, Choon</author><author>Song, Juhyun</author></authors></contributors><titles><title>The Role of Glucagon-Like Peptide 1 (GLP1) in Type 3 Diabetes: GLP-1 Controls Insulin Resistance, Neuroinflammation and Neurogenesis in the Brain</title><secondary-title>International Journal of Molecular Sciences</secondary-title></titles><pages>2493</pages><volume>18</volume><number>11</number><dates><year>2017</year><pub-dates><date>2017/11/22</date></pub-dates></dates><publisher>MDPI AG</publisher><isbn>1422-0067</isbn><urls><related-urls><url> agonists are known to readily cross the blood-brain barrier and directly affect the brain, where they may act like neurotrophic factors PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HaGFzZW1pPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3OTI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zNjEsMzcwPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc5Mjwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5Ij4zNzkyPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5HaGFzZW1pLCBSYXNvdWw8L2F1

dGhvcj48YXV0aG9yPkRhcmdhaGksIExlaWxhPC9hdXRob3I+PGF1dGhvcj5IYWVyaSwgQWxpPC9h

dXRob3I+PGF1dGhvcj5Nb29zYXZpLCBNYXJ5YW08L2F1dGhvcj48YXV0aG9yPk1vaGFtZWQsIFph

aHVyaW48L2F1dGhvcj48YXV0aG9yPkFobWFkaWFuaSwgQWJvbGhhc3NhbjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5CcmFpbiBJbnN1bGluIER5c3JlZ3Vs

YXRpb246IEltcGxpY2F0aW9uIGZvciBOZXVyb2xvZ2ljYWwgYW5kIE5ldXJvcHN5Y2hpYXRyaWMg

RGlzb3JkZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk1vbGVjdWxhciBOZXVyb2Jpb2xvZ3k8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTA0NS0xMDY1PC9wYWdlcz48dm9sdW1l

PjQ3PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT4yMDEzLzAxLzIwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxp

c2hlcj5TcHJpbmdlciBOYXR1cmU8L3B1Ymxpc2hlcj48aXNibj4wODkzLTc2NDgmI3hEOzE1NTkt

MTE4MjwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAu

MTAwNy9zMTIwMzUtMDEzLTg0MDQtejwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMTIwMzUtMDEzLTg0MDQtejwvZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+S29zYXJhanU8L0F1dGhv

cj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNOdW0+MzgwMjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1i

ZXI+MzgwMjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3

YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5

Ij4zODAyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs

ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Lb3NhcmFqdSwg

SmF5YXNhbmthcjwvYXV0aG9yPjxhdXRob3I+TXVydGh5LCBWaXNoYWthbnRoYTwvYXV0aG9yPjxh

dXRob3I+S2hhdHdhbCwgUml6d2FuIEJhc2hhPC9hdXRob3I+PGF1dGhvcj5EdWJhbGEsIEFuaWw8

L2F1dGhvcj48YXV0aG9yPkNoaW5uaSwgU2FudGhpdmFyZGhhbjwvYXV0aG9yPjxhdXRob3I+TXV0

aHVyZWRkeSBOYXRhcmFqLCBTYXRpc2ggS3VtYXI8L2F1dGhvcj48YXV0aG9yPkJhc2F2YW4sIER1

cmFpc3dhbXk8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+

VmlsZGFnbGlwdGluOiBhbiBhbnRpLWRpYWJldGVzIGFnZW50IGFtZWxpb3JhdGVzIGNvZ25pdGl2

ZSBkZWZpY2l0cyBhbmQgcGF0aG9sb2d5IG9ic2VydmVkIGluIHN0cmVwdG96b3RvY2luLWluZHVj

ZWQgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkpvdXJu

YWwgb2YgUGhhcm1hY3kgYW5kIFBoYXJtYWNvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwYWdlcz4xNzczLTE3ODQ8L3BhZ2VzPjx2b2x1bWU+NjU8L3ZvbHVtZT48bnVtYmVyPjEyPC9u

dW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDEzLzEwLzEw

PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5XaWxleTwvcHVibGlzaGVyPjxp

c2JuPjAwMjItMzU3MzwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRv

aS5vcmcvMTAuMTExMS9qcGhwLjEyMTQ4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVj

dHJvbmljLXJlc291cmNlLW51bT4xMC4xMTExL2pwaHAuMTIxNDg8L2VsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HaGFzZW1pPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3OTI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zNjEsMzcwPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc5Mjwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5Ij4zNzkyPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5HaGFzZW1pLCBSYXNvdWw8L2F1

dGhvcj48YXV0aG9yPkRhcmdhaGksIExlaWxhPC9hdXRob3I+PGF1dGhvcj5IYWVyaSwgQWxpPC9h

dXRob3I+PGF1dGhvcj5Nb29zYXZpLCBNYXJ5YW08L2F1dGhvcj48YXV0aG9yPk1vaGFtZWQsIFph

aHVyaW48L2F1dGhvcj48YXV0aG9yPkFobWFkaWFuaSwgQWJvbGhhc3NhbjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5CcmFpbiBJbnN1bGluIER5c3JlZ3Vs

YXRpb246IEltcGxpY2F0aW9uIGZvciBOZXVyb2xvZ2ljYWwgYW5kIE5ldXJvcHN5Y2hpYXRyaWMg

RGlzb3JkZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk1vbGVjdWxhciBOZXVyb2Jpb2xvZ3k8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTA0NS0xMDY1PC9wYWdlcz48dm9sdW1l

PjQ3PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT4yMDEzLzAxLzIwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxp

c2hlcj5TcHJpbmdlciBOYXR1cmU8L3B1Ymxpc2hlcj48aXNibj4wODkzLTc2NDgmI3hEOzE1NTkt

MTE4MjwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAu

MTAwNy9zMTIwMzUtMDEzLTg0MDQtejwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMTIwMzUtMDEzLTg0MDQtejwvZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+S29zYXJhanU8L0F1dGhv

cj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNOdW0+MzgwMjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1i

ZXI+MzgwMjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3

YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5

Ij4zODAyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs

ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Lb3NhcmFqdSwg

SmF5YXNhbmthcjwvYXV0aG9yPjxhdXRob3I+TXVydGh5LCBWaXNoYWthbnRoYTwvYXV0aG9yPjxh

dXRob3I+S2hhdHdhbCwgUml6d2FuIEJhc2hhPC9hdXRob3I+PGF1dGhvcj5EdWJhbGEsIEFuaWw8

L2F1dGhvcj48YXV0aG9yPkNoaW5uaSwgU2FudGhpdmFyZGhhbjwvYXV0aG9yPjxhdXRob3I+TXV0

aHVyZWRkeSBOYXRhcmFqLCBTYXRpc2ggS3VtYXI8L2F1dGhvcj48YXV0aG9yPkJhc2F2YW4sIER1

cmFpc3dhbXk8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+

VmlsZGFnbGlwdGluOiBhbiBhbnRpLWRpYWJldGVzIGFnZW50IGFtZWxpb3JhdGVzIGNvZ25pdGl2

ZSBkZWZpY2l0cyBhbmQgcGF0aG9sb2d5IG9ic2VydmVkIGluIHN0cmVwdG96b3RvY2luLWluZHVj

ZWQgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkpvdXJu

YWwgb2YgUGhhcm1hY3kgYW5kIFBoYXJtYWNvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwYWdlcz4xNzczLTE3ODQ8L3BhZ2VzPjx2b2x1bWU+NjU8L3ZvbHVtZT48bnVtYmVyPjEyPC9u

dW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDEzLzEwLzEw

PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5XaWxleTwvcHVibGlzaGVyPjxp

c2JuPjAwMjItMzU3MzwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRv

aS5vcmcvMTAuMTExMS9qcGhwLjEyMTQ4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVj

dHJvbmljLXJlc291cmNlLW51bT4xMC4xMTExL2pwaHAuMTIxNDg8L2VsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 361,370. Mounting evidence point towards a neuroprotective role of GLP-1R agonists against in vitro and in vivo AD ADDIN EN.CITE <EndNote><Cite><Author>Kosaraju</Author><Year>2013</Year><RecNum>3802</RecNum><DisplayText><style face="superscript">370</style></DisplayText><record><rec-number>3802</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535919119">3802</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kosaraju, Jayasankar</author><author>Murthy, Vishakantha</author><author>Khatwal, Rizwan Basha</author><author>Dubala, Anil</author><author>Chinni, Santhivardhan</author><author>Muthureddy Nataraj, Satish Kumar</author><author>Basavan, Duraiswamy</author></authors></contributors><titles><title>Vildagliptin: an anti-diabetes agent ameliorates cognitive deficits and pathology observed in streptozotocin-induced Alzheimer&apos;s disease</title><secondary-title>Journal of Pharmacy and Pharmacology</secondary-title></titles><pages>1773-1784</pages><volume>65</volume><number>12</number><dates><year>2013</year><pub-dates><date>2013/10/10</date></pub-dates></dates><publisher>Wiley</publisher><isbn>0022-3573</isbn><urls><related-urls><url> PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJlY051

bT4zODA0PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+Mzcy

LDM3Mzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM4MDQ8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxOTExOSI+MzgwNDwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TGksIFpodTwvYXV0aG9yPjxhdXRob3I+

TmksIENoYW5nLUxpbjwvYXV0aG9yPjxhdXRob3I+WWFvLCBaaGk8L2F1dGhvcj48YXV0aG9yPkNo

ZW4sIExpLU1pbmc8L2F1dGhvcj48YXV0aG9yPk5pdSwgV2VuLVlhbjwvYXV0aG9yPjwvYXV0aG9y

cz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5MaXJhZ2x1dGlkZSBlbmhhbmNlcyBnbHVj

b3NlIHRyYW5zcG9ydGVyIDQgdHJhbnNsb2NhdGlvbiB2aWEgcmVndWxhdGlvbiBvZiBBTVAtYWN0

aXZhdGVkIHByb3RlaW4ga2luYXNlIHNpZ25hbGluZyBwYXRod2F5cyBpbiBtb3VzZSBza2VsZXRh

bCBtdXNjbGUgY2VsbHM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TWV0YWJvbGlzbTwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMDIyLTEwMzA8L3BhZ2VzPjx2b2x1bWU+NjM8L3Zv

bHVtZT48bnVtYmVyPjg8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48cHViLWRhdGVz

PjxkYXRlPjIwMTQvMDg8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2

aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MDAyNi0wNDk1PC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2oubWV0YWJvbC4yMDE0LjA1LjAwODwv

dXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAx

Ni9qLm1ldGFib2wuMjAxNC4wNS4wMDg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3Jk

PjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkxpPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVjTnVt

PjM4Njk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM4Njk8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkyMzExNCI+Mzg2OTwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+TGksIFkuPC9hdXRob3I+PGF1dGhvcj5MaSwgTC48L2F1dGhv

cj48YXV0aG9yPkhvbHNjaGVyLCBDLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48

dGl0bGVzPjx0aXRsZT5JbmNyZXRpbi1iYXNlZCB0aGVyYXB5IGZvciB0eXBlIDIgZGlhYmV0ZXMg

bWVsbGl0dXMgaXMgcHJvbWlzaW5nIGZvciB0cmVhdGluZyBuZXVyb2RlZ2VuZXJhdGl2ZSBkaXNl

YXNlczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5SZXYgTmV1cm9zY2k8L3NlY29uZGFyeS10aXRs

ZT48L3RpdGxlcz48cGFnZXM+Njg5LTcxMTwvcGFnZXM+PHZvbHVtZT4yNzwvdm9sdW1lPjxudW1i

ZXI+NzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3Jk

PkRpYWJldGVzIE1lbGxpdHVzLCBUeXBlIDIvKmRydWcgdGhlcmFweTwva2V5d29yZD48a2V5d29y

ZD5HYXN0cmljIEluaGliaXRvcnkgUG9seXBlcHRpZGUvcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IeXBvZ2x5Y2VtaWMgQWdlbnRzLyp0aGVy

YXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+SW5jcmV0aW5zLyp0aGVyYXBldXRpYyB1c2U8

L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9kZWdlbmVyYXRpdmUgRGlzZWFzZXMvKmRydWcgdGhlcmFw

eTwva2V5d29yZD48a2V5d29yZD5QZXB0aWRlcy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtl

eXdvcmQ+VmVub21zL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+T2N0IDE8L2RhdGU+PC9wdWItZGF0ZXM+

PC9kYXRlcz48aXNibj4wMzM0LTE3NjMgKFByaW50KSYjeEQ7MDMzNC0xNzYzIChMaW5raW5nKTwv

aXNibj48YWNjZXNzaW9uLW51bT4yNzI3NjUyODwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRl

ZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNzI3NjUyODwv

dXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTUx

NS9yZXZuZXVyby0yMDE2LTAwMTg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJlY051

bT4zODA0PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+Mzcy

LDM3Mzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM4MDQ8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxOTExOSI+MzgwNDwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TGksIFpodTwvYXV0aG9yPjxhdXRob3I+

TmksIENoYW5nLUxpbjwvYXV0aG9yPjxhdXRob3I+WWFvLCBaaGk8L2F1dGhvcj48YXV0aG9yPkNo

ZW4sIExpLU1pbmc8L2F1dGhvcj48YXV0aG9yPk5pdSwgV2VuLVlhbjwvYXV0aG9yPjwvYXV0aG9y

cz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5MaXJhZ2x1dGlkZSBlbmhhbmNlcyBnbHVj

b3NlIHRyYW5zcG9ydGVyIDQgdHJhbnNsb2NhdGlvbiB2aWEgcmVndWxhdGlvbiBvZiBBTVAtYWN0

aXZhdGVkIHByb3RlaW4ga2luYXNlIHNpZ25hbGluZyBwYXRod2F5cyBpbiBtb3VzZSBza2VsZXRh

bCBtdXNjbGUgY2VsbHM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TWV0YWJvbGlzbTwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMDIyLTEwMzA8L3BhZ2VzPjx2b2x1bWU+NjM8L3Zv

bHVtZT48bnVtYmVyPjg8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48cHViLWRhdGVz

PjxkYXRlPjIwMTQvMDg8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2

aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MDAyNi0wNDk1PC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2oubWV0YWJvbC4yMDE0LjA1LjAwODwv

dXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAx

Ni9qLm1ldGFib2wuMjAxNC4wNS4wMDg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3Jk

PjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkxpPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVjTnVt

PjM4Njk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM4Njk8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkyMzExNCI+Mzg2OTwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+TGksIFkuPC9hdXRob3I+PGF1dGhvcj5MaSwgTC48L2F1dGhv

cj48YXV0aG9yPkhvbHNjaGVyLCBDLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48

dGl0bGVzPjx0aXRsZT5JbmNyZXRpbi1iYXNlZCB0aGVyYXB5IGZvciB0eXBlIDIgZGlhYmV0ZXMg

bWVsbGl0dXMgaXMgcHJvbWlzaW5nIGZvciB0cmVhdGluZyBuZXVyb2RlZ2VuZXJhdGl2ZSBkaXNl

YXNlczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5SZXYgTmV1cm9zY2k8L3NlY29uZGFyeS10aXRs

ZT48L3RpdGxlcz48cGFnZXM+Njg5LTcxMTwvcGFnZXM+PHZvbHVtZT4yNzwvdm9sdW1lPjxudW1i

ZXI+NzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3Jk

PkRpYWJldGVzIE1lbGxpdHVzLCBUeXBlIDIvKmRydWcgdGhlcmFweTwva2V5d29yZD48a2V5d29y

ZD5HYXN0cmljIEluaGliaXRvcnkgUG9seXBlcHRpZGUvcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IeXBvZ2x5Y2VtaWMgQWdlbnRzLyp0aGVy

YXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+SW5jcmV0aW5zLyp0aGVyYXBldXRpYyB1c2U8

L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9kZWdlbmVyYXRpdmUgRGlzZWFzZXMvKmRydWcgdGhlcmFw

eTwva2V5d29yZD48a2V5d29yZD5QZXB0aWRlcy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtl

eXdvcmQ+VmVub21zL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+T2N0IDE8L2RhdGU+PC9wdWItZGF0ZXM+

PC9kYXRlcz48aXNibj4wMzM0LTE3NjMgKFByaW50KSYjeEQ7MDMzNC0xNzYzIChMaW5raW5nKTwv

aXNibj48YWNjZXNzaW9uLW51bT4yNzI3NjUyODwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRl

ZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNzI3NjUyODwv

dXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTUx

NS9yZXZuZXVyby0yMDE2LTAwMTg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 372,373. Specifically, these drugs attenuated Aβ, APP and hyperphosphorylated Tau levels, neuroinflammation, oxidative/ER stress and neuronal death in AD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HaGFzZW1pPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3OTI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zNjEsMzcwLDM3MiwzNzM8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJl

cj4zNzkyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndh

MHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTkxMTki

PjM3OTI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xl

Ij4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkdoYXNlbWksIFJh

c291bDwvYXV0aG9yPjxhdXRob3I+RGFyZ2FoaSwgTGVpbGE8L2F1dGhvcj48YXV0aG9yPkhhZXJp

LCBBbGk8L2F1dGhvcj48YXV0aG9yPk1vb3NhdmksIE1hcnlhbTwvYXV0aG9yPjxhdXRob3I+TW9o

YW1lZCwgWmFodXJpbjwvYXV0aG9yPjxhdXRob3I+QWhtYWRpYW5pLCBBYm9saGFzc2FuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkJyYWluIEluc3VsaW4g

RHlzcmVndWxhdGlvbjogSW1wbGljYXRpb24gZm9yIE5ldXJvbG9naWNhbCBhbmQgTmV1cm9wc3lj

aGlhdHJpYyBEaXNvcmRlcnM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TW9sZWN1bGFyIE5ldXJv

YmlvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMDQ1LTEwNjU8L3BhZ2Vz

Pjx2b2x1bWU+NDc8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxMzwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTMvMDEvMjA8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48cHVibGlzaGVyPlNwcmluZ2VyIE5hdHVyZTwvcHVibGlzaGVyPjxpc2JuPjA4OTMtNzY0OCYj

eEQ7MTU1OS0xMTgyPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9p

Lm9yZy8xMC4xMDA3L3MxMjAzNS0wMTMtODQwNC16PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxz

PjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDA3L3MxMjAzNS0wMTMtODQwNC16PC9lbGVj

dHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5Lb3NhcmFq

dTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJlY051bT4zODAyPC9SZWNOdW0+PHJlY29yZD48

cmVjLW51bWJlcj4zODAyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk

Yi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1

MzU5MTkxMTkiPjM4MDI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h

bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPktv

c2FyYWp1LCBKYXlhc2Fua2FyPC9hdXRob3I+PGF1dGhvcj5NdXJ0aHksIFZpc2hha2FudGhhPC9h

dXRob3I+PGF1dGhvcj5LaGF0d2FsLCBSaXp3YW4gQmFzaGE8L2F1dGhvcj48YXV0aG9yPkR1YmFs

YSwgQW5pbDwvYXV0aG9yPjxhdXRob3I+Q2hpbm5pLCBTYW50aGl2YXJkaGFuPC9hdXRob3I+PGF1

dGhvcj5NdXRodXJlZGR5IE5hdGFyYWosIFNhdGlzaCBLdW1hcjwvYXV0aG9yPjxhdXRob3I+QmFz

YXZhbiwgRHVyYWlzd2FteTwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVz

Pjx0aXRsZT5WaWxkYWdsaXB0aW46IGFuIGFudGktZGlhYmV0ZXMgYWdlbnQgYW1lbGlvcmF0ZXMg

Y29nbml0aXZlIGRlZmljaXRzIGFuZCBwYXRob2xvZ3kgb2JzZXJ2ZWQgaW4gc3RyZXB0b3pvdG9j

aW4taW5kdWNlZCBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0

bGU+Sm91cm5hbCBvZiBQaGFybWFjeSBhbmQgUGhhcm1hY29sb2d5PC9zZWNvbmRhcnktdGl0bGU+

PC90aXRsZXM+PHBhZ2VzPjE3NzMtMTc4NDwvcGFnZXM+PHZvbHVtZT42NTwvdm9sdW1lPjxudW1i

ZXI+MTI8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIw

MTMvMTAvMTA8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPldpbGV5PC9wdWJs

aXNoZXI+PGlzYm4+MDAyMi0zNTczPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRw

Oi8vZHguZG9pLm9yZy8xMC4xMTExL2pwaHAuMTIxNDg8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExMTEvanBocC4xMjE0ODwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TGk8L0F1dGhvcj48

WWVhcj4yMDE0PC9ZZWFyPjxSZWNOdW0+MzgwNDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+

MzgwNDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTBy

eDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5Ij4z

ODA0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+

MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5MaSwgWmh1PC9hdXRo

b3I+PGF1dGhvcj5OaSwgQ2hhbmctTGluPC9hdXRob3I+PGF1dGhvcj5ZYW8sIFpoaTwvYXV0aG9y

PjxhdXRob3I+Q2hlbiwgTGktTWluZzwvYXV0aG9yPjxhdXRob3I+Tml1LCBXZW4tWWFuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkxpcmFnbHV0aWRlIGVu

aGFuY2VzIGdsdWNvc2UgdHJhbnNwb3J0ZXIgNCB0cmFuc2xvY2F0aW9uIHZpYSByZWd1bGF0aW9u

IG9mIEFNUC1hY3RpdmF0ZWQgcHJvdGVpbiBraW5hc2Ugc2lnbmFsaW5nIHBhdGh3YXlzIGluIG1v

dXNlIHNrZWxldGFsIG11c2NsZSBjZWxsczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5NZXRhYm9s

aXNtPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEwMjItMTAzMDwvcGFnZXM+PHZv

bHVtZT42Mzwvdm9sdW1lPjxudW1iZXI+ODwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDE0PC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+MjAxNC8wODwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxwdWJs

aXNoZXI+RWxzZXZpZXIgQlY8L3B1Ymxpc2hlcj48aXNibj4wMDI2LTA0OTU8L2lzYm4+PHVybHM+

PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjEwMTYvai5tZXRhYm9sLjIw

MTQuMDUuMDA4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNl

LW51bT4xMC4xMDE2L2oubWV0YWJvbC4yMDE0LjA1LjAwODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TGk8L0F1dGhvcj48WWVhcj4yMDE2PC9Z

ZWFyPjxSZWNOdW0+Mzg2OTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzg2OTwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTIzMTE0Ij4zODY5PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5MaSwgWS48L2F1dGhvcj48YXV0aG9yPkxp

LCBMLjwvYXV0aG9yPjxhdXRob3I+SG9sc2NoZXIsIEMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkluY3JldGluLWJhc2VkIHRoZXJhcHkgZm9yIHR5cGUg

MiBkaWFiZXRlcyBtZWxsaXR1cyBpcyBwcm9taXNpbmcgZm9yIHRyZWF0aW5nIG5ldXJvZGVnZW5l

cmF0aXZlIGRpc2Vhc2VzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlJldiBOZXVyb3NjaTwvc2Vj

b25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz42ODktNzExPC9wYWdlcz48dm9sdW1lPjI3PC92

b2x1bWU+PG51bWJlcj43PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdv

cmQ+PGtleXdvcmQ+RGlhYmV0ZXMgTWVsbGl0dXMsIFR5cGUgMi8qZHJ1ZyB0aGVyYXB5PC9rZXl3

b3JkPjxrZXl3b3JkPkdhc3RyaWMgSW5oaWJpdG9yeSBQb2x5cGVwdGlkZS9waGFybWFjb2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvKnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5JbmNyZXRpbnMvKnRoZXJh

cGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5OZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcy8q

ZHJ1ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPlBlcHRpZGVzL3RoZXJhcGV1dGljIHVzZTwv

a2V5d29yZD48a2V5d29yZD5WZW5vbXMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29y

ZHM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5PY3QgMTwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAzMzQtMTc2MyAoUHJpbnQpJiN4RDswMzM0LTE3NjMg

KExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3Mjc2NTI4PC9hY2Nlc3Npb24tbnVtPjx1

cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVk

LzI3Mjc2NTI4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNl

LW51bT4xMC4xNTE1L3Jldm5ldXJvLTIwMTYtMDAxODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HaGFzZW1pPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3OTI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zNjEsMzcwLDM3MiwzNzM8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJl

cj4zNzkyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndh

MHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTkxMTki

PjM3OTI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xl

Ij4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkdoYXNlbWksIFJh

c291bDwvYXV0aG9yPjxhdXRob3I+RGFyZ2FoaSwgTGVpbGE8L2F1dGhvcj48YXV0aG9yPkhhZXJp

LCBBbGk8L2F1dGhvcj48YXV0aG9yPk1vb3NhdmksIE1hcnlhbTwvYXV0aG9yPjxhdXRob3I+TW9o

YW1lZCwgWmFodXJpbjwvYXV0aG9yPjxhdXRob3I+QWhtYWRpYW5pLCBBYm9saGFzc2FuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkJyYWluIEluc3VsaW4g

RHlzcmVndWxhdGlvbjogSW1wbGljYXRpb24gZm9yIE5ldXJvbG9naWNhbCBhbmQgTmV1cm9wc3lj

aGlhdHJpYyBEaXNvcmRlcnM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TW9sZWN1bGFyIE5ldXJv

YmlvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMDQ1LTEwNjU8L3BhZ2Vz

Pjx2b2x1bWU+NDc8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxMzwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTMvMDEvMjA8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48cHVibGlzaGVyPlNwcmluZ2VyIE5hdHVyZTwvcHVibGlzaGVyPjxpc2JuPjA4OTMtNzY0OCYj

eEQ7MTU1OS0xMTgyPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9p

Lm9yZy8xMC4xMDA3L3MxMjAzNS0wMTMtODQwNC16PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxz

PjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDA3L3MxMjAzNS0wMTMtODQwNC16PC9lbGVj

dHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5Lb3NhcmFq

dTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJlY051bT4zODAyPC9SZWNOdW0+PHJlY29yZD48

cmVjLW51bWJlcj4zODAyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk

Yi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1

MzU5MTkxMTkiPjM4MDI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h

bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPktv

c2FyYWp1LCBKYXlhc2Fua2FyPC9hdXRob3I+PGF1dGhvcj5NdXJ0aHksIFZpc2hha2FudGhhPC9h

dXRob3I+PGF1dGhvcj5LaGF0d2FsLCBSaXp3YW4gQmFzaGE8L2F1dGhvcj48YXV0aG9yPkR1YmFs

YSwgQW5pbDwvYXV0aG9yPjxhdXRob3I+Q2hpbm5pLCBTYW50aGl2YXJkaGFuPC9hdXRob3I+PGF1

dGhvcj5NdXRodXJlZGR5IE5hdGFyYWosIFNhdGlzaCBLdW1hcjwvYXV0aG9yPjxhdXRob3I+QmFz

YXZhbiwgRHVyYWlzd2FteTwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVz

Pjx0aXRsZT5WaWxkYWdsaXB0aW46IGFuIGFudGktZGlhYmV0ZXMgYWdlbnQgYW1lbGlvcmF0ZXMg

Y29nbml0aXZlIGRlZmljaXRzIGFuZCBwYXRob2xvZ3kgb2JzZXJ2ZWQgaW4gc3RyZXB0b3pvdG9j

aW4taW5kdWNlZCBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0

bGU+Sm91cm5hbCBvZiBQaGFybWFjeSBhbmQgUGhhcm1hY29sb2d5PC9zZWNvbmRhcnktdGl0bGU+

PC90aXRsZXM+PHBhZ2VzPjE3NzMtMTc4NDwvcGFnZXM+PHZvbHVtZT42NTwvdm9sdW1lPjxudW1i

ZXI+MTI8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIw

MTMvMTAvMTA8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPldpbGV5PC9wdWJs

aXNoZXI+PGlzYm4+MDAyMi0zNTczPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRw

Oi8vZHguZG9pLm9yZy8xMC4xMTExL2pwaHAuMTIxNDg8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExMTEvanBocC4xMjE0ODwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TGk8L0F1dGhvcj48

WWVhcj4yMDE0PC9ZZWFyPjxSZWNOdW0+MzgwNDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+

MzgwNDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTBy

eDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5Ij4z

ODA0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+

MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5MaSwgWmh1PC9hdXRo

b3I+PGF1dGhvcj5OaSwgQ2hhbmctTGluPC9hdXRob3I+PGF1dGhvcj5ZYW8sIFpoaTwvYXV0aG9y

PjxhdXRob3I+Q2hlbiwgTGktTWluZzwvYXV0aG9yPjxhdXRob3I+Tml1LCBXZW4tWWFuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkxpcmFnbHV0aWRlIGVu

aGFuY2VzIGdsdWNvc2UgdHJhbnNwb3J0ZXIgNCB0cmFuc2xvY2F0aW9uIHZpYSByZWd1bGF0aW9u

IG9mIEFNUC1hY3RpdmF0ZWQgcHJvdGVpbiBraW5hc2Ugc2lnbmFsaW5nIHBhdGh3YXlzIGluIG1v

dXNlIHNrZWxldGFsIG11c2NsZSBjZWxsczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5NZXRhYm9s

aXNtPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjEwMjItMTAzMDwvcGFnZXM+PHZv

bHVtZT42Mzwvdm9sdW1lPjxudW1iZXI+ODwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDE0PC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+MjAxNC8wODwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxwdWJs

aXNoZXI+RWxzZXZpZXIgQlY8L3B1Ymxpc2hlcj48aXNibj4wMDI2LTA0OTU8L2lzYm4+PHVybHM+

PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly9keC5kb2kub3JnLzEwLjEwMTYvai5tZXRhYm9sLjIw

MTQuMDUuMDA4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNl

LW51bT4xMC4xMDE2L2oubWV0YWJvbC4yMDE0LjA1LjAwODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TGk8L0F1dGhvcj48WWVhcj4yMDE2PC9Z

ZWFyPjxSZWNOdW0+Mzg2OTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzg2OTwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTIzMTE0Ij4zODY5PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5MaSwgWS48L2F1dGhvcj48YXV0aG9yPkxp

LCBMLjwvYXV0aG9yPjxhdXRob3I+SG9sc2NoZXIsIEMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkluY3JldGluLWJhc2VkIHRoZXJhcHkgZm9yIHR5cGUg

MiBkaWFiZXRlcyBtZWxsaXR1cyBpcyBwcm9taXNpbmcgZm9yIHRyZWF0aW5nIG5ldXJvZGVnZW5l

cmF0aXZlIGRpc2Vhc2VzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlJldiBOZXVyb3NjaTwvc2Vj

b25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz42ODktNzExPC9wYWdlcz48dm9sdW1lPjI3PC92

b2x1bWU+PG51bWJlcj43PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdv

cmQ+PGtleXdvcmQ+RGlhYmV0ZXMgTWVsbGl0dXMsIFR5cGUgMi8qZHJ1ZyB0aGVyYXB5PC9rZXl3

b3JkPjxrZXl3b3JkPkdhc3RyaWMgSW5oaWJpdG9yeSBQb2x5cGVwdGlkZS9waGFybWFjb2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBB

Z2VudHMvKnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5JbmNyZXRpbnMvKnRoZXJh

cGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5OZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcy8q

ZHJ1ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPlBlcHRpZGVzL3RoZXJhcGV1dGljIHVzZTwv

a2V5d29yZD48a2V5d29yZD5WZW5vbXMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjwva2V5d29y

ZHM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5PY3QgMTwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAzMzQtMTc2MyAoUHJpbnQpJiN4RDswMzM0LTE3NjMg

KExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3Mjc2NTI4PC9hY2Nlc3Npb24tbnVtPjx1

cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVk

LzI3Mjc2NTI4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNl

LW51bT4xMC4xNTE1L3Jldm5ldXJvLTIwMTYtMDAxODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 361,370,372,373. These were mirrored by increased insulin degrading enzyme and insulin signaling, which may recover glucose metabolism, synaptic transmission/plasticity, neurogenesis and, ultimately, memory and cognitive performance PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HaGFzZW1pPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3OTI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMTUsMzYxLDM3MCwzNzIsMzczPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1u

dW1iZXI+Mzc5MjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9

ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5

MTE5Ij4zNzkyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0

aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5HaGFzZW1p

LCBSYXNvdWw8L2F1dGhvcj48YXV0aG9yPkRhcmdhaGksIExlaWxhPC9hdXRob3I+PGF1dGhvcj5I

YWVyaSwgQWxpPC9hdXRob3I+PGF1dGhvcj5Nb29zYXZpLCBNYXJ5YW08L2F1dGhvcj48YXV0aG9y

Pk1vaGFtZWQsIFphaHVyaW48L2F1dGhvcj48YXV0aG9yPkFobWFkaWFuaSwgQWJvbGhhc3Nhbjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5CcmFpbiBJbnN1

bGluIER5c3JlZ3VsYXRpb246IEltcGxpY2F0aW9uIGZvciBOZXVyb2xvZ2ljYWwgYW5kIE5ldXJv

cHN5Y2hpYXRyaWMgRGlzb3JkZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk1vbGVjdWxhciBO

ZXVyb2Jpb2xvZ3k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTA0NS0xMDY1PC9w

YWdlcz48dm9sdW1lPjQ3PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDEzLzAxLzIwPC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PHB1Ymxpc2hlcj5TcHJpbmdlciBOYXR1cmU8L3B1Ymxpc2hlcj48aXNibj4wODkzLTc2

NDgmI3hEOzE1NTktMTE4MjwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4

LmRvaS5vcmcvMTAuMTAwNy9zMTIwMzUtMDEzLTg0MDQtejwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMTIwMzUtMDEzLTg0MDQtejwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+S29z

YXJhanU8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNOdW0+MzgwMjwvUmVjTnVtPjxyZWNv

cmQ+PHJlYy1udW1iZXI+MzgwMjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1w

PSIxNTM1OTE5MTE5Ij4zODAyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5Lb3NhcmFqdSwgSmF5YXNhbmthcjwvYXV0aG9yPjxhdXRob3I+TXVydGh5LCBWaXNoYWthbnRo

YTwvYXV0aG9yPjxhdXRob3I+S2hhdHdhbCwgUml6d2FuIEJhc2hhPC9hdXRob3I+PGF1dGhvcj5E

dWJhbGEsIEFuaWw8L2F1dGhvcj48YXV0aG9yPkNoaW5uaSwgU2FudGhpdmFyZGhhbjwvYXV0aG9y

PjxhdXRob3I+TXV0aHVyZWRkeSBOYXRhcmFqLCBTYXRpc2ggS3VtYXI8L2F1dGhvcj48YXV0aG9y

PkJhc2F2YW4sIER1cmFpc3dhbXk8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+VmlsZGFnbGlwdGluOiBhbiBhbnRpLWRpYWJldGVzIGFnZW50IGFtZWxpb3Jh

dGVzIGNvZ25pdGl2ZSBkZWZpY2l0cyBhbmQgcGF0aG9sb2d5IG9ic2VydmVkIGluIHN0cmVwdG96

b3RvY2luLWluZHVjZWQgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPkpvdXJuYWwgb2YgUGhhcm1hY3kgYW5kIFBoYXJtYWNvbG9neTwvc2Vjb25kYXJ5LXRp

dGxlPjwvdGl0bGVzPjxwYWdlcz4xNzczLTE3ODQ8L3BhZ2VzPjx2b2x1bWU+NjU8L3ZvbHVtZT48

bnVtYmVyPjEyPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT4yMDEzLzEwLzEwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5XaWxleTwv

cHVibGlzaGVyPjxpc2JuPjAwMjItMzU3MzwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+

aHR0cDovL2R4LmRvaS5vcmcvMTAuMTExMS9qcGhwLjEyMTQ4PC91cmw+PC9yZWxhdGVkLXVybHM+

PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTExL2pwaHAuMTIxNDg8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkxpPC9BdXRo

b3I+PFllYXI+MjAxNDwvWWVhcj48UmVjTnVtPjM4MDQ8L1JlY051bT48cmVjb3JkPjxyZWMtbnVt

YmVyPjM4MDQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJm

d2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxOTEx

OSI+MzgwNDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj

bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TGksIFpodTwv

YXV0aG9yPjxhdXRob3I+TmksIENoYW5nLUxpbjwvYXV0aG9yPjxhdXRob3I+WWFvLCBaaGk8L2F1

dGhvcj48YXV0aG9yPkNoZW4sIExpLU1pbmc8L2F1dGhvcj48YXV0aG9yPk5pdSwgV2VuLVlhbjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5MaXJhZ2x1dGlk

ZSBlbmhhbmNlcyBnbHVjb3NlIHRyYW5zcG9ydGVyIDQgdHJhbnNsb2NhdGlvbiB2aWEgcmVndWxh

dGlvbiBvZiBBTVAtYWN0aXZhdGVkIHByb3RlaW4ga2luYXNlIHNpZ25hbGluZyBwYXRod2F5cyBp

biBtb3VzZSBza2VsZXRhbCBtdXNjbGUgY2VsbHM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TWV0

YWJvbGlzbTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMDIyLTEwMzA8L3BhZ2Vz

Pjx2b2x1bWU+NjM8L3ZvbHVtZT48bnVtYmVyPjg8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNDwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTQvMDg8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MDAyNi0wNDk1PC9pc2JuPjx1

cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2oubWV0YWJv

bC4yMDE0LjA1LjAwODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+MTAuMTAxNi9qLm1ldGFib2wuMjAxNC4wNS4wMDg8L2VsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkxpPC9BdXRob3I+PFllYXI+MjAx

NjwvWWVhcj48UmVjTnVtPjM4Njk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM4Njk8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkyMzExNCI+Mzg2OTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TGksIFkuPC9hdXRob3I+PGF1dGhv

cj5MaSwgTC48L2F1dGhvcj48YXV0aG9yPkhvbHNjaGVyLCBDLjwvYXV0aG9yPjwvYXV0aG9ycz48

L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5JbmNyZXRpbi1iYXNlZCB0aGVyYXB5IGZvciB0

eXBlIDIgZGlhYmV0ZXMgbWVsbGl0dXMgaXMgcHJvbWlzaW5nIGZvciB0cmVhdGluZyBuZXVyb2Rl

Z2VuZXJhdGl2ZSBkaXNlYXNlczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5SZXYgTmV1cm9zY2k8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+Njg5LTcxMTwvcGFnZXM+PHZvbHVtZT4y

Nzwvdm9sdW1lPjxudW1iZXI+NzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9r

ZXl3b3JkPjxrZXl3b3JkPkRpYWJldGVzIE1lbGxpdHVzLCBUeXBlIDIvKmRydWcgdGhlcmFweTwv

a2V5d29yZD48a2V5d29yZD5HYXN0cmljIEluaGliaXRvcnkgUG9seXBlcHRpZGUvcGhhcm1hY29s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IeXBvZ2x5Y2Vt

aWMgQWdlbnRzLyp0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+SW5jcmV0aW5zLyp0

aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9kZWdlbmVyYXRpdmUgRGlzZWFz

ZXMvKmRydWcgdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5QZXB0aWRlcy90aGVyYXBldXRpYyB1

c2U8L2tleXdvcmQ+PGtleXdvcmQ+VmVub21zL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+T2N0IDE8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMzM0LTE3NjMgKFByaW50KSYjeEQ7MDMzNC0x

NzYzIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNzI3NjUyODwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8yNzI3NjUyODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+MTAuMTUxNS9yZXZuZXVyby0yMDE2LTAwMTg8L2VsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlZlcmRpbGU8L0F1dGhvcj48WWVhcj4y

MDE1PC9ZZWFyPjxSZWNOdW0+MzU2ODwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MzU2ODwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE0NDA0Ij4zNTY4PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5WZXJkaWxlLCBHLjwvYXV0aG9y

PjxhdXRob3I+RnVsbGVyLCBTLiBKLjwvYXV0aG9yPjxhdXRob3I+TWFydGlucywgUi4gTi48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5TY2hvb2wgb2YgQmlv

bWVkaWNhbCBTY2llbmNlcywgQ0hJUkkgQmlvc2NpZW5jZXMsIEN1cnRpbiBVbml2ZXJzaXR5LCBC

ZW50bGV5LCBXZXN0ZXJuIEF1c3RyYWxpYSA2MTAyLCBBdXN0cmFsaWE7IENlbnRyZSBvZiBFeGNl

bGxlbmNlIGZvciBBbHpoZWltZXImYXBvcztzIERpc2Vhc2UgUmVzZWFyY2ggYW5kIENhcmUsIFNj

aG9vbCBvZiBNZWRpY2FsIFNjaWVuY2VzLCBFZGl0aCBDb3dhbiBVbml2ZXJzaXR5LCBKb29uZGFs

dXAsIFdlc3Rlcm4gQXVzdHJhbGlhIDYwMjcsIEF1c3RyYWxpYTsgU2lyIEphbWVzIE1jQ3Vza2Vy

IEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZSBSZXNlYXJjaCBVbml0LCBTY2hvb2wgb2YgUHN5Y2hp

YXRyeSBhbmQgQ2xpbmljYWwgTmV1cm9zY2llbmNlcywgVW5pdmVyc2l0eSBvZiBXZXN0ZXJuIEF1

c3RyYWxpYSwgQ3Jhd2xleSwgV2VzdGVybiBBdXN0cmFsaWEgNjAwOSwgQXVzdHJhbGlhLiYjeEQ7

U2lyIEphbWVzIE1jQ3Vza2VyIEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZSBSZXNlYXJjaCBVbml0

LCBTY2hvb2wgb2YgUHN5Y2hpYXRyeSBhbmQgQ2xpbmljYWwgTmV1cm9zY2llbmNlcywgVW5pdmVy

c2l0eSBvZiBXZXN0ZXJuIEF1c3RyYWxpYSwgQ3Jhd2xleSwgV2VzdGVybiBBdXN0cmFsaWEgNjAw

OSwgQXVzdHJhbGlhLiYjeEQ7U2Nob29sIG9mIEJpb21lZGljYWwgU2NpZW5jZXMsIENISVJJIEJp

b3NjaWVuY2VzLCBDdXJ0aW4gVW5pdmVyc2l0eSwgQmVudGxleSwgV2VzdGVybiBBdXN0cmFsaWEg

NjEwMiwgQXVzdHJhbGlhOyBDZW50cmUgb2YgRXhjZWxsZW5jZSBmb3IgQWx6aGVpbWVyJmFwb3M7

cyBEaXNlYXNlIFJlc2VhcmNoIGFuZCBDYXJlLCBTY2hvb2wgb2YgTWVkaWNhbCBTY2llbmNlcywg

RWRpdGggQ293YW4gVW5pdmVyc2l0eSwgSm9vbmRhbHVwLCBXZXN0ZXJuIEF1c3RyYWxpYSA2MDI3

LCBBdXN0cmFsaWE7IFNpciBKYW1lcyBNY0N1c2tlciBBbHpoZWltZXImYXBvcztzIERpc2Vhc2Ug

UmVzZWFyY2ggVW5pdCwgU2Nob29sIG9mIFBzeWNoaWF0cnkgYW5kIENsaW5pY2FsIE5ldXJvc2Np

ZW5jZXMsIFVuaXZlcnNpdHkgb2YgV2VzdGVybiBBdXN0cmFsaWEsIENyYXdsZXksIFdlc3Rlcm4g

QXVzdHJhbGlhIDYwMDksIEF1c3RyYWxpYS4gRWxlY3Ryb25pYyBhZGRyZXNzOiByLm1hcnRpbnNA

ZWN1LmVkdS5hdS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5UaGUgcm9sZSBvZiB0eXBl

IDIgZGlhYmV0ZXMgaW4gbmV1cm9kZWdlbmVyYXRpb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+

TmV1cm9iaW9sIERpczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxs

LXRpdGxlPk5ldXJvYmlvbCBEaXM8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yMi0z

ODwvcGFnZXM+PHZvbHVtZT44NDwvdm9sdW1lPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9r

ZXl3b3JkPjxrZXl3b3JkPkJyYWluL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+RGlhYmV0

ZXMgTWVsbGl0dXMsIFR5cGUgMi8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8

L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9kZWdlbmVyYXRpdmUgRGlzZWFzZXMvKm1ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3

b3JkPkFteWxpbjwva2V5d29yZD48a2V5d29yZD5CZXRhIGFteWxvaWQ8L2tleXdvcmQ+PGtleXdv

cmQ+RGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9kZWdlbmVyYXRpb248L2tleXdvcmQ+

PGtleXdvcmQ+VGF1PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5EZWM8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMDk1

LTk1M1ggKEVsZWN0cm9uaWMpJiN4RDswOTY5LTk5NjEgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI1OTI2MzQ5PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI1OTI2MzQ5PC91cmw+PC9yZWxhdGVk

LXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2oubmJkLjIwMTUu

MDQuMDA4PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3Rl

Pn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HaGFzZW1pPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

UmVjTnVtPjM3OTI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zMTUsMzYxLDM3MCwzNzIsMzczPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1u

dW1iZXI+Mzc5MjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9

ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5

MTE5Ij4zNzkyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0

aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5HaGFzZW1p

LCBSYXNvdWw8L2F1dGhvcj48YXV0aG9yPkRhcmdhaGksIExlaWxhPC9hdXRob3I+PGF1dGhvcj5I

YWVyaSwgQWxpPC9hdXRob3I+PGF1dGhvcj5Nb29zYXZpLCBNYXJ5YW08L2F1dGhvcj48YXV0aG9y

Pk1vaGFtZWQsIFphaHVyaW48L2F1dGhvcj48YXV0aG9yPkFobWFkaWFuaSwgQWJvbGhhc3Nhbjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5CcmFpbiBJbnN1

bGluIER5c3JlZ3VsYXRpb246IEltcGxpY2F0aW9uIGZvciBOZXVyb2xvZ2ljYWwgYW5kIE5ldXJv

cHN5Y2hpYXRyaWMgRGlzb3JkZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk1vbGVjdWxhciBO

ZXVyb2Jpb2xvZ3k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTA0NS0xMDY1PC9w

YWdlcz48dm9sdW1lPjQ3PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIw

MTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDEzLzAxLzIwPC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PHB1Ymxpc2hlcj5TcHJpbmdlciBOYXR1cmU8L3B1Ymxpc2hlcj48aXNibj4wODkzLTc2

NDgmI3hEOzE1NTktMTE4MjwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4

LmRvaS5vcmcvMTAuMTAwNy9zMTIwMzUtMDEzLTg0MDQtejwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMTIwMzUtMDEzLTg0MDQtejwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+S29z

YXJhanU8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNOdW0+MzgwMjwvUmVjTnVtPjxyZWNv

cmQ+PHJlYy1udW1iZXI+MzgwMjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1w

PSIxNTM1OTE5MTE5Ij4zODAyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5Lb3NhcmFqdSwgSmF5YXNhbmthcjwvYXV0aG9yPjxhdXRob3I+TXVydGh5LCBWaXNoYWthbnRo

YTwvYXV0aG9yPjxhdXRob3I+S2hhdHdhbCwgUml6d2FuIEJhc2hhPC9hdXRob3I+PGF1dGhvcj5E

dWJhbGEsIEFuaWw8L2F1dGhvcj48YXV0aG9yPkNoaW5uaSwgU2FudGhpdmFyZGhhbjwvYXV0aG9y

PjxhdXRob3I+TXV0aHVyZWRkeSBOYXRhcmFqLCBTYXRpc2ggS3VtYXI8L2F1dGhvcj48YXV0aG9y

PkJhc2F2YW4sIER1cmFpc3dhbXk8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+VmlsZGFnbGlwdGluOiBhbiBhbnRpLWRpYWJldGVzIGFnZW50IGFtZWxpb3Jh

dGVzIGNvZ25pdGl2ZSBkZWZpY2l0cyBhbmQgcGF0aG9sb2d5IG9ic2VydmVkIGluIHN0cmVwdG96

b3RvY2luLWluZHVjZWQgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPkpvdXJuYWwgb2YgUGhhcm1hY3kgYW5kIFBoYXJtYWNvbG9neTwvc2Vjb25kYXJ5LXRp

dGxlPjwvdGl0bGVzPjxwYWdlcz4xNzczLTE3ODQ8L3BhZ2VzPjx2b2x1bWU+NjU8L3ZvbHVtZT48

bnVtYmVyPjEyPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT4yMDEzLzEwLzEwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5XaWxleTwv

cHVibGlzaGVyPjxpc2JuPjAwMjItMzU3MzwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+

aHR0cDovL2R4LmRvaS5vcmcvMTAuMTExMS9qcGhwLjEyMTQ4PC91cmw+PC9yZWxhdGVkLXVybHM+

PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTExL2pwaHAuMTIxNDg8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkxpPC9BdXRo

b3I+PFllYXI+MjAxNDwvWWVhcj48UmVjTnVtPjM4MDQ8L1JlY051bT48cmVjb3JkPjxyZWMtbnVt

YmVyPjM4MDQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJm

d2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxOTEx

OSI+MzgwNDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj

bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TGksIFpodTwv

YXV0aG9yPjxhdXRob3I+TmksIENoYW5nLUxpbjwvYXV0aG9yPjxhdXRob3I+WWFvLCBaaGk8L2F1

dGhvcj48YXV0aG9yPkNoZW4sIExpLU1pbmc8L2F1dGhvcj48YXV0aG9yPk5pdSwgV2VuLVlhbjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5MaXJhZ2x1dGlk

ZSBlbmhhbmNlcyBnbHVjb3NlIHRyYW5zcG9ydGVyIDQgdHJhbnNsb2NhdGlvbiB2aWEgcmVndWxh

dGlvbiBvZiBBTVAtYWN0aXZhdGVkIHByb3RlaW4ga2luYXNlIHNpZ25hbGluZyBwYXRod2F5cyBp

biBtb3VzZSBza2VsZXRhbCBtdXNjbGUgY2VsbHM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TWV0

YWJvbGlzbTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMDIyLTEwMzA8L3BhZ2Vz

Pjx2b2x1bWU+NjM8L3ZvbHVtZT48bnVtYmVyPjg8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNDwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTQvMDg8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

cHVibGlzaGVyPkVsc2V2aWVyIEJWPC9wdWJsaXNoZXI+PGlzYm4+MDAyNi0wNDk1PC9pc2JuPjx1

cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2oubWV0YWJv

bC4yMDE0LjA1LjAwODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+MTAuMTAxNi9qLm1ldGFib2wuMjAxNC4wNS4wMDg8L2VsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkxpPC9BdXRob3I+PFllYXI+MjAx

NjwvWWVhcj48UmVjTnVtPjM4Njk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM4Njk8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkyMzExNCI+Mzg2OTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TGksIFkuPC9hdXRob3I+PGF1dGhv

cj5MaSwgTC48L2F1dGhvcj48YXV0aG9yPkhvbHNjaGVyLCBDLjwvYXV0aG9yPjwvYXV0aG9ycz48

L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5JbmNyZXRpbi1iYXNlZCB0aGVyYXB5IGZvciB0

eXBlIDIgZGlhYmV0ZXMgbWVsbGl0dXMgaXMgcHJvbWlzaW5nIGZvciB0cmVhdGluZyBuZXVyb2Rl

Z2VuZXJhdGl2ZSBkaXNlYXNlczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5SZXYgTmV1cm9zY2k8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+Njg5LTcxMTwvcGFnZXM+PHZvbHVtZT4y

Nzwvdm9sdW1lPjxudW1iZXI+NzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9r

ZXl3b3JkPjxrZXl3b3JkPkRpYWJldGVzIE1lbGxpdHVzLCBUeXBlIDIvKmRydWcgdGhlcmFweTwv

a2V5d29yZD48a2V5d29yZD5HYXN0cmljIEluaGliaXRvcnkgUG9seXBlcHRpZGUvcGhhcm1hY29s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IeXBvZ2x5Y2Vt

aWMgQWdlbnRzLyp0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+SW5jcmV0aW5zLyp0

aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9kZWdlbmVyYXRpdmUgRGlzZWFz

ZXMvKmRydWcgdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5QZXB0aWRlcy90aGVyYXBldXRpYyB1

c2U8L2tleXdvcmQ+PGtleXdvcmQ+VmVub21zL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+T2N0IDE8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMzM0LTE3NjMgKFByaW50KSYjeEQ7MDMzNC0x

NzYzIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNzI3NjUyODwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8yNzI3NjUyODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+MTAuMTUxNS9yZXZuZXVyby0yMDE2LTAwMTg8L2VsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlZlcmRpbGU8L0F1dGhvcj48WWVhcj4y

MDE1PC9ZZWFyPjxSZWNOdW0+MzU2ODwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MzU2ODwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE0NDA0Ij4zNTY4PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5WZXJkaWxlLCBHLjwvYXV0aG9y

PjxhdXRob3I+RnVsbGVyLCBTLiBKLjwvYXV0aG9yPjxhdXRob3I+TWFydGlucywgUi4gTi48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5TY2hvb2wgb2YgQmlv

bWVkaWNhbCBTY2llbmNlcywgQ0hJUkkgQmlvc2NpZW5jZXMsIEN1cnRpbiBVbml2ZXJzaXR5LCBC

ZW50bGV5LCBXZXN0ZXJuIEF1c3RyYWxpYSA2MTAyLCBBdXN0cmFsaWE7IENlbnRyZSBvZiBFeGNl

bGxlbmNlIGZvciBBbHpoZWltZXImYXBvcztzIERpc2Vhc2UgUmVzZWFyY2ggYW5kIENhcmUsIFNj

aG9vbCBvZiBNZWRpY2FsIFNjaWVuY2VzLCBFZGl0aCBDb3dhbiBVbml2ZXJzaXR5LCBKb29uZGFs

dXAsIFdlc3Rlcm4gQXVzdHJhbGlhIDYwMjcsIEF1c3RyYWxpYTsgU2lyIEphbWVzIE1jQ3Vza2Vy

IEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZSBSZXNlYXJjaCBVbml0LCBTY2hvb2wgb2YgUHN5Y2hp

YXRyeSBhbmQgQ2xpbmljYWwgTmV1cm9zY2llbmNlcywgVW5pdmVyc2l0eSBvZiBXZXN0ZXJuIEF1

c3RyYWxpYSwgQ3Jhd2xleSwgV2VzdGVybiBBdXN0cmFsaWEgNjAwOSwgQXVzdHJhbGlhLiYjeEQ7

U2lyIEphbWVzIE1jQ3Vza2VyIEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZSBSZXNlYXJjaCBVbml0

LCBTY2hvb2wgb2YgUHN5Y2hpYXRyeSBhbmQgQ2xpbmljYWwgTmV1cm9zY2llbmNlcywgVW5pdmVy

c2l0eSBvZiBXZXN0ZXJuIEF1c3RyYWxpYSwgQ3Jhd2xleSwgV2VzdGVybiBBdXN0cmFsaWEgNjAw

OSwgQXVzdHJhbGlhLiYjeEQ7U2Nob29sIG9mIEJpb21lZGljYWwgU2NpZW5jZXMsIENISVJJIEJp

b3NjaWVuY2VzLCBDdXJ0aW4gVW5pdmVyc2l0eSwgQmVudGxleSwgV2VzdGVybiBBdXN0cmFsaWEg

NjEwMiwgQXVzdHJhbGlhOyBDZW50cmUgb2YgRXhjZWxsZW5jZSBmb3IgQWx6aGVpbWVyJmFwb3M7

cyBEaXNlYXNlIFJlc2VhcmNoIGFuZCBDYXJlLCBTY2hvb2wgb2YgTWVkaWNhbCBTY2llbmNlcywg

RWRpdGggQ293YW4gVW5pdmVyc2l0eSwgSm9vbmRhbHVwLCBXZXN0ZXJuIEF1c3RyYWxpYSA2MDI3

LCBBdXN0cmFsaWE7IFNpciBKYW1lcyBNY0N1c2tlciBBbHpoZWltZXImYXBvcztzIERpc2Vhc2Ug

UmVzZWFyY2ggVW5pdCwgU2Nob29sIG9mIFBzeWNoaWF0cnkgYW5kIENsaW5pY2FsIE5ldXJvc2Np

ZW5jZXMsIFVuaXZlcnNpdHkgb2YgV2VzdGVybiBBdXN0cmFsaWEsIENyYXdsZXksIFdlc3Rlcm4g

QXVzdHJhbGlhIDYwMDksIEF1c3RyYWxpYS4gRWxlY3Ryb25pYyBhZGRyZXNzOiByLm1hcnRpbnNA

ZWN1LmVkdS5hdS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5UaGUgcm9sZSBvZiB0eXBl

IDIgZGlhYmV0ZXMgaW4gbmV1cm9kZWdlbmVyYXRpb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+

TmV1cm9iaW9sIERpczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxs

LXRpdGxlPk5ldXJvYmlvbCBEaXM8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yMi0z

ODwvcGFnZXM+PHZvbHVtZT44NDwvdm9sdW1lPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9r

ZXl3b3JkPjxrZXl3b3JkPkJyYWluL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+RGlhYmV0

ZXMgTWVsbGl0dXMsIFR5cGUgMi8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8

L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9kZWdlbmVyYXRpdmUgRGlzZWFzZXMvKm1ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3

b3JkPkFteWxpbjwva2V5d29yZD48a2V5d29yZD5CZXRhIGFteWxvaWQ8L2tleXdvcmQ+PGtleXdv

cmQ+RGlhYmV0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9kZWdlbmVyYXRpb248L2tleXdvcmQ+

PGtleXdvcmQ+VGF1PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5EZWM8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMDk1

LTk1M1ggKEVsZWN0cm9uaWMpJiN4RDswOTY5LTk5NjEgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI1OTI2MzQ5PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI1OTI2MzQ5PC91cmw+PC9yZWxhdGVk

LXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2oubmJkLjIwMTUu

MDQuMDA4PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3Rl

Pn==

ADDIN EN.CITE.DATA 315,361,370,372,373. Similar results were recently reported with Lixisenatide PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdXNjb2dpdXJpPC9BdXRob3I+PFllYXI+MjAxNzwvWWVh

cj48UmVjTnVtPjM4OTA8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2Ny

aXB0Ij4zNzQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zODkwPC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MjMzODIiPjM4OTA8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk11c2NvZ2l1cmksIEcuPC9hdXRo

b3I+PGF1dGhvcj5EZUZyb256bywgUi4gQS48L2F1dGhvcj48YXV0aG9yPkdhc3RhbGRlbGxpLCBB

LjwvYXV0aG9yPjxhdXRob3I+SG9sc3QsIEouIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp

YnV0b3JzPjxhdXRoLWFkZHJlc3M+SW9zIGFuZCBDb2xlbWFuIE1lZGljaW5hIEZ1dHVyYSBNZWRp

Y2FsIENlbnRlciwgTmFwbGVzLCBJdGFseS4mI3hEO0RpYWJldGVzIERpdmlzaW9uLCBVbml2ZXJz

aXR5IG9mIFRleGFzIEhlYWx0aCBTY2llbmNlIENlbnRlciwgU2FuIEFudG9uaW8sIFRYLCBVU0Eu

JiN4RDtEaWFiZXRlcyBEaXZpc2lvbiwgVW5pdmVyc2l0eSBvZiBUZXhhcyBIZWFsdGggU2NpZW5j

ZSBDZW50ZXIsIFNhbiBBbnRvbmlvLCBUWCwgVVNBOyBJbnN0aXR1dGUgb2YgQ2xpbmljYWwgUGh5

c2lvbG9neSBvZiB0aGUgTmF0aW9uYWwgUmVzZWFyY2ggQ291bmNpbCAoQ05SKSwgUGlzYSwgSXRh

bHkuIEVsZWN0cm9uaWMgYWRkcmVzczogYW1hbGlhQGlmYy5jbnIuaXQuJiN4RDtOTkYgQ2VudGVy

IGZvciBCYXNpYyBNZXRhYm9saWMgUmVzZWFyY2ggYW5kIERlcGFydG1lbnQgb2YgQmlvbWVkaWNh

bCBTY2llbmNlcywgVGhlIFBhbnVtIEluc3RpdHV0ZSwgVW5pdmVyc2l0eSBvZiBDb3BlbmhhZ2Vu

LCBDb3BlbmhhZ2VuLCBEZW5tYXJrLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkdsdWNh

Z29uLWxpa2UgUGVwdGlkZS0xIGFuZCB0aGUgQ2VudHJhbC9QZXJpcGhlcmFsIE5lcnZvdXMgU3lz

dGVtOiBDcm9zc3RhbGsgaW4gRGlhYmV0ZXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+VHJlbmRz

IEVuZG9jcmlub2wgTWV0YWI8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+ODgtMTAz

PC9wYWdlcz48dm9sdW1lPjI4PC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGtleXdvcmRzPjxr

ZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2VudHJhbCBOZXJ2b3VzIFN5c3RlbS8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBNZWxsaXR1cy8qbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBNZWxsaXR1cywgVHlwZSAyL21ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y2Fnb24tTGlrZSBQZXB0aWRlIDEvKm1ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvZGVnZW5lcmF0aXZl

IERpc2Vhc2VzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UGVyaXBoZXJhbCBOZXJ2b3Vz

IFN5c3RlbS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD4qYXBwZXRpdGU8L2tleXdvcmQ+

PGtleXdvcmQ+KmNlbnRyYWwgbmVydm91cyBzeXN0ZW08L2tleXdvcmQ+PGtleXdvcmQ+KmdsdWNh

Z29uLWxpa2UgcGVwdGlkZS0xPC9rZXl3b3JkPjxrZXl3b3JkPipuZXVyb2RlZ2VuZXJhdGl2ZSBk

aXNlYXNlczwva2V5d29yZD48a2V5d29yZD4qdHlwZSAyIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5

d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5GZWI8L2RhdGU+

PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xODc5LTMwNjEgKEVsZWN0cm9uaWMpJiN4RDsxMDQz

LTI3NjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3ODcxNjc1PC9hY2Nlc3Npb24t

bnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3Yv

cHVibWVkLzI3ODcxNjc1PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4xMDE2L2oudGVtLjIwMTYuMTAuMDAxPC9lbGVjdHJvbmljLXJlc291cmNl

LW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdXNjb2dpdXJpPC9BdXRob3I+PFllYXI+MjAxNzwvWWVh

cj48UmVjTnVtPjM4OTA8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2Ny

aXB0Ij4zNzQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zODkwPC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MjMzODIiPjM4OTA8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk11c2NvZ2l1cmksIEcuPC9hdXRo

b3I+PGF1dGhvcj5EZUZyb256bywgUi4gQS48L2F1dGhvcj48YXV0aG9yPkdhc3RhbGRlbGxpLCBB

LjwvYXV0aG9yPjxhdXRob3I+SG9sc3QsIEouIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp

YnV0b3JzPjxhdXRoLWFkZHJlc3M+SW9zIGFuZCBDb2xlbWFuIE1lZGljaW5hIEZ1dHVyYSBNZWRp

Y2FsIENlbnRlciwgTmFwbGVzLCBJdGFseS4mI3hEO0RpYWJldGVzIERpdmlzaW9uLCBVbml2ZXJz

aXR5IG9mIFRleGFzIEhlYWx0aCBTY2llbmNlIENlbnRlciwgU2FuIEFudG9uaW8sIFRYLCBVU0Eu

JiN4RDtEaWFiZXRlcyBEaXZpc2lvbiwgVW5pdmVyc2l0eSBvZiBUZXhhcyBIZWFsdGggU2NpZW5j

ZSBDZW50ZXIsIFNhbiBBbnRvbmlvLCBUWCwgVVNBOyBJbnN0aXR1dGUgb2YgQ2xpbmljYWwgUGh5

c2lvbG9neSBvZiB0aGUgTmF0aW9uYWwgUmVzZWFyY2ggQ291bmNpbCAoQ05SKSwgUGlzYSwgSXRh

bHkuIEVsZWN0cm9uaWMgYWRkcmVzczogYW1hbGlhQGlmYy5jbnIuaXQuJiN4RDtOTkYgQ2VudGVy

IGZvciBCYXNpYyBNZXRhYm9saWMgUmVzZWFyY2ggYW5kIERlcGFydG1lbnQgb2YgQmlvbWVkaWNh

bCBTY2llbmNlcywgVGhlIFBhbnVtIEluc3RpdHV0ZSwgVW5pdmVyc2l0eSBvZiBDb3BlbmhhZ2Vu

LCBDb3BlbmhhZ2VuLCBEZW5tYXJrLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkdsdWNh

Z29uLWxpa2UgUGVwdGlkZS0xIGFuZCB0aGUgQ2VudHJhbC9QZXJpcGhlcmFsIE5lcnZvdXMgU3lz

dGVtOiBDcm9zc3RhbGsgaW4gRGlhYmV0ZXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+VHJlbmRz

IEVuZG9jcmlub2wgTWV0YWI8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+ODgtMTAz

PC9wYWdlcz48dm9sdW1lPjI4PC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGtleXdvcmRzPjxr

ZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2VudHJhbCBOZXJ2b3VzIFN5c3RlbS8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBNZWxsaXR1cy8qbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBNZWxsaXR1cywgVHlwZSAyL21ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y2Fnb24tTGlrZSBQZXB0aWRlIDEvKm1ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvZGVnZW5lcmF0aXZl

IERpc2Vhc2VzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UGVyaXBoZXJhbCBOZXJ2b3Vz

IFN5c3RlbS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD4qYXBwZXRpdGU8L2tleXdvcmQ+

PGtleXdvcmQ+KmNlbnRyYWwgbmVydm91cyBzeXN0ZW08L2tleXdvcmQ+PGtleXdvcmQ+KmdsdWNh

Z29uLWxpa2UgcGVwdGlkZS0xPC9rZXl3b3JkPjxrZXl3b3JkPipuZXVyb2RlZ2VuZXJhdGl2ZSBk

aXNlYXNlczwva2V5d29yZD48a2V5d29yZD4qdHlwZSAyIGRpYWJldGVzPC9rZXl3b3JkPjwva2V5

d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5GZWI8L2RhdGU+

PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xODc5LTMwNjEgKEVsZWN0cm9uaWMpJiN4RDsxMDQz

LTI3NjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3ODcxNjc1PC9hY2Nlc3Npb24t

bnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3Yv

cHVibWVkLzI3ODcxNjc1PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4xMDE2L2oudGVtLjIwMTYuMTAuMDAxPC9lbGVjdHJvbmljLXJlc291cmNl

LW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 374.Results are awaited from the two recently completed clinical trials on Exendin-4 (Phase II; NCT01255163; involving MCI or mild AD individuals, aged ≥60 years) and Liraglutide (Small randomized; NCT01469351; involving early-onset AD patients), as well as from a recently started large-scale, phase II clinical trial on Liraglutide in early AD patients, aged 50–85 years (ELAD, NCT01843075). The novel and still unexplored anti-AD therapeutic potential of SGLT2 inhibitorsThe main SGLT2 inhibitors used to treat T2D are Empagliflozin and Dapagliflozin. Although they exert their glucose-lowering effects mainly through a novel, insulin-independent mechanism (via increased renal glycosuria), one cannot exclude the increase in peripheral insulin sensitivity, GLP-1 levels and/or β-cell function PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWNrc3RlaW48L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFy

PjxSZWNOdW0+MzgxODwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjMzMiwzNzUtMzc5PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+

MzgxODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTBy

eDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5Mjg5Ij4z

ODE4PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+

MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LaWNrc3RlaW4sIEUu

PC9hdXRob3I+PGF1dGhvcj5LcmF1c3MsIFMuPC9hdXRob3I+PGF1dGhvcj5UaG9ybmhpbGwsIFAu

PC9hdXRob3I+PGF1dGhvcj5SdXRzY2hvdywgRC48L2F1dGhvcj48YXV0aG9yPlplbGxlciwgUi48

L2F1dGhvcj48YXV0aG9yPlNoYXJrZXksIEouPC9hdXRob3I+PGF1dGhvcj5XaWxsaWFtc29uLCBS

LjwvYXV0aG9yPjxhdXRob3I+RnVjaHMsIE0uPC9hdXRob3I+PGF1dGhvcj5Lb2hsZXIsIEEuPC9h

dXRob3I+PGF1dGhvcj5HbG9zc21hbm4sIEguPC9hdXRob3I+PGF1dGhvcj5TY2huZWlkZXIsIFIu

PC9hdXRob3I+PGF1dGhvcj5TdXRoZXJsYW5kLCBDLjwvYXV0aG9yPjxhdXRob3I+U2Nod2VpZ2Vy

LCBTLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPk1heC1Q

bGFuY2sgSW5zdGl0dXRlIGZvciBNb2xlY3VsYXIgR2VuZXRpY3MsMTQxOTUgQmVybGluLCBHZXJt

YW55LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkJpZ3VhbmlkZSBtZXRmb3JtaW4gYWN0

cyBvbiB0YXUgcGhvc3Bob3J5bGF0aW9uIHZpYSBtVE9SL3Byb3RlaW4gcGhvc3BoYXRhc2UgMkEg

KFBQMkEpIHNpZ25hbGluZzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Qcm9jIE5hdGwgQWNhZCBT

Y2kgVSBTIEE8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRs

ZT5Qcm9jIE5hdGwgQWNhZCBTY2kgVSBTIEE8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdl

cz4yMTgzMC01PC9wYWdlcz48dm9sdW1lPjEwNzwvdm9sdW1lPjxudW1iZXI+NTA8L251bWJlcj48

a2V5d29yZHM+PGtleXdvcmQ+QWRlbnlsYXRlIEtpbmFzZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxr

ZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL21ldGFib2xpc20vcGF0aG9sb2d5L3BoeXNpb3BhdGhv

bG9neTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGxzLCBD

dWx0dXJlZDwva2V5d29yZD48a2V5d29yZD5Fbnp5bWUgSW5oaWJpdG9ycy9waGFybWFjb2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+RXBpdG9wZXM8L2tleXdvcmQ+PGtleXdvcmQ+SGVMYSBDZWxsczwv

a2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlwb2dseWNlbWljIEFn

ZW50cy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWVjaGFuaXN0aWMgVGFyZ2V0IG9m

IFJhcGFteWNpbiBDb21wbGV4IDE8L2tleXdvcmQ+PGtleXdvcmQ+TWV0Zm9ybWluLypwaGFybWFj

b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFu

c2dlbmljPC9rZXl3b3JkPjxrZXl3b3JkPk11bHRpcHJvdGVpbiBDb21wbGV4ZXM8L2tleXdvcmQ+

PGtleXdvcmQ+TmV1cm9maWJyaWxsYXJ5IFRhbmdsZXMvKm1ldGFib2xpc20vcGF0aG9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPk5ldXJvbnMvY3l0b2xvZ3kvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5Pa2FkYWljIEFjaWQvcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBob3NwaG9y

eWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5Qcm90ZWluIFBob3NwaGF0YXNlIDIvZ2VuZXRpY3Mv

Km1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVpbnMvbWV0YWJvbGlzbTwva2V5d29y

ZD48a2V5d29yZD5TaWduYWwgVHJhbnNkdWN0aW9uL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5

d29yZD5UT1IgU2VyaW5lLVRocmVvbmluZSBLaW5hc2VzL2dlbmV0aWNzLyptZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPnRhdSBQcm90ZWlucy9nZW5ldGljcy8qbWV0YWJvbGlzbTwva2V5d29y

ZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RGVj

IDE0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA5MS02NDkwIChFbGVjdHJvbmlj

KSYjeEQ7MDAyNy04NDI0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMTA5ODI4Nzwv

YWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5s

bS5uaWguZ292L3B1Ym1lZC8yMTA5ODI4NzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3Vz

dG9tMj5QTUMzMDAzMDcyPC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDcz

L3BuYXMuMDkxMjc5MzEwNzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRl

PjxDaXRlPjxBdXRob3I+TWFqZXdza2k8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNOdW0+

MzgwODwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MzgwODwvcmVjLW51bWJlcj48Zm9yZWln

bi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6

cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5Ij4zODA4PC9rZXk+PC9mb3JlaWduLWtleXM+

PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRv

cnM+PGF1dGhvcnM+PGF1dGhvcj5NYWpld3NraSwgQ29sbGVlbjwvYXV0aG9yPjxhdXRob3I+QmFr

cmlzLCBHZW9yZ2UgTC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48

dGl0bGU+Qmxvb2QgUHJlc3N1cmUgUmVkdWN0aW9uOiBBbiBBZGRlZCBCZW5lZml0IG9mIFNvZGl1

beKAk0dsdWNvc2UgQ290cmFuc3BvcnRlciAyIEluaGliaXRvcnMgaW4gUGF0aWVudHMgV2l0aCBU

eXBlIDIgRGlhYmV0ZXM6IFRhYmxlIDE8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+RGlhYmV0ZXMg

Q2FyZTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz40MjktNDMwPC9wYWdlcz48dm9s

dW1lPjM4PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT4yMDE1LzAyLzI0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1

Ymxpc2hlcj5BbWVyaWNhbiBEaWFiZXRlcyBBc3NvY2lhdGlvbjwvcHVibGlzaGVyPjxpc2JuPjAx

NDktNTk5MiYjeEQ7MTkzNS01NTQ4PC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRw

Oi8vZHguZG9pLm9yZy8xMC4yMzM3L2RjMTQtMTU5NjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMjMzNy9kYzE0LTE1OTY8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlNvbGluaTwvQXV0aG9y

PjxZZWFyPjIwMTU8L1llYXI+PFJlY051bT4zODEwPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJl

cj4zODEwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndh

MHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTkxMTki

PjM4MTA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xl

Ij4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNvbGluaSwgQW5u

YTwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5FeHRyYS1n

bHljYWVtaWMgcHJvcGVydGllcyBvZiBlbXBhZ2xpZmxvemluPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPkRpYWJldGVzL01ldGFib2xpc20gUmVzZWFyY2ggYW5kIFJldmlld3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+MjMwLTIzNzwvcGFnZXM+PHZvbHVtZT4zMjwvdm9sdW1lPjxu

dW1iZXI+MzwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDE1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

MjAxNS8wNi8yNTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxwdWJsaXNoZXI+V2lsZXk8L3B1

Ymxpc2hlcj48aXNibj4xNTIwLTc1NTI8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0

dHA6Ly9keC5kb2kub3JnLzEwLjEwMDIvZG1yci4yNjY2PC91cmw+PC9yZWxhdGVkLXVybHM+PC91

cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDAyL2RtcnIuMjY2NjwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Q2FpPC9BdXRob3I+

PFllYXI+MjAxNzwvWWVhcj48UmVjTnVtPjM4OTE8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVy

PjM4OTE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ew

cng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkyMzY4OCI+

Mzg5MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi

PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Q2FpLCBILiBZLjwv

YXV0aG9yPjxhdXRob3I+V2FuZywgWi4gSi48L2F1dGhvcj48YXV0aG9yPkhvbHNjaGVyLCBDLjwv

YXV0aG9yPjxhdXRob3I+WXVhbiwgTC48L2F1dGhvcj48YXV0aG9yPlpoYW5nLCBKLjwvYXV0aG9y

PjxhdXRob3I+U3VuLCBQLjwvYXV0aG9yPjxhdXRob3I+TGksIEouPC9hdXRob3I+PGF1dGhvcj5Z

YW5nLCBXLjwvYXV0aG9yPjxhdXRob3I+V3UsIE0uIE4uPC9hdXRob3I+PGF1dGhvcj5RaSwgSi4g

Uy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRt

ZW50IG9mIE1pY3JvYmlvbG9neSBhbmQgSW1tdW5vbG9neSwgU2hhbnhpIE1lZGljYWwgVW5pdmVy

c2l0eSwgVGFpeXVhbiAwMzAwMDEsIENoaW5hLiYjeEQ7RGVwYXJ0bWVudCBvZiBQaHlzaW9sb2d5

LCBTaGFueGkgTWVkaWNhbCBVbml2ZXJzaXR5LCBUYWl5dWFuIDAzMDAwMSwgQ2hpbmEuJiN4RDtE

aXZpc2lvbiBvZiBCaW9tZWQgYW5kIExpZmUgU2NpZW5jZXMsIEZhY3VsdHkgb2YgSGVhbHRoIGFu

ZCBNZWRpY2luZSBMYW5jYXN0ZXIgVW5pdmVyc2l0eSwgTGFuY2FzdGVyLCBMQTEgNFlRLCBVSy4m

I3hEO0RlcGFydG1lbnQgb2YgUGh5c2lvbG9neSwgU2hhbnhpIE1lZGljYWwgVW5pdmVyc2l0eSwg

VGFpeXVhbiAwMzAwMDEsIENoaW5hLiBFbGVjdHJvbmljIGFkZHJlc3M6IGppbnNodW5xaTIwMDlA

MTYzLmNvbS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5MaXhpc2VuYXRpZGUgYXR0ZW51

YXRlcyB0aGUgZGV0cmltZW50YWwgZWZmZWN0cyBvZiBhbXlsb2lkIGJldGEgcHJvdGVpbiBvbiBz

cGF0aWFsIHdvcmtpbmcgbWVtb3J5IGFuZCBoaXBwb2NhbXBhbCBuZXVyb25zIGluIHJhdHM8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+QmVoYXYgQnJhaW4gUmVzPC9zZWNvbmRhcnktdGl0bGU+PC90

aXRsZXM+PHBhZ2VzPjI4LTM1PC9wYWdlcz48dm9sdW1lPjMxODwvdm9sdW1lPjxrZXl3b3Jkcz48

a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvKmFudGFnb25pc3RzICZhbXA7IGluaGliaXRv

cnMvcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdv

cmQ+QnV0YWRpZW5lcy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2FsY2l1bS9tZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgU3Vydml2YWwvZHJ1ZyBlZmZlY3RzPC9rZXl3

b3JkPjxrZXl3b3JkPkhpcHBvY2FtcHVzLypkcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+

TWF6ZSBMZWFybmluZy9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+TWVtb3J5LCBTaG9y

dC1UZXJtLypkcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9ucy9kcnVnIGVmZmVj

dHM8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9wcm90ZWN0aXZlIEFnZW50cy9waGFybWFjb2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+Tml0cmlsZXMvcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PlBlcHRpZGUgRnJhZ21lbnRzLyphbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzL3BoYXJtYWNv

bG9neTwva2V5d29yZD48a2V5d29yZD5QZXB0aWRlcy8qcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPlByaW1hcnkgQ2VsbCBDdWx0dXJlPC9rZXl3b3JkPjxrZXl3b3JkPlJhdHM8L2tleXdv

cmQ+PGtleXdvcmQ+U2lnbmFsIFRyYW5zZHVjdGlvbi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtl

eXdvcmQ+KkFrdC1NRUsxLzIgc2lnbmFsIHBhdGh3YXk8L2tleXdvcmQ+PGtleXdvcmQ+KkFteWxv

aWQgYmV0YSBwcm90ZWluPC9rZXl3b3JkPjxrZXl3b3JkPipDZWxsIHZpYWJpbGl0eTwva2V5d29y

ZD48a2V5d29yZD4qSW50cmFjZWxsdWxhciBjYWxjaXVtIGNvbmNlbnRyYXRpb248L2tleXdvcmQ+

PGtleXdvcmQ+KkxpeGlzZW5hdGlkZTwva2V5d29yZD48a2V5d29yZD4qV29ya2luZyBtZW1vcnk8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxk

YXRlPkZlYiAxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTg3Mi03NTQ5IChFbGVj

dHJvbmljKSYjeEQ7MDE2Ni00MzI4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNzc3

Njk5MzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNzc3Njk5MzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmJici4yMDE2LjEwLjAzMzwvZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+RmVycmFu

bmluaTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJlY051bT4zODkyPC9SZWNOdW0+PHJlY29y

ZD48cmVjLW51bWJlcj4zODkyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9

IjE1MzU5MjM3NjEiPjM4OTI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PkZlcnJhbm5pbmksIEUuPC9hdXRob3I+PGF1dGhvcj5NdXNjZWxsaSwgRS48L2F1dGhvcj48YXV0

aG9yPkZyYXNjZXJyYSwgUy48L2F1dGhvcj48YXV0aG9yPkJhbGRpLCBTLjwvYXV0aG9yPjxhdXRo

b3I+TWFyaSwgQS48L2F1dGhvcj48YXV0aG9yPkhlaXNlLCBULjwvYXV0aG9yPjxhdXRob3I+QnJv

ZWRsLCBVLiBDLjwvYXV0aG9yPjxhdXRob3I+V29lcmxlLCBILiBKLjwvYXV0aG9yPjwvYXV0aG9y

cz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5NZXRhYm9saWMgcmVzcG9uc2UgdG8gc29k

aXVtLWdsdWNvc2UgY290cmFuc3BvcnRlciAyIGluaGliaXRpb24gaW4gdHlwZSAyIGRpYWJldGlj

IHBhdGllbnRzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogQ2xpbiBJbnZlc3Q8L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGFnZXM+NDk5LTUwODwvcGFnZXM+PHZvbHVtZT4xMjQ8L3ZvbHVt

ZT48bnVtYmVyPjI8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5

d29yZD5BcmVhIFVuZGVyIEN1cnZlPC9rZXl3b3JkPjxrZXl3b3JkPkJlbnpoeWRyeWwgQ29tcG91

bmRzLyp0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+Qmxvb2QgR2x1Y29zZS9hbmFs

eXNpczwva2V5d29yZD48a2V5d29yZD5Cb2R5IE1hc3MgSW5kZXg8L2tleXdvcmQ+PGtleXdvcmQ+

Q2Fsb3JpbWV0cnkvbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBNZWxsaXR1cywg

VHlwZSAyLypkcnVnIHRoZXJhcHkvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8

L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y29zZS9hZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2U8L2tl

eXdvcmQ+PGtleXdvcmQ+R2x1Y29zaWRlcy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3

b3JkPkdseWNhdGVkIEhlbW9nbG9iaW4gQS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkds

eWNvc3VyaWEvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtl

eXdvcmQ+SW5zdWxpbi9hbmFseXNpcy9ibG9vZDwva2V5d29yZD48a2V5d29yZD5JbnN1bGluLVNl

Y3JldGluZyBDZWxscy9jeXRvbG9neS9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFs

ZTwva2V5d29yZD48a2V5d29yZD5NZXRmb3JtaW4vdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxr

ZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPk94eWdlbi9jaGVtaXN0cnk8L2tl

eXdvcmQ+PGtleXdvcmQ+UG9zdHByYW5kaWFsIFBlcmlvZDwva2V5d29yZD48a2V5d29yZD5Tb2Rp

dW0tR2x1Y29zZSBUcmFuc3BvcnRlciAyLyphbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzL21l

dGFib2xpc208L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48cHVi

LWRhdGVzPjxkYXRlPkZlYjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTgtODIz

OCAoRWxlY3Ryb25pYykmI3hEOzAwMjEtOTczOCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1u

dW0+MjQ0NjM0NTQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6

Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjQ0NjM0NTQ8L3VybD48L3JlbGF0ZWQtdXJs

cz48L3VybHM+PGN1c3RvbTI+UE1DMzkwNDYyNzwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJj

ZS1udW0+MTAuMTE3Mi9KQ0k3MjIyNzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+

PC9DaXRlPjxDaXRlPjxBdXRob3I+U29saW5pPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVj

TnVtPjM4OTM8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM4OTM8L3JlYy1udW1iZXI+PGZv

cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6

dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkyMzkzMSI+Mzg5Mzwva2V5PjwvZm9yZWlnbi1r

ZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJp

YnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U29saW5pLCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2Nv

bnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgQ2xpbmljYWwgYW5kIEV4cGVy

aW1lbnRhbCBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBQaXNhLCBQaXNhLCBJdGFseS48L2F1dGgt

YWRkcmVzcz48dGl0bGVzPjx0aXRsZT5FeHRyYS1nbHljYWVtaWMgcHJvcGVydGllcyBvZiBlbXBh

Z2xpZmxvemluPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkRpYWJldGVzIE1ldGFiIFJlcyBSZXY8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MjMwLTc8L3BhZ2VzPjx2b2x1bWU+MzI8

L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QmVuemh5ZHJ5bCBD

b21wb3VuZHMvKnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBNZWxs

aXR1cywgVHlwZSAyLypkcnVnIHRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y29zaWRlcy8q

dGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29y

ZD5IeXBlcmdseWNlbWlhLypwcmV2ZW50aW9uICZhbXA7IGNvbnRyb2w8L2tleXdvcmQ+PGtleXdv

cmQ+SHlwb2dseWNlbWljIEFnZW50cy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3Jk

PlNHTFQyIGluaGliaXRvcnM8L2tleXdvcmQ+PGtleXdvcmQ+Ymxvb2QgcHJlc3N1cmU8L2tleXdv

cmQ+PGtleXdvcmQ+Ym9keSB3ZWlnaHQ8L2tleXdvcmQ+PGtleXdvcmQ+bmVwaHJvcHJvdGVjdGlv

bjwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+

PGRhdGU+TWFyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUyMC03NTYwIChFbGVj

dHJvbmljKSYjeEQ7MTUyMC03NTUyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNTk5

NDUxMzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNTk5NDUxMzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwMi9kbXJyLjI2NjY8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWNrc3RlaW48L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFy

PjxSZWNOdW0+MzgxODwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjMzMiwzNzUtMzc5PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+

MzgxODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTBy

eDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5Mjg5Ij4z

ODE4PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+

MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LaWNrc3RlaW4sIEUu

PC9hdXRob3I+PGF1dGhvcj5LcmF1c3MsIFMuPC9hdXRob3I+PGF1dGhvcj5UaG9ybmhpbGwsIFAu

PC9hdXRob3I+PGF1dGhvcj5SdXRzY2hvdywgRC48L2F1dGhvcj48YXV0aG9yPlplbGxlciwgUi48

L2F1dGhvcj48YXV0aG9yPlNoYXJrZXksIEouPC9hdXRob3I+PGF1dGhvcj5XaWxsaWFtc29uLCBS

LjwvYXV0aG9yPjxhdXRob3I+RnVjaHMsIE0uPC9hdXRob3I+PGF1dGhvcj5Lb2hsZXIsIEEuPC9h

dXRob3I+PGF1dGhvcj5HbG9zc21hbm4sIEguPC9hdXRob3I+PGF1dGhvcj5TY2huZWlkZXIsIFIu

PC9hdXRob3I+PGF1dGhvcj5TdXRoZXJsYW5kLCBDLjwvYXV0aG9yPjxhdXRob3I+U2Nod2VpZ2Vy

LCBTLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPk1heC1Q

bGFuY2sgSW5zdGl0dXRlIGZvciBNb2xlY3VsYXIgR2VuZXRpY3MsMTQxOTUgQmVybGluLCBHZXJt

YW55LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkJpZ3VhbmlkZSBtZXRmb3JtaW4gYWN0

cyBvbiB0YXUgcGhvc3Bob3J5bGF0aW9uIHZpYSBtVE9SL3Byb3RlaW4gcGhvc3BoYXRhc2UgMkEg

KFBQMkEpIHNpZ25hbGluZzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Qcm9jIE5hdGwgQWNhZCBT

Y2kgVSBTIEE8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRs

ZT5Qcm9jIE5hdGwgQWNhZCBTY2kgVSBTIEE8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdl

cz4yMTgzMC01PC9wYWdlcz48dm9sdW1lPjEwNzwvdm9sdW1lPjxudW1iZXI+NTA8L251bWJlcj48

a2V5d29yZHM+PGtleXdvcmQ+QWRlbnlsYXRlIEtpbmFzZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxr

ZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL21ldGFib2xpc20vcGF0aG9sb2d5L3BoeXNpb3BhdGhv

bG9neTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGxzLCBD

dWx0dXJlZDwva2V5d29yZD48a2V5d29yZD5Fbnp5bWUgSW5oaWJpdG9ycy9waGFybWFjb2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+RXBpdG9wZXM8L2tleXdvcmQ+PGtleXdvcmQ+SGVMYSBDZWxsczwv

a2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlwb2dseWNlbWljIEFn

ZW50cy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWVjaGFuaXN0aWMgVGFyZ2V0IG9m

IFJhcGFteWNpbiBDb21wbGV4IDE8L2tleXdvcmQ+PGtleXdvcmQ+TWV0Zm9ybWluLypwaGFybWFj

b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFu

c2dlbmljPC9rZXl3b3JkPjxrZXl3b3JkPk11bHRpcHJvdGVpbiBDb21wbGV4ZXM8L2tleXdvcmQ+

PGtleXdvcmQ+TmV1cm9maWJyaWxsYXJ5IFRhbmdsZXMvKm1ldGFib2xpc20vcGF0aG9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPk5ldXJvbnMvY3l0b2xvZ3kvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5Pa2FkYWljIEFjaWQvcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBob3NwaG9y

eWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5Qcm90ZWluIFBob3NwaGF0YXNlIDIvZ2VuZXRpY3Mv

Km1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVpbnMvbWV0YWJvbGlzbTwva2V5d29y

ZD48a2V5d29yZD5TaWduYWwgVHJhbnNkdWN0aW9uL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5

d29yZD5UT1IgU2VyaW5lLVRocmVvbmluZSBLaW5hc2VzL2dlbmV0aWNzLyptZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPnRhdSBQcm90ZWlucy9nZW5ldGljcy8qbWV0YWJvbGlzbTwva2V5d29y

ZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RGVj

IDE0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA5MS02NDkwIChFbGVjdHJvbmlj

KSYjeEQ7MDAyNy04NDI0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMTA5ODI4Nzwv

YWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5s

bS5uaWguZ292L3B1Ym1lZC8yMTA5ODI4NzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3Vz

dG9tMj5QTUMzMDAzMDcyPC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDcz

L3BuYXMuMDkxMjc5MzEwNzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRl

PjxDaXRlPjxBdXRob3I+TWFqZXdza2k8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNOdW0+

MzgwODwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MzgwODwvcmVjLW51bWJlcj48Zm9yZWln

bi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6

cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTE5MTE5Ij4zODA4PC9rZXk+PC9mb3JlaWduLWtleXM+

PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRv

cnM+PGF1dGhvcnM+PGF1dGhvcj5NYWpld3NraSwgQ29sbGVlbjwvYXV0aG9yPjxhdXRob3I+QmFr

cmlzLCBHZW9yZ2UgTC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48

dGl0bGU+Qmxvb2QgUHJlc3N1cmUgUmVkdWN0aW9uOiBBbiBBZGRlZCBCZW5lZml0IG9mIFNvZGl1

beKAk0dsdWNvc2UgQ290cmFuc3BvcnRlciAyIEluaGliaXRvcnMgaW4gUGF0aWVudHMgV2l0aCBU

eXBlIDIgRGlhYmV0ZXM6IFRhYmxlIDE8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+RGlhYmV0ZXMg

Q2FyZTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz40MjktNDMwPC9wYWdlcz48dm9s

dW1lPjM4PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT4yMDE1LzAyLzI0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1

Ymxpc2hlcj5BbWVyaWNhbiBEaWFiZXRlcyBBc3NvY2lhdGlvbjwvcHVibGlzaGVyPjxpc2JuPjAx

NDktNTk5MiYjeEQ7MTkzNS01NTQ4PC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRw

Oi8vZHguZG9pLm9yZy8xMC4yMzM3L2RjMTQtMTU5NjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMjMzNy9kYzE0LTE1OTY8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlNvbGluaTwvQXV0aG9y

PjxZZWFyPjIwMTU8L1llYXI+PFJlY051bT4zODEwPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJl

cj4zODEwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndh

MHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MTkxMTki

PjM4MTA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xl

Ij4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNvbGluaSwgQW5u

YTwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5FeHRyYS1n

bHljYWVtaWMgcHJvcGVydGllcyBvZiBlbXBhZ2xpZmxvemluPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPkRpYWJldGVzL01ldGFib2xpc20gUmVzZWFyY2ggYW5kIFJldmlld3M8L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+MjMwLTIzNzwvcGFnZXM+PHZvbHVtZT4zMjwvdm9sdW1lPjxu

dW1iZXI+MzwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDE1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

MjAxNS8wNi8yNTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxwdWJsaXNoZXI+V2lsZXk8L3B1

Ymxpc2hlcj48aXNibj4xNTIwLTc1NTI8L2lzYm4+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0

dHA6Ly9keC5kb2kub3JnLzEwLjEwMDIvZG1yci4yNjY2PC91cmw+PC9yZWxhdGVkLXVybHM+PC91

cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDAyL2RtcnIuMjY2NjwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Q2FpPC9BdXRob3I+

PFllYXI+MjAxNzwvWWVhcj48UmVjTnVtPjM4OTE8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVy

PjM4OTE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ew

cng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkyMzY4OCI+

Mzg5MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi

PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Q2FpLCBILiBZLjwv

YXV0aG9yPjxhdXRob3I+V2FuZywgWi4gSi48L2F1dGhvcj48YXV0aG9yPkhvbHNjaGVyLCBDLjwv

YXV0aG9yPjxhdXRob3I+WXVhbiwgTC48L2F1dGhvcj48YXV0aG9yPlpoYW5nLCBKLjwvYXV0aG9y

PjxhdXRob3I+U3VuLCBQLjwvYXV0aG9yPjxhdXRob3I+TGksIEouPC9hdXRob3I+PGF1dGhvcj5Z

YW5nLCBXLjwvYXV0aG9yPjxhdXRob3I+V3UsIE0uIE4uPC9hdXRob3I+PGF1dGhvcj5RaSwgSi4g

Uy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRt

ZW50IG9mIE1pY3JvYmlvbG9neSBhbmQgSW1tdW5vbG9neSwgU2hhbnhpIE1lZGljYWwgVW5pdmVy

c2l0eSwgVGFpeXVhbiAwMzAwMDEsIENoaW5hLiYjeEQ7RGVwYXJ0bWVudCBvZiBQaHlzaW9sb2d5

LCBTaGFueGkgTWVkaWNhbCBVbml2ZXJzaXR5LCBUYWl5dWFuIDAzMDAwMSwgQ2hpbmEuJiN4RDtE

aXZpc2lvbiBvZiBCaW9tZWQgYW5kIExpZmUgU2NpZW5jZXMsIEZhY3VsdHkgb2YgSGVhbHRoIGFu

ZCBNZWRpY2luZSBMYW5jYXN0ZXIgVW5pdmVyc2l0eSwgTGFuY2FzdGVyLCBMQTEgNFlRLCBVSy4m

I3hEO0RlcGFydG1lbnQgb2YgUGh5c2lvbG9neSwgU2hhbnhpIE1lZGljYWwgVW5pdmVyc2l0eSwg

VGFpeXVhbiAwMzAwMDEsIENoaW5hLiBFbGVjdHJvbmljIGFkZHJlc3M6IGppbnNodW5xaTIwMDlA

MTYzLmNvbS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5MaXhpc2VuYXRpZGUgYXR0ZW51

YXRlcyB0aGUgZGV0cmltZW50YWwgZWZmZWN0cyBvZiBhbXlsb2lkIGJldGEgcHJvdGVpbiBvbiBz

cGF0aWFsIHdvcmtpbmcgbWVtb3J5IGFuZCBoaXBwb2NhbXBhbCBuZXVyb25zIGluIHJhdHM8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+QmVoYXYgQnJhaW4gUmVzPC9zZWNvbmRhcnktdGl0bGU+PC90

aXRsZXM+PHBhZ2VzPjI4LTM1PC9wYWdlcz48dm9sdW1lPjMxODwvdm9sdW1lPjxrZXl3b3Jkcz48

a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvKmFudGFnb25pc3RzICZhbXA7IGluaGliaXRv

cnMvcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdv

cmQ+QnV0YWRpZW5lcy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2FsY2l1bS9tZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgU3Vydml2YWwvZHJ1ZyBlZmZlY3RzPC9rZXl3

b3JkPjxrZXl3b3JkPkhpcHBvY2FtcHVzLypkcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+

TWF6ZSBMZWFybmluZy9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+TWVtb3J5LCBTaG9y

dC1UZXJtLypkcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9ucy9kcnVnIGVmZmVj

dHM8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9wcm90ZWN0aXZlIEFnZW50cy9waGFybWFjb2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+Tml0cmlsZXMvcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PlBlcHRpZGUgRnJhZ21lbnRzLyphbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzL3BoYXJtYWNv

bG9neTwva2V5d29yZD48a2V5d29yZD5QZXB0aWRlcy8qcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPlByaW1hcnkgQ2VsbCBDdWx0dXJlPC9rZXl3b3JkPjxrZXl3b3JkPlJhdHM8L2tleXdv

cmQ+PGtleXdvcmQ+U2lnbmFsIFRyYW5zZHVjdGlvbi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtl

eXdvcmQ+KkFrdC1NRUsxLzIgc2lnbmFsIHBhdGh3YXk8L2tleXdvcmQ+PGtleXdvcmQ+KkFteWxv

aWQgYmV0YSBwcm90ZWluPC9rZXl3b3JkPjxrZXl3b3JkPipDZWxsIHZpYWJpbGl0eTwva2V5d29y

ZD48a2V5d29yZD4qSW50cmFjZWxsdWxhciBjYWxjaXVtIGNvbmNlbnRyYXRpb248L2tleXdvcmQ+

PGtleXdvcmQ+KkxpeGlzZW5hdGlkZTwva2V5d29yZD48a2V5d29yZD4qV29ya2luZyBtZW1vcnk8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxk

YXRlPkZlYiAxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTg3Mi03NTQ5IChFbGVj

dHJvbmljKSYjeEQ7MDE2Ni00MzI4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNzc3

Njk5MzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNzc3Njk5MzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmJici4yMDE2LjEwLjAzMzwvZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+RmVycmFu

bmluaTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJlY051bT4zODkyPC9SZWNOdW0+PHJlY29y

ZD48cmVjLW51bWJlcj4zODkyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9

IjE1MzU5MjM3NjEiPjM4OTI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PkZlcnJhbm5pbmksIEUuPC9hdXRob3I+PGF1dGhvcj5NdXNjZWxsaSwgRS48L2F1dGhvcj48YXV0

aG9yPkZyYXNjZXJyYSwgUy48L2F1dGhvcj48YXV0aG9yPkJhbGRpLCBTLjwvYXV0aG9yPjxhdXRo

b3I+TWFyaSwgQS48L2F1dGhvcj48YXV0aG9yPkhlaXNlLCBULjwvYXV0aG9yPjxhdXRob3I+QnJv

ZWRsLCBVLiBDLjwvYXV0aG9yPjxhdXRob3I+V29lcmxlLCBILiBKLjwvYXV0aG9yPjwvYXV0aG9y

cz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5NZXRhYm9saWMgcmVzcG9uc2UgdG8gc29k

aXVtLWdsdWNvc2UgY290cmFuc3BvcnRlciAyIGluaGliaXRpb24gaW4gdHlwZSAyIGRpYWJldGlj

IHBhdGllbnRzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogQ2xpbiBJbnZlc3Q8L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGFnZXM+NDk5LTUwODwvcGFnZXM+PHZvbHVtZT4xMjQ8L3ZvbHVt

ZT48bnVtYmVyPjI8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5

d29yZD5BcmVhIFVuZGVyIEN1cnZlPC9rZXl3b3JkPjxrZXl3b3JkPkJlbnpoeWRyeWwgQ29tcG91

bmRzLyp0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+Qmxvb2QgR2x1Y29zZS9hbmFs

eXNpczwva2V5d29yZD48a2V5d29yZD5Cb2R5IE1hc3MgSW5kZXg8L2tleXdvcmQ+PGtleXdvcmQ+

Q2Fsb3JpbWV0cnkvbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBNZWxsaXR1cywg

VHlwZSAyLypkcnVnIHRoZXJhcHkvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8

L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y29zZS9hZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2U8L2tl

eXdvcmQ+PGtleXdvcmQ+R2x1Y29zaWRlcy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3

b3JkPkdseWNhdGVkIEhlbW9nbG9iaW4gQS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkds

eWNvc3VyaWEvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtl

eXdvcmQ+SW5zdWxpbi9hbmFseXNpcy9ibG9vZDwva2V5d29yZD48a2V5d29yZD5JbnN1bGluLVNl

Y3JldGluZyBDZWxscy9jeXRvbG9neS9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFs

ZTwva2V5d29yZD48a2V5d29yZD5NZXRmb3JtaW4vdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxr

ZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPk94eWdlbi9jaGVtaXN0cnk8L2tl

eXdvcmQ+PGtleXdvcmQ+UG9zdHByYW5kaWFsIFBlcmlvZDwva2V5d29yZD48a2V5d29yZD5Tb2Rp

dW0tR2x1Y29zZSBUcmFuc3BvcnRlciAyLyphbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzL21l

dGFib2xpc208L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48cHVi

LWRhdGVzPjxkYXRlPkZlYjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTgtODIz

OCAoRWxlY3Ryb25pYykmI3hEOzAwMjEtOTczOCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1u

dW0+MjQ0NjM0NTQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6

Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjQ0NjM0NTQ8L3VybD48L3JlbGF0ZWQtdXJs

cz48L3VybHM+PGN1c3RvbTI+UE1DMzkwNDYyNzwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJj

ZS1udW0+MTAuMTE3Mi9KQ0k3MjIyNzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+

PC9DaXRlPjxDaXRlPjxBdXRob3I+U29saW5pPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVj

TnVtPjM4OTM8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM4OTM8L3JlYy1udW1iZXI+PGZv

cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6

dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkyMzkzMSI+Mzg5Mzwva2V5PjwvZm9yZWlnbi1r

ZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJp

YnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U29saW5pLCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2Nv

bnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgQ2xpbmljYWwgYW5kIEV4cGVy

aW1lbnRhbCBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBQaXNhLCBQaXNhLCBJdGFseS48L2F1dGgt

YWRkcmVzcz48dGl0bGVzPjx0aXRsZT5FeHRyYS1nbHljYWVtaWMgcHJvcGVydGllcyBvZiBlbXBh

Z2xpZmxvemluPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkRpYWJldGVzIE1ldGFiIFJlcyBSZXY8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MjMwLTc8L3BhZ2VzPjx2b2x1bWU+MzI8

L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QmVuemh5ZHJ5bCBD

b21wb3VuZHMvKnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBNZWxs

aXR1cywgVHlwZSAyLypkcnVnIHRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y29zaWRlcy8q

dGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29y

ZD5IeXBlcmdseWNlbWlhLypwcmV2ZW50aW9uICZhbXA7IGNvbnRyb2w8L2tleXdvcmQ+PGtleXdv

cmQ+SHlwb2dseWNlbWljIEFnZW50cy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3Jk

PlNHTFQyIGluaGliaXRvcnM8L2tleXdvcmQ+PGtleXdvcmQ+Ymxvb2QgcHJlc3N1cmU8L2tleXdv

cmQ+PGtleXdvcmQ+Ym9keSB3ZWlnaHQ8L2tleXdvcmQ+PGtleXdvcmQ+bmVwaHJvcHJvdGVjdGlv

bjwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+

PGRhdGU+TWFyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUyMC03NTYwIChFbGVj

dHJvbmljKSYjeEQ7MTUyMC03NTUyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNTk5

NDUxMzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNTk5NDUxMzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwMi9kbXJyLjI2NjY8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 332,375-379. This may be accompanied by decreased leptin levels, endothelial dysfunction, oxidative stress, and inflammation markers, ultimately reducing blood pressure and body weight ADDIN EN.CITE <EndNote><Cite><Author>Vickers</Author><Year>2014</Year><RecNum>3894</RecNum><DisplayText><style face="superscript">380</style></DisplayText><record><rec-number>3894</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535924035">3894</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vickers, S. P.</author><author>Cheetham, S. C.</author><author>Headland, K. R.</author><author>Dickinson, K.</author><author>Grempler, R.</author><author>Mayoux, E.</author><author>Mark, M.</author><author>Klein, T.</author></authors></contributors><auth-address>RenaSci, BioCity Nottingham, Nottingham, UK.&#xD;Boehringer Ingelheim Pharma, Biberach an der Riss, Germany.</auth-address><titles><title>Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body-weight reduction and glucose homeostasis of obese rats fed a cafeteria diet</title><secondary-title>Diabetes Metab Syndr Obes</secondary-title></titles><pages>265-75</pages><volume>7</volume><keywords><keyword>Sglt2</keyword><keyword>combination</keyword><keyword>empagliflozin</keyword><keyword>obesity</keyword><keyword>rat</keyword><keyword>sibutramine</keyword></keywords><dates><year>2014</year></dates><isbn>1178-7007 (Print)&#xD;1178-7007 (Linking)</isbn><accession-num>25061325</accession-num><urls><related-urls><url>. Thus, SGLT2 inhibitors may optimally reduce the long-term complications associated with T2D, with a low risk of hypoglycemia and hypotension PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYWk8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNO

dW0+Mzg5MTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjM3

NywzODE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zODkxPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MjM2ODgiPjM4OTE8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkNhaSwgSC4gWS48L2F1dGhvcj48YXV0

aG9yPldhbmcsIFouIEouPC9hdXRob3I+PGF1dGhvcj5Ib2xzY2hlciwgQy48L2F1dGhvcj48YXV0

aG9yPll1YW4sIEwuPC9hdXRob3I+PGF1dGhvcj5aaGFuZywgSi48L2F1dGhvcj48YXV0aG9yPlN1

biwgUC48L2F1dGhvcj48YXV0aG9yPkxpLCBKLjwvYXV0aG9yPjxhdXRob3I+WWFuZywgVy48L2F1

dGhvcj48YXV0aG9yPld1LCBNLiBOLjwvYXV0aG9yPjxhdXRob3I+UWksIEouIFMuPC9hdXRob3I+

PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBNaWNy

b2Jpb2xvZ3kgYW5kIEltbXVub2xvZ3ksIFNoYW54aSBNZWRpY2FsIFVuaXZlcnNpdHksIFRhaXl1

YW4gMDMwMDAxLCBDaGluYS4mI3hEO0RlcGFydG1lbnQgb2YgUGh5c2lvbG9neSwgU2hhbnhpIE1l

ZGljYWwgVW5pdmVyc2l0eSwgVGFpeXVhbiAwMzAwMDEsIENoaW5hLiYjeEQ7RGl2aXNpb24gb2Yg

QmlvbWVkIGFuZCBMaWZlIFNjaWVuY2VzLCBGYWN1bHR5IG9mIEhlYWx0aCBhbmQgTWVkaWNpbmUg

TGFuY2FzdGVyIFVuaXZlcnNpdHksIExhbmNhc3RlciwgTEExIDRZUSwgVUsuJiN4RDtEZXBhcnRt

ZW50IG9mIFBoeXNpb2xvZ3ksIFNoYW54aSBNZWRpY2FsIFVuaXZlcnNpdHksIFRhaXl1YW4gMDMw

MDAxLCBDaGluYS4gRWxlY3Ryb25pYyBhZGRyZXNzOiBqaW5zaHVucWkyMDA5QDE2My5jb20uPC9h

dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+TGl4aXNlbmF0aWRlIGF0dGVudWF0ZXMgdGhlIGRl

dHJpbWVudGFsIGVmZmVjdHMgb2YgYW15bG9pZCBiZXRhIHByb3RlaW4gb24gc3BhdGlhbCB3b3Jr

aW5nIG1lbW9yeSBhbmQgaGlwcG9jYW1wYWwgbmV1cm9ucyBpbiByYXRzPC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPkJlaGF2IEJyYWluIFJlczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdl

cz4yOC0zNTwvcGFnZXM+PHZvbHVtZT4zMTg8L3ZvbHVtZT48a2V5d29yZHM+PGtleXdvcmQ+QW15

bG9pZCBiZXRhLVBlcHRpZGVzLyphbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzL3BoYXJtYWNv

bG9neTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJ1dGFkaWVu

ZXMvcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNhbGNpdW0vbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5DZWxsIFN1cnZpdmFsL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29y

ZD5IaXBwb2NhbXB1cy8qZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPk1hemUgTGVhcm5p

bmcvZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPk1lbW9yeSwgU2hvcnQtVGVybS8qZHJ1

ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbnMvZHJ1ZyBlZmZlY3RzPC9rZXl3b3Jk

PjxrZXl3b3JkPk5ldXJvcHJvdGVjdGl2ZSBBZ2VudHMvcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPk5pdHJpbGVzL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5QZXB0aWRlIEZy

YWdtZW50cy8qYW50YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9ycy9waGFybWFjb2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+UGVwdGlkZXMvKnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5Qcmlt

YXJ5IENlbGwgQ3VsdHVyZTwva2V5d29yZD48a2V5d29yZD5SYXRzPC9rZXl3b3JkPjxrZXl3b3Jk

PlNpZ25hbCBUcmFuc2R1Y3Rpb24vZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPipBa3Qt

TUVLMS8yIHNpZ25hbCBwYXRod2F5PC9rZXl3b3JkPjxrZXl3b3JkPipBbXlsb2lkIGJldGEgcHJv

dGVpbjwva2V5d29yZD48a2V5d29yZD4qQ2VsbCB2aWFiaWxpdHk8L2tleXdvcmQ+PGtleXdvcmQ+

KkludHJhY2VsbHVsYXIgY2FsY2l1bSBjb25jZW50cmF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPipM

aXhpc2VuYXRpZGU8L2tleXdvcmQ+PGtleXdvcmQ+KldvcmtpbmcgbWVtb3J5PC9rZXl3b3JkPjwv

a2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5GZWIgMTwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE4NzItNzU0OSAoRWxlY3Ryb25pYykmI3hE

OzAxNjYtNDMyOCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjc3NzY5OTM8L2FjY2Vz

c2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmlo

Lmdvdi9wdWJtZWQvMjc3NzY5OTM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5iYnIuMjAxNi4xMC4wMzM8L2VsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkNoaWx0b248L0F1dGhvcj48

WWVhcj4yMDE0PC9ZZWFyPjxSZWNOdW0+Mzg5NTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+

Mzg5NTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTBy

eDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTI0MjAzIj4z

ODk1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkdlbmVyaWMiPjEzPC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Q2hpbHRvbiwgUm9iZXJ0PC9hdXRo

b3I+PGF1dGhvcj5UaWtrYW5lbiwgSWxra2E8L2F1dGhvcj48YXV0aG9yPkNyb3dlLCBTdXNhbm5l

PC9hdXRob3I+PGF1dGhvcj5Kb2hhbnNlbiwgT2RkIEVyaWs8L2F1dGhvcj48YXV0aG9yPkJyb2Vk

bCwgVWxpIEM8L2F1dGhvcj48YXV0aG9yPldvZXJsZSwgSGFucyBKPC9hdXRob3I+PGF1dGhvcj5I

YWNoLCBUaG9tYXM8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0

bGU+RW1wYWdsaWZsb3ppbiBSZWR1Y2VzIFN5c3RvbGljIEJsb29kIFByZXNzdXJlIGluIERpcHBl

ciBhbmQgTm9uLURpcHBlciBQYXRpZW50cyB3aXRoIFR5cGUgMiBEaWFiZXRlcyBhbmQgSHlwZXJ0

ZW5zaW9uPC90aXRsZT48L3RpdGxlcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48L2RhdGVzPjxw

dWJsaXNoZXI+QW0gSGVhcnQgQXNzb2M8L3B1Ymxpc2hlcj48aXNibj4wMDA5LTczMjI8L2lzYm4+

PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYWk8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNO

dW0+Mzg5MTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjM3

NywzODE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zODkxPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZl

cDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MjM2ODgiPjM4OTE8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkNhaSwgSC4gWS48L2F1dGhvcj48YXV0

aG9yPldhbmcsIFouIEouPC9hdXRob3I+PGF1dGhvcj5Ib2xzY2hlciwgQy48L2F1dGhvcj48YXV0

aG9yPll1YW4sIEwuPC9hdXRob3I+PGF1dGhvcj5aaGFuZywgSi48L2F1dGhvcj48YXV0aG9yPlN1

biwgUC48L2F1dGhvcj48YXV0aG9yPkxpLCBKLjwvYXV0aG9yPjxhdXRob3I+WWFuZywgVy48L2F1

dGhvcj48YXV0aG9yPld1LCBNLiBOLjwvYXV0aG9yPjxhdXRob3I+UWksIEouIFMuPC9hdXRob3I+

PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBNaWNy

b2Jpb2xvZ3kgYW5kIEltbXVub2xvZ3ksIFNoYW54aSBNZWRpY2FsIFVuaXZlcnNpdHksIFRhaXl1

YW4gMDMwMDAxLCBDaGluYS4mI3hEO0RlcGFydG1lbnQgb2YgUGh5c2lvbG9neSwgU2hhbnhpIE1l

ZGljYWwgVW5pdmVyc2l0eSwgVGFpeXVhbiAwMzAwMDEsIENoaW5hLiYjeEQ7RGl2aXNpb24gb2Yg

QmlvbWVkIGFuZCBMaWZlIFNjaWVuY2VzLCBGYWN1bHR5IG9mIEhlYWx0aCBhbmQgTWVkaWNpbmUg

TGFuY2FzdGVyIFVuaXZlcnNpdHksIExhbmNhc3RlciwgTEExIDRZUSwgVUsuJiN4RDtEZXBhcnRt

ZW50IG9mIFBoeXNpb2xvZ3ksIFNoYW54aSBNZWRpY2FsIFVuaXZlcnNpdHksIFRhaXl1YW4gMDMw

MDAxLCBDaGluYS4gRWxlY3Ryb25pYyBhZGRyZXNzOiBqaW5zaHVucWkyMDA5QDE2My5jb20uPC9h

dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+TGl4aXNlbmF0aWRlIGF0dGVudWF0ZXMgdGhlIGRl

dHJpbWVudGFsIGVmZmVjdHMgb2YgYW15bG9pZCBiZXRhIHByb3RlaW4gb24gc3BhdGlhbCB3b3Jr

aW5nIG1lbW9yeSBhbmQgaGlwcG9jYW1wYWwgbmV1cm9ucyBpbiByYXRzPC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPkJlaGF2IEJyYWluIFJlczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdl

cz4yOC0zNTwvcGFnZXM+PHZvbHVtZT4zMTg8L3ZvbHVtZT48a2V5d29yZHM+PGtleXdvcmQ+QW15

bG9pZCBiZXRhLVBlcHRpZGVzLyphbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzL3BoYXJtYWNv

bG9neTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJ1dGFkaWVu

ZXMvcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNhbGNpdW0vbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5DZWxsIFN1cnZpdmFsL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29y

ZD5IaXBwb2NhbXB1cy8qZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPk1hemUgTGVhcm5p

bmcvZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPk1lbW9yeSwgU2hvcnQtVGVybS8qZHJ1

ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbnMvZHJ1ZyBlZmZlY3RzPC9rZXl3b3Jk

PjxrZXl3b3JkPk5ldXJvcHJvdGVjdGl2ZSBBZ2VudHMvcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPk5pdHJpbGVzL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5QZXB0aWRlIEZy

YWdtZW50cy8qYW50YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9ycy9waGFybWFjb2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+UGVwdGlkZXMvKnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5Qcmlt

YXJ5IENlbGwgQ3VsdHVyZTwva2V5d29yZD48a2V5d29yZD5SYXRzPC9rZXl3b3JkPjxrZXl3b3Jk

PlNpZ25hbCBUcmFuc2R1Y3Rpb24vZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPipBa3Qt

TUVLMS8yIHNpZ25hbCBwYXRod2F5PC9rZXl3b3JkPjxrZXl3b3JkPipBbXlsb2lkIGJldGEgcHJv

dGVpbjwva2V5d29yZD48a2V5d29yZD4qQ2VsbCB2aWFiaWxpdHk8L2tleXdvcmQ+PGtleXdvcmQ+

KkludHJhY2VsbHVsYXIgY2FsY2l1bSBjb25jZW50cmF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPipM

aXhpc2VuYXRpZGU8L2tleXdvcmQ+PGtleXdvcmQ+KldvcmtpbmcgbWVtb3J5PC9rZXl3b3JkPjwv

a2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5GZWIgMTwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE4NzItNzU0OSAoRWxlY3Ryb25pYykmI3hE

OzAxNjYtNDMyOCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjc3NzY5OTM8L2FjY2Vz

c2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmlo

Lmdvdi9wdWJtZWQvMjc3NzY5OTM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5iYnIuMjAxNi4xMC4wMzM8L2VsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkNoaWx0b248L0F1dGhvcj48

WWVhcj4yMDE0PC9ZZWFyPjxSZWNOdW0+Mzg5NTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+

Mzg5NTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTBy

eDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1OTI0MjAzIj4z

ODk1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkdlbmVyaWMiPjEzPC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Q2hpbHRvbiwgUm9iZXJ0PC9hdXRo

b3I+PGF1dGhvcj5UaWtrYW5lbiwgSWxra2E8L2F1dGhvcj48YXV0aG9yPkNyb3dlLCBTdXNhbm5l

PC9hdXRob3I+PGF1dGhvcj5Kb2hhbnNlbiwgT2RkIEVyaWs8L2F1dGhvcj48YXV0aG9yPkJyb2Vk

bCwgVWxpIEM8L2F1dGhvcj48YXV0aG9yPldvZXJsZSwgSGFucyBKPC9hdXRob3I+PGF1dGhvcj5I

YWNoLCBUaG9tYXM8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0

bGU+RW1wYWdsaWZsb3ppbiBSZWR1Y2VzIFN5c3RvbGljIEJsb29kIFByZXNzdXJlIGluIERpcHBl

ciBhbmQgTm9uLURpcHBlciBQYXRpZW50cyB3aXRoIFR5cGUgMiBEaWFiZXRlcyBhbmQgSHlwZXJ0

ZW5zaW9uPC90aXRsZT48L3RpdGxlcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48L2RhdGVzPjxw

dWJsaXNoZXI+QW0gSGVhcnQgQXNzb2M8L3B1Ymxpc2hlcj48aXNibj4wMDA5LTczMjI8L2lzYm4+

PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 377,381. Although little is known on its neuroprotective role, Empagliflozin may protect obese T2D mice against brain oxidative stress and DNA damage probably via the recovery in serum insulin levels and vascular function, ultimately rescuing their learning and memory function PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaWtrYW5lbjwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+

PFJlY051bT4zODEzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MzgyLDM4Mzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM4MTM8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxOTExOSI+MzgxMzwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+VGlra2FuZW4sIElsa2thPC9h

dXRob3I+PGF1dGhvcj5DaGlsdG9uLCBSb2JlcnQ8L2F1dGhvcj48YXV0aG9yPkpvaGFuc2VuLCBP

ZGQgRXJpazwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5Q

b3RlbnRpYWwgcm9sZSBvZiBzb2RpdW0gZ2x1Y29zZSBjb3RyYW5zcG9ydGVyIDIgaW5oaWJpdG9y

cyBpbiB0aGUgdHJlYXRtZW50IG9mIGh5cGVydGVuc2lvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5DdXJyZW50IE9waW5pb24gaW4gTmVwaHJvbG9neSBhbmQgSHlwZXJ0ZW5zaW9uPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjgxLTg2PC9wYWdlcz48dm9sdW1lPjI1PC92b2x1bWU+

PG51bWJlcj4yPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT4yMDE2LzAzPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5PdmlkIFRlY2hu

b2xvZ2llcyAoV29sdGVycyBLbHV3ZXIgSGVhbHRoKTwvcHVibGlzaGVyPjxpc2JuPjEwNjItNDgy

MTwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTA5

Ny9tbmguMDAwMDAwMDAwMDAwMDE5OTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTA5Ny9tbmguMDAwMDAwMDAwMDAwMDE5OTwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+T3R0PC9BdXRob3I+

PFllYXI+MjAxNzwvWWVhcj48UmVjTnVtPjM4OTY8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVy

PjM4OTY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ew

cng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkyNDM4MCI+

Mzg5Njwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi

PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+T3R0LCBDLjwvYXV0

aG9yPjxhdXRob3I+SnVtYXIsIEEuPC9hdXRob3I+PGF1dGhvcj5TdHJpZXBlLCBLLjwvYXV0aG9y

PjxhdXRob3I+RnJpZWRyaWNoLCBTLjwvYXV0aG9yPjxhdXRob3I+S2FyZywgTS4gVi48L2F1dGhv

cj48YXV0aG9yPkJyYW1sYWdlLCBQLjwvYXV0aG9yPjxhdXRob3I+U2NobWllZGVyLCBSLiBFLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQg

b2YgTmVwaHJvbG9neSBhbmQgSHlwZXJ0ZW5zaW9uLCBGcmllZHJpY2gtQWxleGFuZGVyLVVuaXZl

cnNpdHkgRXJsYW5nZW4tTnVybmJlcmcgKEZBVSksIFVsbWVud2VnIDE4LCA5MTA1NCwgRXJsYW5n

ZW4sIEdlcm1hbnkuJiN4RDtJbnN0aXR1dGUgZm9yIFBoYXJtYWNvbG9neSBhbmQgUHJldmVudGl2

ZSBNZWRpY2luZSwgTWFobG93LCBHZXJtYW55LiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXBocm9sb2d5

IGFuZCBIeXBlcnRlbnNpb24sIEZyaWVkcmljaC1BbGV4YW5kZXItVW5pdmVyc2l0eSBFcmxhbmdl

bi1OdXJuYmVyZyAoRkFVKSwgVWxtZW53ZWcgMTgsIDkxMDU0LCBFcmxhbmdlbiwgR2VybWFueS4g

cm9sYW5kLnNjaG1pZWRlckB1ay1lcmxhbmdlbi5kZS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0

aXRsZT5BIHJhbmRvbWlzZWQgc3R1ZHkgb2YgdGhlIGltcGFjdCBvZiB0aGUgU0dMVDIgaW5oaWJp

dG9yIGRhcGFnbGlmbG96aW4gb24gbWljcm92YXNjdWxhciBhbmQgbWFjcm92YXNjdWxhciBjaXJj

dWxhdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5DYXJkaW92YXNjIERpYWJldG9sPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjI2PC9wYWdlcz48dm9sdW1lPjE2PC92b2x1bWU+

PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdv

cmQ+QmVuemh5ZHJ5bCBDb21wb3VuZHMvcGhhcm1hY29sb2d5Lyp0aGVyYXBldXRpYyB1c2U8L2tl

eXdvcmQ+PGtleXdvcmQ+Qmxvb2QgR2x1Y29zZS9kcnVnIGVmZmVjdHMvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5CbG9vZCBQcmVzc3VyZS8qZHJ1ZyBlZmZlY3RzL3BoeXNpb2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+Q3Jvc3MtT3ZlciBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkRpYWJl

dGVzIE1lbGxpdHVzLCBUeXBlIDIvYmxvb2QvKmRydWcgdGhlcmFweS9waHlzaW9wYXRob2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+RG91YmxlLUJsaW5kIE1ldGhvZDwva2V5d29yZD48a2V5d29yZD5G

ZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y29zaWRlcy9waGFybWFjb2xvZ3kvKnRoZXJhcGV1

dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

biBSZXNpc3RhbmNlL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TGFzZXItRG9wcGxlciBG

bG93bWV0cnkvbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1pY3JvY2lyY3VsYXRpb24vKmRydWcgZWZmZWN0cy9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPk1pY3JvdmVzc2Vscy8qZHJ1ZyBlZmZlY3RzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UHJvc3BlY3RpdmUgU3R1ZGllczwva2V5

d29yZD48a2V5d29yZD5Tb2RpdW0tR2x1Y29zZSBUcmFuc3BvcnRlciAyLyphbnRhZ29uaXN0cyAm

YW1wOyBpbmhpYml0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPipBcnRlcmlhbCByZW1vZGVsbGluZzwv

a2V5d29yZD48a2V5d29yZD4qQmxvb2QgcHJlc3N1cmU8L2tleXdvcmQ+PGtleXdvcmQ+Kkluc3Vs

aW4gcmVzaXN0YW5jZTwva2V5d29yZD48a2V5d29yZD4qUHVsc2Ugd2F2ZSBhbmFseXNpczwva2V5

d29yZD48a2V5d29yZD4qU0dMVDIgaW5oaWJpdG9yczwva2V5d29yZD48a2V5d29yZD4qU2Nhbm5p

bmcgbGFzZXIgRG9wcGxlciBmbG93bWV0cnksIHZhc2N1bGFyIHByb3RlY3Rpb248L2tleXdvcmQ+

PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkZlYiAy

MzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0NzUtMjg0MCAoRWxlY3Ryb25pYykm

I3hEOzE0NzUtMjg0MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjgyMzE4MzE8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMjgyMzE4MzE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3Rv

bTI+UE1DNTMyNDI3MjwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTE4Ni9z

MTI5MzMtMDE3LTA1MTAtMTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRl

PjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaWtrYW5lbjwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+

PFJlY051bT4zODEzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MzgyLDM4Mzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM4MTM8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxOTExOSI+MzgxMzwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+VGlra2FuZW4sIElsa2thPC9h

dXRob3I+PGF1dGhvcj5DaGlsdG9uLCBSb2JlcnQ8L2F1dGhvcj48YXV0aG9yPkpvaGFuc2VuLCBP

ZGQgRXJpazwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5Q

b3RlbnRpYWwgcm9sZSBvZiBzb2RpdW0gZ2x1Y29zZSBjb3RyYW5zcG9ydGVyIDIgaW5oaWJpdG9y

cyBpbiB0aGUgdHJlYXRtZW50IG9mIGh5cGVydGVuc2lvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5DdXJyZW50IE9waW5pb24gaW4gTmVwaHJvbG9neSBhbmQgSHlwZXJ0ZW5zaW9uPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjgxLTg2PC9wYWdlcz48dm9sdW1lPjI1PC92b2x1bWU+

PG51bWJlcj4yPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT4yMDE2LzAzPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5PdmlkIFRlY2hu

b2xvZ2llcyAoV29sdGVycyBLbHV3ZXIgSGVhbHRoKTwvcHVibGlzaGVyPjxpc2JuPjEwNjItNDgy

MTwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTA5

Ny9tbmguMDAwMDAwMDAwMDAwMDE5OTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTA5Ny9tbmguMDAwMDAwMDAwMDAwMDE5OTwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+T3R0PC9BdXRob3I+

PFllYXI+MjAxNzwvWWVhcj48UmVjTnVtPjM4OTY8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVy

PjM4OTY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ew

cng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkyNDM4MCI+

Mzg5Njwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi

PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+T3R0LCBDLjwvYXV0

aG9yPjxhdXRob3I+SnVtYXIsIEEuPC9hdXRob3I+PGF1dGhvcj5TdHJpZXBlLCBLLjwvYXV0aG9y

PjxhdXRob3I+RnJpZWRyaWNoLCBTLjwvYXV0aG9yPjxhdXRob3I+S2FyZywgTS4gVi48L2F1dGhv

cj48YXV0aG9yPkJyYW1sYWdlLCBQLjwvYXV0aG9yPjxhdXRob3I+U2NobWllZGVyLCBSLiBFLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQg

b2YgTmVwaHJvbG9neSBhbmQgSHlwZXJ0ZW5zaW9uLCBGcmllZHJpY2gtQWxleGFuZGVyLVVuaXZl

cnNpdHkgRXJsYW5nZW4tTnVybmJlcmcgKEZBVSksIFVsbWVud2VnIDE4LCA5MTA1NCwgRXJsYW5n

ZW4sIEdlcm1hbnkuJiN4RDtJbnN0aXR1dGUgZm9yIFBoYXJtYWNvbG9neSBhbmQgUHJldmVudGl2

ZSBNZWRpY2luZSwgTWFobG93LCBHZXJtYW55LiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXBocm9sb2d5

IGFuZCBIeXBlcnRlbnNpb24sIEZyaWVkcmljaC1BbGV4YW5kZXItVW5pdmVyc2l0eSBFcmxhbmdl

bi1OdXJuYmVyZyAoRkFVKSwgVWxtZW53ZWcgMTgsIDkxMDU0LCBFcmxhbmdlbiwgR2VybWFueS4g

cm9sYW5kLnNjaG1pZWRlckB1ay1lcmxhbmdlbi5kZS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0

aXRsZT5BIHJhbmRvbWlzZWQgc3R1ZHkgb2YgdGhlIGltcGFjdCBvZiB0aGUgU0dMVDIgaW5oaWJp

dG9yIGRhcGFnbGlmbG96aW4gb24gbWljcm92YXNjdWxhciBhbmQgbWFjcm92YXNjdWxhciBjaXJj

dWxhdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5DYXJkaW92YXNjIERpYWJldG9sPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjI2PC9wYWdlcz48dm9sdW1lPjE2PC92b2x1bWU+

PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdv

cmQ+QmVuemh5ZHJ5bCBDb21wb3VuZHMvcGhhcm1hY29sb2d5Lyp0aGVyYXBldXRpYyB1c2U8L2tl

eXdvcmQ+PGtleXdvcmQ+Qmxvb2QgR2x1Y29zZS9kcnVnIGVmZmVjdHMvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5CbG9vZCBQcmVzc3VyZS8qZHJ1ZyBlZmZlY3RzL3BoeXNpb2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+Q3Jvc3MtT3ZlciBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkRpYWJl

dGVzIE1lbGxpdHVzLCBUeXBlIDIvYmxvb2QvKmRydWcgdGhlcmFweS9waHlzaW9wYXRob2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+RG91YmxlLUJsaW5kIE1ldGhvZDwva2V5d29yZD48a2V5d29yZD5G

ZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y29zaWRlcy9waGFybWFjb2xvZ3kvKnRoZXJhcGV1

dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

biBSZXNpc3RhbmNlL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TGFzZXItRG9wcGxlciBG

bG93bWV0cnkvbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1pY3JvY2lyY3VsYXRpb24vKmRydWcgZWZmZWN0cy9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPk1pY3JvdmVzc2Vscy8qZHJ1ZyBlZmZlY3RzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UHJvc3BlY3RpdmUgU3R1ZGllczwva2V5

d29yZD48a2V5d29yZD5Tb2RpdW0tR2x1Y29zZSBUcmFuc3BvcnRlciAyLyphbnRhZ29uaXN0cyAm

YW1wOyBpbmhpYml0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPipBcnRlcmlhbCByZW1vZGVsbGluZzwv

a2V5d29yZD48a2V5d29yZD4qQmxvb2QgcHJlc3N1cmU8L2tleXdvcmQ+PGtleXdvcmQ+Kkluc3Vs

aW4gcmVzaXN0YW5jZTwva2V5d29yZD48a2V5d29yZD4qUHVsc2Ugd2F2ZSBhbmFseXNpczwva2V5

d29yZD48a2V5d29yZD4qU0dMVDIgaW5oaWJpdG9yczwva2V5d29yZD48a2V5d29yZD4qU2Nhbm5p

bmcgbGFzZXIgRG9wcGxlciBmbG93bWV0cnksIHZhc2N1bGFyIHByb3RlY3Rpb248L2tleXdvcmQ+

PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkZlYiAy

MzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0NzUtMjg0MCAoRWxlY3Ryb25pYykm

I3hEOzE0NzUtMjg0MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjgyMzE4MzE8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMjgyMzE4MzE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3Rv

bTI+UE1DNTMyNDI3MjwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTE4Ni9z

MTI5MzMtMDE3LTA1MTAtMTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRl

PjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 382,383. Additionally, Dapagliflozin-mediated attenuation of retinal capillary hyperperfusion, arteriole wall thickening and microvascular remodeling in T2D were followed by a decrease in brain markers for oxidative stress, inflammation and apoptosis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaWtrYW5lbjwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+

PFJlY051bT4zODEzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MzgyLDM4NDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM4MTM8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxOTExOSI+MzgxMzwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+VGlra2FuZW4sIElsa2thPC9h

dXRob3I+PGF1dGhvcj5DaGlsdG9uLCBSb2JlcnQ8L2F1dGhvcj48YXV0aG9yPkpvaGFuc2VuLCBP

ZGQgRXJpazwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5Q

b3RlbnRpYWwgcm9sZSBvZiBzb2RpdW0gZ2x1Y29zZSBjb3RyYW5zcG9ydGVyIDIgaW5oaWJpdG9y

cyBpbiB0aGUgdHJlYXRtZW50IG9mIGh5cGVydGVuc2lvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5DdXJyZW50IE9waW5pb24gaW4gTmVwaHJvbG9neSBhbmQgSHlwZXJ0ZW5zaW9uPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjgxLTg2PC9wYWdlcz48dm9sdW1lPjI1PC92b2x1bWU+

PG51bWJlcj4yPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT4yMDE2LzAzPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5PdmlkIFRlY2hu

b2xvZ2llcyAoV29sdGVycyBLbHV3ZXIgSGVhbHRoKTwvcHVibGlzaGVyPjxpc2JuPjEwNjItNDgy

MTwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTA5

Ny9tbmguMDAwMDAwMDAwMDAwMDE5OTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTA5Ny9tbmguMDAwMDAwMDAwMDAwMDE5OTwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TGluPC9BdXRob3I+

PFllYXI+MjAxNDwvWWVhcj48UmVjTnVtPjM4OTc8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVy

PjM4OTc8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ew

cng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkyNDUwNCI+

Mzg5Nzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi

PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TGluLCBCLjwvYXV0

aG9yPjxhdXRob3I+S29pYnVjaGksIE4uPC9hdXRob3I+PGF1dGhvcj5IYXNlZ2F3YSwgWS48L2F1

dGhvcj48YXV0aG9yPlN1ZXRhLCBELjwvYXV0aG9yPjxhdXRob3I+VG95YW1hLCBLLjwvYXV0aG9y

PjxhdXRob3I+VWVrYXdhLCBLLjwvYXV0aG9yPjxhdXRob3I+TWEsIE0uPC9hdXRob3I+PGF1dGhv

cj5OYWthZ2F3YSwgVC48L2F1dGhvcj48YXV0aG9yPkt1c2FrYSwgSC48L2F1dGhvcj48YXV0aG9y

PktpbS1NaXRzdXlhbWEsIFMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo

LWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xvZ3kgYW5kIE1vbGVjdWxhciBUaGVyYXBl

dXRpY3MsIEt1bWFtb3RvIFVuaXZlcnNpdHkgR3JhZHVhdGUgU2Nob29sIG9mIE1lZGljYWwgU2Np

ZW5jZXMsIDEtMS0xIEhvbmp5bywgS3VtYW1vdG8sIDg2MC04NTU2LCBKYXBhbi4gcGFya21vb24x

OTgyQHlhaG9vLmNvLmpwLiYjeEQ7RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xvZ3kgYW5kIE1vbGVj

dWxhciBUaGVyYXBldXRpY3MsIEt1bWFtb3RvIFVuaXZlcnNpdHkgR3JhZHVhdGUgU2Nob29sIG9m

IE1lZGljYWwgU2NpZW5jZXMsIDEtMS0xIEhvbmp5bywgS3VtYW1vdG8sIDg2MC04NTU2LCBKYXBh

bi4ga29pYnVjaGktY2lyY0B1bWluLmFjLmpwLiYjeEQ7RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xv

Z3kgYW5kIE1vbGVjdWxhciBUaGVyYXBldXRpY3MsIEt1bWFtb3RvIFVuaXZlcnNpdHkgR3JhZHVh

dGUgU2Nob29sIG9mIE1lZGljYWwgU2NpZW5jZXMsIDEtMS0xIEhvbmp5bywgS3VtYW1vdG8sIDg2

MC04NTU2LCBKYXBhbi4gZnBtaGFzc2VAeWFob28uY28uanAuJiN4RDtEZXBhcnRtZW50IG9mIFBo

YXJtYWNvbG9neSBhbmQgTW9sZWN1bGFyIFRoZXJhcGV1dGljcywgS3VtYW1vdG8gVW5pdmVyc2l0

eSBHcmFkdWF0ZSBTY2hvb2wgb2YgTWVkaWNhbCBTY2llbmNlcywgMS0xLTEgSG9uanlvLCBLdW1h

bW90bywgODYwLTg1NTYsIEphcGFuLiBkYWlzdWtlc3VldGFAZ21haWwuY29tLiYjeEQ7RGVwYXJ0

bWVudCBvZiBQaGFybWFjb2xvZ3kgYW5kIE1vbGVjdWxhciBUaGVyYXBldXRpY3MsIEt1bWFtb3Rv

IFVuaXZlcnNpdHkgR3JhZHVhdGUgU2Nob29sIG9mIE1lZGljYWwgU2NpZW5jZXMsIDEtMS0xIEhv

bmp5bywgS3VtYW1vdG8sIDg2MC04NTU2LCBKYXBhbi4gay10b3lhbWFAa3VtYW1vdG8tdS5hYy5q

cC4mI3hEO0RlcGFydG1lbnQgb2YgUGhhcm1hY29sb2d5IGFuZCBNb2xlY3VsYXIgVGhlcmFwZXV0

aWNzLCBLdW1hbW90byBVbml2ZXJzaXR5IEdyYWR1YXRlIFNjaG9vbCBvZiBNZWRpY2FsIFNjaWVu

Y2VzLCAxLTEtMSBIb25qeW8sIEt1bWFtb3RvLCA4NjAtODU1NiwgSmFwYW4uIDEwMXI1MTAyQHN0

Lmt1bWFtb3RvLXUuYWMuanAuJiN4RDtEZXBhcnRtZW50IG9mIFBoYXJtYWNvbG9neSBhbmQgTW9s

ZWN1bGFyIFRoZXJhcGV1dGljcywgS3VtYW1vdG8gVW5pdmVyc2l0eSBHcmFkdWF0ZSBTY2hvb2wg

b2YgTWVkaWNhbCBTY2llbmNlcywgMS0xLTEgSG9uanlvLCBLdW1hbW90bywgODYwLTg1NTYsIEph

cGFuLiBtYW1pbmdqaWUxMTI0QHlhaG9vLmNvLmpwLiYjeEQ7RGVwYXJ0bWVudCBvZiBQaGFybWFj

b2xvZ3kgYW5kIE1vbGVjdWxhciBUaGVyYXBldXRpY3MsIEt1bWFtb3RvIFVuaXZlcnNpdHkgR3Jh

ZHVhdGUgU2Nob29sIG9mIE1lZGljYWwgU2NpZW5jZXMsIDEtMS0xIEhvbmp5bywgS3VtYW1vdG8s

IDg2MC04NTU2LCBKYXBhbi4gMTEzcjUxMzNAc3Qua3VtYW1vdG8tdS5hYy5qcC4mI3hEO0RlcGFy

dG1lbnQgb2YgUGhhcm1hY29sb2d5IGFuZCBNb2xlY3VsYXIgVGhlcmFwZXV0aWNzLCBLdW1hbW90

byBVbml2ZXJzaXR5IEdyYWR1YXRlIFNjaG9vbCBvZiBNZWRpY2FsIFNjaWVuY2VzLCAxLTEtMSBI

b25qeW8sIEt1bWFtb3RvLCA4NjAtODU1NiwgSmFwYW4uIGt1c2FrYUBrdW1hbW90by11LmFjLmpw

LiYjeEQ7RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xvZ3kgYW5kIE1vbGVjdWxhciBUaGVyYXBldXRp

Y3MsIEt1bWFtb3RvIFVuaXZlcnNpdHkgR3JhZHVhdGUgU2Nob29sIG9mIE1lZGljYWwgU2NpZW5j

ZXMsIDEtMS0xIEhvbmp5bywgS3VtYW1vdG8sIDg2MC04NTU2LCBKYXBhbi4gbWl0c3V5YW1AZ3Bv

Lmt1bWFtb3RvLXUuYWMuanAuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+R2x5Y2VtaWMg

Y29udHJvbCB3aXRoIGVtcGFnbGlmbG96aW4sIGEgbm92ZWwgc2VsZWN0aXZlIFNHTFQyIGluaGli

aXRvciwgYW1lbGlvcmF0ZXMgY2FyZGlvdmFzY3VsYXIgaW5qdXJ5IGFuZCBjb2duaXRpdmUgZHlz

ZnVuY3Rpb24gaW4gb2Jlc2UgYW5kIHR5cGUgMiBkaWFiZXRpYyBtaWNlPC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPkNhcmRpb3Zhc2MgRGlhYmV0b2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48

cGFnZXM+MTQ4PC9wYWdlcz48dm9sdW1lPjEzPC92b2x1bWU+PGtleXdvcmRzPjxrZXl3b3JkPkFu

aW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QmVuemh5ZHJ5bCBDb21wb3VuZHMvKnBoYXJtYWNvbG9n

eTwva2V5d29yZD48a2V5d29yZD5CbG9vZCBHbHVjb3NlL2RydWcgZWZmZWN0czwva2V5d29yZD48

a2V5d29yZD5DYXJkaW92YXNjdWxhciBEaXNlYXNlcy9ibG9vZC8qZHJ1ZyB0aGVyYXB5PC9rZXl3

b3JkPjxrZXl3b3JkPkNvZ25pdGlvbiBEaXNvcmRlcnMvKmRydWcgdGhlcmFweS9ldGlvbG9neTwv

a2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBNZWxsaXR1cywgRXhwZXJpbWVudGFsLypkcnVnIHRo

ZXJhcHkvcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkRpYWJldGVzIE1lbGxpdHVz

LCBUeXBlIDIvY29tcGxpY2F0aW9ucy8qZHJ1ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkds

dWNvc2lkZXMvKnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5IeXBvZ2x5Y2VtaWMgQWdl

bnRzLypwaGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29y

ZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+T2Jlc2l0eS8qY29tcGxpY2F0

aW9ucy9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+U29kaXVtLUdsdWNvc2UgVHJh

bnNwb3J0ZXIgMi9hbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzPC9rZXl3b3JkPjwva2V5d29y

ZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5PY3QgMjY8L2RhdGU+

PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDc1LTI4NDAgKEVsZWN0cm9uaWMpJiN4RDsxNDc1

LTI4NDAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1MzQ0Njk0PC9hY2Nlc3Npb24t

bnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3Yv

cHVibWVkLzI1MzQ0Njk0PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQy

MTkwMzE8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExODYvczEyOTMzLTAx

NC0wMTQ4LTE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5v

dGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaWtrYW5lbjwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+

PFJlY051bT4zODEzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MzgyLDM4NDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM4MTM8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxOTExOSI+MzgxMzwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+VGlra2FuZW4sIElsa2thPC9h

dXRob3I+PGF1dGhvcj5DaGlsdG9uLCBSb2JlcnQ8L2F1dGhvcj48YXV0aG9yPkpvaGFuc2VuLCBP

ZGQgRXJpazwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5Q

b3RlbnRpYWwgcm9sZSBvZiBzb2RpdW0gZ2x1Y29zZSBjb3RyYW5zcG9ydGVyIDIgaW5oaWJpdG9y

cyBpbiB0aGUgdHJlYXRtZW50IG9mIGh5cGVydGVuc2lvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5DdXJyZW50IE9waW5pb24gaW4gTmVwaHJvbG9neSBhbmQgSHlwZXJ0ZW5zaW9uPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjgxLTg2PC9wYWdlcz48dm9sdW1lPjI1PC92b2x1bWU+

PG51bWJlcj4yPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT4yMDE2LzAzPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5PdmlkIFRlY2hu

b2xvZ2llcyAoV29sdGVycyBLbHV3ZXIgSGVhbHRoKTwvcHVibGlzaGVyPjxpc2JuPjEwNjItNDgy

MTwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTA5

Ny9tbmguMDAwMDAwMDAwMDAwMDE5OTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTA5Ny9tbmguMDAwMDAwMDAwMDAwMDE5OTwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TGluPC9BdXRob3I+

PFllYXI+MjAxNDwvWWVhcj48UmVjTnVtPjM4OTc8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVy

PjM4OTc8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ew

cng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkyNDUwNCI+

Mzg5Nzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi

PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TGluLCBCLjwvYXV0

aG9yPjxhdXRob3I+S29pYnVjaGksIE4uPC9hdXRob3I+PGF1dGhvcj5IYXNlZ2F3YSwgWS48L2F1

dGhvcj48YXV0aG9yPlN1ZXRhLCBELjwvYXV0aG9yPjxhdXRob3I+VG95YW1hLCBLLjwvYXV0aG9y

PjxhdXRob3I+VWVrYXdhLCBLLjwvYXV0aG9yPjxhdXRob3I+TWEsIE0uPC9hdXRob3I+PGF1dGhv

cj5OYWthZ2F3YSwgVC48L2F1dGhvcj48YXV0aG9yPkt1c2FrYSwgSC48L2F1dGhvcj48YXV0aG9y

PktpbS1NaXRzdXlhbWEsIFMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo

LWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xvZ3kgYW5kIE1vbGVjdWxhciBUaGVyYXBl

dXRpY3MsIEt1bWFtb3RvIFVuaXZlcnNpdHkgR3JhZHVhdGUgU2Nob29sIG9mIE1lZGljYWwgU2Np

ZW5jZXMsIDEtMS0xIEhvbmp5bywgS3VtYW1vdG8sIDg2MC04NTU2LCBKYXBhbi4gcGFya21vb24x

OTgyQHlhaG9vLmNvLmpwLiYjeEQ7RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xvZ3kgYW5kIE1vbGVj

dWxhciBUaGVyYXBldXRpY3MsIEt1bWFtb3RvIFVuaXZlcnNpdHkgR3JhZHVhdGUgU2Nob29sIG9m

IE1lZGljYWwgU2NpZW5jZXMsIDEtMS0xIEhvbmp5bywgS3VtYW1vdG8sIDg2MC04NTU2LCBKYXBh

bi4ga29pYnVjaGktY2lyY0B1bWluLmFjLmpwLiYjeEQ7RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xv

Z3kgYW5kIE1vbGVjdWxhciBUaGVyYXBldXRpY3MsIEt1bWFtb3RvIFVuaXZlcnNpdHkgR3JhZHVh

dGUgU2Nob29sIG9mIE1lZGljYWwgU2NpZW5jZXMsIDEtMS0xIEhvbmp5bywgS3VtYW1vdG8sIDg2

MC04NTU2LCBKYXBhbi4gZnBtaGFzc2VAeWFob28uY28uanAuJiN4RDtEZXBhcnRtZW50IG9mIFBo

YXJtYWNvbG9neSBhbmQgTW9sZWN1bGFyIFRoZXJhcGV1dGljcywgS3VtYW1vdG8gVW5pdmVyc2l0

eSBHcmFkdWF0ZSBTY2hvb2wgb2YgTWVkaWNhbCBTY2llbmNlcywgMS0xLTEgSG9uanlvLCBLdW1h

bW90bywgODYwLTg1NTYsIEphcGFuLiBkYWlzdWtlc3VldGFAZ21haWwuY29tLiYjeEQ7RGVwYXJ0

bWVudCBvZiBQaGFybWFjb2xvZ3kgYW5kIE1vbGVjdWxhciBUaGVyYXBldXRpY3MsIEt1bWFtb3Rv

IFVuaXZlcnNpdHkgR3JhZHVhdGUgU2Nob29sIG9mIE1lZGljYWwgU2NpZW5jZXMsIDEtMS0xIEhv

bmp5bywgS3VtYW1vdG8sIDg2MC04NTU2LCBKYXBhbi4gay10b3lhbWFAa3VtYW1vdG8tdS5hYy5q

cC4mI3hEO0RlcGFydG1lbnQgb2YgUGhhcm1hY29sb2d5IGFuZCBNb2xlY3VsYXIgVGhlcmFwZXV0

aWNzLCBLdW1hbW90byBVbml2ZXJzaXR5IEdyYWR1YXRlIFNjaG9vbCBvZiBNZWRpY2FsIFNjaWVu

Y2VzLCAxLTEtMSBIb25qeW8sIEt1bWFtb3RvLCA4NjAtODU1NiwgSmFwYW4uIDEwMXI1MTAyQHN0

Lmt1bWFtb3RvLXUuYWMuanAuJiN4RDtEZXBhcnRtZW50IG9mIFBoYXJtYWNvbG9neSBhbmQgTW9s

ZWN1bGFyIFRoZXJhcGV1dGljcywgS3VtYW1vdG8gVW5pdmVyc2l0eSBHcmFkdWF0ZSBTY2hvb2wg

b2YgTWVkaWNhbCBTY2llbmNlcywgMS0xLTEgSG9uanlvLCBLdW1hbW90bywgODYwLTg1NTYsIEph

cGFuLiBtYW1pbmdqaWUxMTI0QHlhaG9vLmNvLmpwLiYjeEQ7RGVwYXJ0bWVudCBvZiBQaGFybWFj

b2xvZ3kgYW5kIE1vbGVjdWxhciBUaGVyYXBldXRpY3MsIEt1bWFtb3RvIFVuaXZlcnNpdHkgR3Jh

ZHVhdGUgU2Nob29sIG9mIE1lZGljYWwgU2NpZW5jZXMsIDEtMS0xIEhvbmp5bywgS3VtYW1vdG8s

IDg2MC04NTU2LCBKYXBhbi4gMTEzcjUxMzNAc3Qua3VtYW1vdG8tdS5hYy5qcC4mI3hEO0RlcGFy

dG1lbnQgb2YgUGhhcm1hY29sb2d5IGFuZCBNb2xlY3VsYXIgVGhlcmFwZXV0aWNzLCBLdW1hbW90

byBVbml2ZXJzaXR5IEdyYWR1YXRlIFNjaG9vbCBvZiBNZWRpY2FsIFNjaWVuY2VzLCAxLTEtMSBI

b25qeW8sIEt1bWFtb3RvLCA4NjAtODU1NiwgSmFwYW4uIGt1c2FrYUBrdW1hbW90by11LmFjLmpw

LiYjeEQ7RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xvZ3kgYW5kIE1vbGVjdWxhciBUaGVyYXBldXRp

Y3MsIEt1bWFtb3RvIFVuaXZlcnNpdHkgR3JhZHVhdGUgU2Nob29sIG9mIE1lZGljYWwgU2NpZW5j

ZXMsIDEtMS0xIEhvbmp5bywgS3VtYW1vdG8sIDg2MC04NTU2LCBKYXBhbi4gbWl0c3V5YW1AZ3Bv

Lmt1bWFtb3RvLXUuYWMuanAuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+R2x5Y2VtaWMg

Y29udHJvbCB3aXRoIGVtcGFnbGlmbG96aW4sIGEgbm92ZWwgc2VsZWN0aXZlIFNHTFQyIGluaGli

aXRvciwgYW1lbGlvcmF0ZXMgY2FyZGlvdmFzY3VsYXIgaW5qdXJ5IGFuZCBjb2duaXRpdmUgZHlz

ZnVuY3Rpb24gaW4gb2Jlc2UgYW5kIHR5cGUgMiBkaWFiZXRpYyBtaWNlPC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPkNhcmRpb3Zhc2MgRGlhYmV0b2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48

cGFnZXM+MTQ4PC9wYWdlcz48dm9sdW1lPjEzPC92b2x1bWU+PGtleXdvcmRzPjxrZXl3b3JkPkFu

aW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QmVuemh5ZHJ5bCBDb21wb3VuZHMvKnBoYXJtYWNvbG9n

eTwva2V5d29yZD48a2V5d29yZD5CbG9vZCBHbHVjb3NlL2RydWcgZWZmZWN0czwva2V5d29yZD48

a2V5d29yZD5DYXJkaW92YXNjdWxhciBEaXNlYXNlcy9ibG9vZC8qZHJ1ZyB0aGVyYXB5PC9rZXl3

b3JkPjxrZXl3b3JkPkNvZ25pdGlvbiBEaXNvcmRlcnMvKmRydWcgdGhlcmFweS9ldGlvbG9neTwv

a2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBNZWxsaXR1cywgRXhwZXJpbWVudGFsLypkcnVnIHRo

ZXJhcHkvcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkRpYWJldGVzIE1lbGxpdHVz

LCBUeXBlIDIvY29tcGxpY2F0aW9ucy8qZHJ1ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkds

dWNvc2lkZXMvKnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5IeXBvZ2x5Y2VtaWMgQWdl

bnRzLypwaGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29y

ZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+T2Jlc2l0eS8qY29tcGxpY2F0

aW9ucy9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+U29kaXVtLUdsdWNvc2UgVHJh

bnNwb3J0ZXIgMi9hbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzPC9rZXl3b3JkPjwva2V5d29y

ZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5PY3QgMjY8L2RhdGU+

PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDc1LTI4NDAgKEVsZWN0cm9uaWMpJiN4RDsxNDc1

LTI4NDAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1MzQ0Njk0PC9hY2Nlc3Npb24t

bnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3Yv

cHVibWVkLzI1MzQ0Njk0PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQy

MTkwMzE8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExODYvczEyOTMzLTAx

NC0wMTQ4LTE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5v

dGU+

ADDIN EN.CITE.DATA 382,384 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWxsYXI8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS

ZWNOdW0+Mzg5ODwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjM4NTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM4OTg8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkyNDU3NiI+Mzg5ODwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWlsbGFyLCBQLjwvYXV0aG9yPjxhdXRo

b3I+UGF0aGFrLCBOLjwvYXV0aG9yPjxhdXRob3I+UGFydGhzYXJhdGh5LCBWLjwvYXV0aG9yPjxh

dXRob3I+QmpvdXJzb24sIEEuIEouPC9hdXRob3I+PGF1dGhvcj5PJmFwb3M7S2FuZSwgTS48L2F1

dGhvcj48YXV0aG9yPlBhdGhhaywgVi48L2F1dGhvcj48YXV0aG9yPk1vZmZldHQsIFIuIEMuPC9h

dXRob3I+PGF1dGhvcj5GbGF0dCwgUC4gUi48L2F1dGhvcj48YXV0aG9yPkdhdWx0LCBWLiBBLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlNBQUQgQ2VudHJl

IGZvciBQaGFybWFjeSBhbmQgRGlhYmV0ZXNTY2hvb2wgb2YgQmlvbWVkaWNhbCBTY2llbmNlcywg

VW5pdmVyc2l0eSBvZiBVbHN0ZXIsIE5vcnRoZXJuIElyZWxhbmQsIFVLLiYjeEQ7Tm9ydGhlcm4g

SXJlbGFuZCBDZW50cmUgZm9yIFN0cmF0aWZpZWQgTWVkaWNpbmVVbml2ZXJzaXR5IG9mIFVsc3Rl

ciwgQy1UUklDIEJ1aWxkaW5nLCBBbHRuYWdlbHZpbiBIb3NwaXRhbCwgTm9ydGhlcm4gSXJlbGFu

ZCwgVUsuJiN4RDtDbGluaWNhbCBDaGVtaXN0cnkgTGFib3JhdG9yeVdlc3Rlcm4gSGVhbHRoIGFu

ZCBTb2NpYWwgQ2FyZSBUcnVzdCwgQWx0bmFnZWx2aW4gSG9zcGl0YWwsIE5vcnRoZXJuIElyZWxh

bmQsIFVLLiYjeEQ7U0FBRCBDZW50cmUgZm9yIFBoYXJtYWN5IGFuZCBEaWFiZXRlc1NjaG9vbCBv

ZiBCaW9tZWRpY2FsIFNjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIFVsc3RlciwgTm9ydGhlcm4gSXJl

bGFuZCwgVUsgdmEuZ2F1bHRAdWxzdGVyLmFjLnVrLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRp

dGxlPk1ldGFib2xpYyBhbmQgbmV1cm9wcm90ZWN0aXZlIGVmZmVjdHMgb2YgZGFwYWdsaWZsb3pp

biBhbmQgbGlyYWdsdXRpZGUgaW4gZGlhYmV0aWMgbWljZTwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5KIEVuZG9jcmlub2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MjU1LTI2Nzwv

cGFnZXM+PHZvbHVtZT4yMzQ8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48a2V5d29yZHM+PGtl

eXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CZW56aHlkcnlsIENvbXBvdW5kcy8qYWRt

aW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlPC9rZXl3b3JkPjxrZXl3b3JkPkJsb29kIEdsdWNvc2Uv

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBNZWxsaXR1cywgRXhwZXJpbWVu

dGFsLypkcnVnIHRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y2Fnb24vbWV0YWJvbGlzbTwv

a2V5d29yZD48a2V5d29yZD5HbHVjYWdvbi1MaWtlIFBlcHRpZGUgMS9tZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPkdsdWNhZ29uLVNlY3JldGluZyBDZWxscy9tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPkdsdWNvc2lkZXMvKmFkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZTwva2V5d29y

ZD48a2V5d29yZD5HbHljYXRlZCBIZW1vZ2xvYmluIEEvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlwb2dseWNlbWljIEFnZW50cy8qYWRtaW5p

c3RyYXRpb24gJmFtcDsgZG9zYWdlPC9rZXl3b3JkPjxrZXl3b3JkPkluc3VsaW4vbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5JbnRlcmxldWtpbi02L21ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+TGlyYWdsdXRpZGUvKmFkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZTwva2V5d29yZD48

a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TmV1

cm9ucy9kcnVnIGVmZmVjdHMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5OZXVyb3Byb3Rl

Y3RpdmUgQWdlbnRzLyphZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2UvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5HbHAtMTwva2V5d29yZD48a2V5d29yZD5kYXBhZ2xpZmxvemluPC9rZXl3

b3JkPjxrZXl3b3JkPmRpYWJldGVzPC9rZXl3b3JkPjxrZXl3b3JkPmdsdWNhZ29uPC9rZXl3b3Jk

PjxrZXl3b3JkPmxpcmFnbHV0aWRlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5TZXA8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNDc5LTY4MDUgKEVsZWN0cm9uaWMpJiN4RDswMDIyLTA3OTUgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjI4NjExMjExPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI4NjExMjExPC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTMwL0pP

RS0xNy0wMjYzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmRO

b3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWxsYXI8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS

ZWNOdW0+Mzg5ODwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjM4NTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM4OTg8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkyNDU3NiI+Mzg5ODwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWlsbGFyLCBQLjwvYXV0aG9yPjxhdXRo

b3I+UGF0aGFrLCBOLjwvYXV0aG9yPjxhdXRob3I+UGFydGhzYXJhdGh5LCBWLjwvYXV0aG9yPjxh

dXRob3I+QmpvdXJzb24sIEEuIEouPC9hdXRob3I+PGF1dGhvcj5PJmFwb3M7S2FuZSwgTS48L2F1

dGhvcj48YXV0aG9yPlBhdGhhaywgVi48L2F1dGhvcj48YXV0aG9yPk1vZmZldHQsIFIuIEMuPC9h

dXRob3I+PGF1dGhvcj5GbGF0dCwgUC4gUi48L2F1dGhvcj48YXV0aG9yPkdhdWx0LCBWLiBBLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlNBQUQgQ2VudHJl

IGZvciBQaGFybWFjeSBhbmQgRGlhYmV0ZXNTY2hvb2wgb2YgQmlvbWVkaWNhbCBTY2llbmNlcywg

VW5pdmVyc2l0eSBvZiBVbHN0ZXIsIE5vcnRoZXJuIElyZWxhbmQsIFVLLiYjeEQ7Tm9ydGhlcm4g

SXJlbGFuZCBDZW50cmUgZm9yIFN0cmF0aWZpZWQgTWVkaWNpbmVVbml2ZXJzaXR5IG9mIFVsc3Rl

ciwgQy1UUklDIEJ1aWxkaW5nLCBBbHRuYWdlbHZpbiBIb3NwaXRhbCwgTm9ydGhlcm4gSXJlbGFu

ZCwgVUsuJiN4RDtDbGluaWNhbCBDaGVtaXN0cnkgTGFib3JhdG9yeVdlc3Rlcm4gSGVhbHRoIGFu

ZCBTb2NpYWwgQ2FyZSBUcnVzdCwgQWx0bmFnZWx2aW4gSG9zcGl0YWwsIE5vcnRoZXJuIElyZWxh

bmQsIFVLLiYjeEQ7U0FBRCBDZW50cmUgZm9yIFBoYXJtYWN5IGFuZCBEaWFiZXRlc1NjaG9vbCBv

ZiBCaW9tZWRpY2FsIFNjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIFVsc3RlciwgTm9ydGhlcm4gSXJl

bGFuZCwgVUsgdmEuZ2F1bHRAdWxzdGVyLmFjLnVrLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRp

dGxlPk1ldGFib2xpYyBhbmQgbmV1cm9wcm90ZWN0aXZlIGVmZmVjdHMgb2YgZGFwYWdsaWZsb3pp

biBhbmQgbGlyYWdsdXRpZGUgaW4gZGlhYmV0aWMgbWljZTwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5KIEVuZG9jcmlub2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MjU1LTI2Nzwv

cGFnZXM+PHZvbHVtZT4yMzQ8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48a2V5d29yZHM+PGtl

eXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CZW56aHlkcnlsIENvbXBvdW5kcy8qYWRt

aW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlPC9rZXl3b3JkPjxrZXl3b3JkPkJsb29kIEdsdWNvc2Uv

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBNZWxsaXR1cywgRXhwZXJpbWVu

dGFsLypkcnVnIHRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y2Fnb24vbWV0YWJvbGlzbTwv

a2V5d29yZD48a2V5d29yZD5HbHVjYWdvbi1MaWtlIFBlcHRpZGUgMS9tZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPkdsdWNhZ29uLVNlY3JldGluZyBDZWxscy9tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPkdsdWNvc2lkZXMvKmFkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZTwva2V5d29y

ZD48a2V5d29yZD5HbHljYXRlZCBIZW1vZ2xvYmluIEEvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlwb2dseWNlbWljIEFnZW50cy8qYWRtaW5p

c3RyYXRpb24gJmFtcDsgZG9zYWdlPC9rZXl3b3JkPjxrZXl3b3JkPkluc3VsaW4vbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5JbnRlcmxldWtpbi02L21ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+TGlyYWdsdXRpZGUvKmFkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZTwva2V5d29yZD48

a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TmV1

cm9ucy9kcnVnIGVmZmVjdHMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5OZXVyb3Byb3Rl

Y3RpdmUgQWdlbnRzLyphZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2UvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5HbHAtMTwva2V5d29yZD48a2V5d29yZD5kYXBhZ2xpZmxvemluPC9rZXl3

b3JkPjxrZXl3b3JkPmRpYWJldGVzPC9rZXl3b3JkPjxrZXl3b3JkPmdsdWNhZ29uPC9rZXl3b3Jk

PjxrZXl3b3JkPmxpcmFnbHV0aWRlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5TZXA8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xNDc5LTY4MDUgKEVsZWN0cm9uaWMpJiN4RDswMDIyLTA3OTUgKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjI4NjExMjExPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI4NjExMjExPC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xNTMwL0pP

RS0xNy0wMjYzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmRO

b3RlPgB=

ADDIN EN.CITE.DATA 385. This was further accompanied by an improved insulin action, mitochondrial function, synaptic density/plasticity, neurogenesis and in learning and memory in T2D patients and animal models PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaWtrYW5lbjwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+

PFJlY051bT4zODEzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MzgyLTM4NTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM4MTM8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxOTExOSI+MzgxMzwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+VGlra2FuZW4sIElsa2thPC9h

dXRob3I+PGF1dGhvcj5DaGlsdG9uLCBSb2JlcnQ8L2F1dGhvcj48YXV0aG9yPkpvaGFuc2VuLCBP

ZGQgRXJpazwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5Q

b3RlbnRpYWwgcm9sZSBvZiBzb2RpdW0gZ2x1Y29zZSBjb3RyYW5zcG9ydGVyIDIgaW5oaWJpdG9y

cyBpbiB0aGUgdHJlYXRtZW50IG9mIGh5cGVydGVuc2lvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5DdXJyZW50IE9waW5pb24gaW4gTmVwaHJvbG9neSBhbmQgSHlwZXJ0ZW5zaW9uPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjgxLTg2PC9wYWdlcz48dm9sdW1lPjI1PC92b2x1bWU+

PG51bWJlcj4yPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT4yMDE2LzAzPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5PdmlkIFRlY2hu

b2xvZ2llcyAoV29sdGVycyBLbHV3ZXIgSGVhbHRoKTwvcHVibGlzaGVyPjxpc2JuPjEwNjItNDgy

MTwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTA5

Ny9tbmguMDAwMDAwMDAwMDAwMDE5OTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTA5Ny9tbmguMDAwMDAwMDAwMDAwMDE5OTwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+T3R0PC9BdXRob3I+

PFllYXI+MjAxNzwvWWVhcj48UmVjTnVtPjM4OTY8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVy

PjM4OTY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ew

cng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkyNDM4MCI+

Mzg5Njwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi

PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+T3R0LCBDLjwvYXV0

aG9yPjxhdXRob3I+SnVtYXIsIEEuPC9hdXRob3I+PGF1dGhvcj5TdHJpZXBlLCBLLjwvYXV0aG9y

PjxhdXRob3I+RnJpZWRyaWNoLCBTLjwvYXV0aG9yPjxhdXRob3I+S2FyZywgTS4gVi48L2F1dGhv

cj48YXV0aG9yPkJyYW1sYWdlLCBQLjwvYXV0aG9yPjxhdXRob3I+U2NobWllZGVyLCBSLiBFLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQg

b2YgTmVwaHJvbG9neSBhbmQgSHlwZXJ0ZW5zaW9uLCBGcmllZHJpY2gtQWxleGFuZGVyLVVuaXZl

cnNpdHkgRXJsYW5nZW4tTnVybmJlcmcgKEZBVSksIFVsbWVud2VnIDE4LCA5MTA1NCwgRXJsYW5n

ZW4sIEdlcm1hbnkuJiN4RDtJbnN0aXR1dGUgZm9yIFBoYXJtYWNvbG9neSBhbmQgUHJldmVudGl2

ZSBNZWRpY2luZSwgTWFobG93LCBHZXJtYW55LiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXBocm9sb2d5

IGFuZCBIeXBlcnRlbnNpb24sIEZyaWVkcmljaC1BbGV4YW5kZXItVW5pdmVyc2l0eSBFcmxhbmdl

bi1OdXJuYmVyZyAoRkFVKSwgVWxtZW53ZWcgMTgsIDkxMDU0LCBFcmxhbmdlbiwgR2VybWFueS4g

cm9sYW5kLnNjaG1pZWRlckB1ay1lcmxhbmdlbi5kZS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0

aXRsZT5BIHJhbmRvbWlzZWQgc3R1ZHkgb2YgdGhlIGltcGFjdCBvZiB0aGUgU0dMVDIgaW5oaWJp

dG9yIGRhcGFnbGlmbG96aW4gb24gbWljcm92YXNjdWxhciBhbmQgbWFjcm92YXNjdWxhciBjaXJj

dWxhdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5DYXJkaW92YXNjIERpYWJldG9sPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjI2PC9wYWdlcz48dm9sdW1lPjE2PC92b2x1bWU+

PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdv

cmQ+QmVuemh5ZHJ5bCBDb21wb3VuZHMvcGhhcm1hY29sb2d5Lyp0aGVyYXBldXRpYyB1c2U8L2tl

eXdvcmQ+PGtleXdvcmQ+Qmxvb2QgR2x1Y29zZS9kcnVnIGVmZmVjdHMvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5CbG9vZCBQcmVzc3VyZS8qZHJ1ZyBlZmZlY3RzL3BoeXNpb2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+Q3Jvc3MtT3ZlciBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkRpYWJl

dGVzIE1lbGxpdHVzLCBUeXBlIDIvYmxvb2QvKmRydWcgdGhlcmFweS9waHlzaW9wYXRob2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+RG91YmxlLUJsaW5kIE1ldGhvZDwva2V5d29yZD48a2V5d29yZD5G

ZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y29zaWRlcy9waGFybWFjb2xvZ3kvKnRoZXJhcGV1

dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

biBSZXNpc3RhbmNlL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TGFzZXItRG9wcGxlciBG

bG93bWV0cnkvbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1pY3JvY2lyY3VsYXRpb24vKmRydWcgZWZmZWN0cy9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPk1pY3JvdmVzc2Vscy8qZHJ1ZyBlZmZlY3RzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UHJvc3BlY3RpdmUgU3R1ZGllczwva2V5

d29yZD48a2V5d29yZD5Tb2RpdW0tR2x1Y29zZSBUcmFuc3BvcnRlciAyLyphbnRhZ29uaXN0cyAm

YW1wOyBpbmhpYml0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPipBcnRlcmlhbCByZW1vZGVsbGluZzwv

a2V5d29yZD48a2V5d29yZD4qQmxvb2QgcHJlc3N1cmU8L2tleXdvcmQ+PGtleXdvcmQ+Kkluc3Vs

aW4gcmVzaXN0YW5jZTwva2V5d29yZD48a2V5d29yZD4qUHVsc2Ugd2F2ZSBhbmFseXNpczwva2V5

d29yZD48a2V5d29yZD4qU0dMVDIgaW5oaWJpdG9yczwva2V5d29yZD48a2V5d29yZD4qU2Nhbm5p

bmcgbGFzZXIgRG9wcGxlciBmbG93bWV0cnksIHZhc2N1bGFyIHByb3RlY3Rpb248L2tleXdvcmQ+

PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkZlYiAy

MzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0NzUtMjg0MCAoRWxlY3Ryb25pYykm

I3hEOzE0NzUtMjg0MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjgyMzE4MzE8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMjgyMzE4MzE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3Rv

bTI+UE1DNTMyNDI3MjwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTE4Ni9z

MTI5MzMtMDE3LTA1MTAtMTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRl

PjxDaXRlPjxBdXRob3I+TGluPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48UmVjTnVtPjM4OTc8

L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM4OTc8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5

cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1

YXYiIHRpbWVzdGFtcD0iMTUzNTkyNDUwNCI+Mzg5Nzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYt

dHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxh

dXRob3JzPjxhdXRob3I+TGluLCBCLjwvYXV0aG9yPjxhdXRob3I+S29pYnVjaGksIE4uPC9hdXRo

b3I+PGF1dGhvcj5IYXNlZ2F3YSwgWS48L2F1dGhvcj48YXV0aG9yPlN1ZXRhLCBELjwvYXV0aG9y

PjxhdXRob3I+VG95YW1hLCBLLjwvYXV0aG9yPjxhdXRob3I+VWVrYXdhLCBLLjwvYXV0aG9yPjxh

dXRob3I+TWEsIE0uPC9hdXRob3I+PGF1dGhvcj5OYWthZ2F3YSwgVC48L2F1dGhvcj48YXV0aG9y

Pkt1c2FrYSwgSC48L2F1dGhvcj48YXV0aG9yPktpbS1NaXRzdXlhbWEsIFMuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQaGFybWFj

b2xvZ3kgYW5kIE1vbGVjdWxhciBUaGVyYXBldXRpY3MsIEt1bWFtb3RvIFVuaXZlcnNpdHkgR3Jh

ZHVhdGUgU2Nob29sIG9mIE1lZGljYWwgU2NpZW5jZXMsIDEtMS0xIEhvbmp5bywgS3VtYW1vdG8s

IDg2MC04NTU2LCBKYXBhbi4gcGFya21vb24xOTgyQHlhaG9vLmNvLmpwLiYjeEQ7RGVwYXJ0bWVu

dCBvZiBQaGFybWFjb2xvZ3kgYW5kIE1vbGVjdWxhciBUaGVyYXBldXRpY3MsIEt1bWFtb3RvIFVu

aXZlcnNpdHkgR3JhZHVhdGUgU2Nob29sIG9mIE1lZGljYWwgU2NpZW5jZXMsIDEtMS0xIEhvbmp5

bywgS3VtYW1vdG8sIDg2MC04NTU2LCBKYXBhbi4ga29pYnVjaGktY2lyY0B1bWluLmFjLmpwLiYj

eEQ7RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xvZ3kgYW5kIE1vbGVjdWxhciBUaGVyYXBldXRpY3Ms

IEt1bWFtb3RvIFVuaXZlcnNpdHkgR3JhZHVhdGUgU2Nob29sIG9mIE1lZGljYWwgU2NpZW5jZXMs

IDEtMS0xIEhvbmp5bywgS3VtYW1vdG8sIDg2MC04NTU2LCBKYXBhbi4gZnBtaGFzc2VAeWFob28u

Y28uanAuJiN4RDtEZXBhcnRtZW50IG9mIFBoYXJtYWNvbG9neSBhbmQgTW9sZWN1bGFyIFRoZXJh

cGV1dGljcywgS3VtYW1vdG8gVW5pdmVyc2l0eSBHcmFkdWF0ZSBTY2hvb2wgb2YgTWVkaWNhbCBT

Y2llbmNlcywgMS0xLTEgSG9uanlvLCBLdW1hbW90bywgODYwLTg1NTYsIEphcGFuLiBkYWlzdWtl

c3VldGFAZ21haWwuY29tLiYjeEQ7RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xvZ3kgYW5kIE1vbGVj

dWxhciBUaGVyYXBldXRpY3MsIEt1bWFtb3RvIFVuaXZlcnNpdHkgR3JhZHVhdGUgU2Nob29sIG9m

IE1lZGljYWwgU2NpZW5jZXMsIDEtMS0xIEhvbmp5bywgS3VtYW1vdG8sIDg2MC04NTU2LCBKYXBh

bi4gay10b3lhbWFAa3VtYW1vdG8tdS5hYy5qcC4mI3hEO0RlcGFydG1lbnQgb2YgUGhhcm1hY29s

b2d5IGFuZCBNb2xlY3VsYXIgVGhlcmFwZXV0aWNzLCBLdW1hbW90byBVbml2ZXJzaXR5IEdyYWR1

YXRlIFNjaG9vbCBvZiBNZWRpY2FsIFNjaWVuY2VzLCAxLTEtMSBIb25qeW8sIEt1bWFtb3RvLCA4

NjAtODU1NiwgSmFwYW4uIDEwMXI1MTAyQHN0Lmt1bWFtb3RvLXUuYWMuanAuJiN4RDtEZXBhcnRt

ZW50IG9mIFBoYXJtYWNvbG9neSBhbmQgTW9sZWN1bGFyIFRoZXJhcGV1dGljcywgS3VtYW1vdG8g

VW5pdmVyc2l0eSBHcmFkdWF0ZSBTY2hvb2wgb2YgTWVkaWNhbCBTY2llbmNlcywgMS0xLTEgSG9u

anlvLCBLdW1hbW90bywgODYwLTg1NTYsIEphcGFuLiBtYW1pbmdqaWUxMTI0QHlhaG9vLmNvLmpw

LiYjeEQ7RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xvZ3kgYW5kIE1vbGVjdWxhciBUaGVyYXBldXRp

Y3MsIEt1bWFtb3RvIFVuaXZlcnNpdHkgR3JhZHVhdGUgU2Nob29sIG9mIE1lZGljYWwgU2NpZW5j

ZXMsIDEtMS0xIEhvbmp5bywgS3VtYW1vdG8sIDg2MC04NTU2LCBKYXBhbi4gMTEzcjUxMzNAc3Qu

a3VtYW1vdG8tdS5hYy5qcC4mI3hEO0RlcGFydG1lbnQgb2YgUGhhcm1hY29sb2d5IGFuZCBNb2xl

Y3VsYXIgVGhlcmFwZXV0aWNzLCBLdW1hbW90byBVbml2ZXJzaXR5IEdyYWR1YXRlIFNjaG9vbCBv

ZiBNZWRpY2FsIFNjaWVuY2VzLCAxLTEtMSBIb25qeW8sIEt1bWFtb3RvLCA4NjAtODU1NiwgSmFw

YW4uIGt1c2FrYUBrdW1hbW90by11LmFjLmpwLiYjeEQ7RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xv

Z3kgYW5kIE1vbGVjdWxhciBUaGVyYXBldXRpY3MsIEt1bWFtb3RvIFVuaXZlcnNpdHkgR3JhZHVh

dGUgU2Nob29sIG9mIE1lZGljYWwgU2NpZW5jZXMsIDEtMS0xIEhvbmp5bywgS3VtYW1vdG8sIDg2

MC04NTU2LCBKYXBhbi4gbWl0c3V5YW1AZ3BvLmt1bWFtb3RvLXUuYWMuanAuPC9hdXRoLWFkZHJl

c3M+PHRpdGxlcz48dGl0bGU+R2x5Y2VtaWMgY29udHJvbCB3aXRoIGVtcGFnbGlmbG96aW4sIGEg

bm92ZWwgc2VsZWN0aXZlIFNHTFQyIGluaGliaXRvciwgYW1lbGlvcmF0ZXMgY2FyZGlvdmFzY3Vs

YXIgaW5qdXJ5IGFuZCBjb2duaXRpdmUgZHlzZnVuY3Rpb24gaW4gb2Jlc2UgYW5kIHR5cGUgMiBk

aWFiZXRpYyBtaWNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNhcmRpb3Zhc2MgRGlhYmV0b2w8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTQ4PC9wYWdlcz48dm9sdW1lPjEzPC92

b2x1bWU+PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QmVuemh5

ZHJ5bCBDb21wb3VuZHMvKnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5CbG9vZCBHbHVj

b3NlL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5DYXJkaW92YXNjdWxhciBEaXNlYXNl

cy9ibG9vZC8qZHJ1ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbiBEaXNvcmRl

cnMvKmRydWcgdGhlcmFweS9ldGlvbG9neTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBNZWxs

aXR1cywgRXhwZXJpbWVudGFsLypkcnVnIHRoZXJhcHkvcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkRpYWJldGVzIE1lbGxpdHVzLCBUeXBlIDIvY29tcGxpY2F0aW9ucy8qZHJ1ZyB0

aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkdsdWNvc2lkZXMvKnBoYXJtYWNvbG9neTwva2V5d29y

ZD48a2V5d29yZD5IeXBvZ2x5Y2VtaWMgQWdlbnRzLypwaGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+

PGtleXdvcmQ+T2Jlc2l0eS8qY29tcGxpY2F0aW9ucy9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+U29kaXVtLUdsdWNvc2UgVHJhbnNwb3J0ZXIgMi9hbnRhZ29uaXN0cyAmYW1wOyBp

bmhpYml0b3JzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT5PY3QgMjY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDc1

LTI4NDAgKEVsZWN0cm9uaWMpJiN4RDsxNDc1LTI4NDAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI1MzQ0Njk0PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI1MzQ0Njk0PC91cmw+PC9yZWxhdGVk

LXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQyMTkwMzE8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjEwLjExODYvczEyOTMzLTAxNC0wMTQ4LTE8L2VsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk1pbGxhcjwvQXV0aG9yPjxZZWFyPjIw

MTc8L1llYXI+PFJlY051bT4zODk4PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zODk4PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MjQ1NzYiPjM4OTg8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1pbGxhciwgUC48L2F1dGhvcj48

YXV0aG9yPlBhdGhhaywgTi48L2F1dGhvcj48YXV0aG9yPlBhcnRoc2FyYXRoeSwgVi48L2F1dGhv

cj48YXV0aG9yPkJqb3Vyc29uLCBBLiBKLjwvYXV0aG9yPjxhdXRob3I+TyZhcG9zO0thbmUsIE0u

PC9hdXRob3I+PGF1dGhvcj5QYXRoYWssIFYuPC9hdXRob3I+PGF1dGhvcj5Nb2ZmZXR0LCBSLiBD

LjwvYXV0aG9yPjxhdXRob3I+RmxhdHQsIFAuIFIuPC9hdXRob3I+PGF1dGhvcj5HYXVsdCwgVi4g

QS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5TQUFEIENl

bnRyZSBmb3IgUGhhcm1hY3kgYW5kIERpYWJldGVzU2Nob29sIG9mIEJpb21lZGljYWwgU2NpZW5j

ZXMsIFVuaXZlcnNpdHkgb2YgVWxzdGVyLCBOb3J0aGVybiBJcmVsYW5kLCBVSy4mI3hEO05vcnRo

ZXJuIElyZWxhbmQgQ2VudHJlIGZvciBTdHJhdGlmaWVkIE1lZGljaW5lVW5pdmVyc2l0eSBvZiBV

bHN0ZXIsIEMtVFJJQyBCdWlsZGluZywgQWx0bmFnZWx2aW4gSG9zcGl0YWwsIE5vcnRoZXJuIEly

ZWxhbmQsIFVLLiYjeEQ7Q2xpbmljYWwgQ2hlbWlzdHJ5IExhYm9yYXRvcnlXZXN0ZXJuIEhlYWx0

aCBhbmQgU29jaWFsIENhcmUgVHJ1c3QsIEFsdG5hZ2VsdmluIEhvc3BpdGFsLCBOb3J0aGVybiBJ

cmVsYW5kLCBVSy4mI3hEO1NBQUQgQ2VudHJlIGZvciBQaGFybWFjeSBhbmQgRGlhYmV0ZXNTY2hv

b2wgb2YgQmlvbWVkaWNhbCBTY2llbmNlcywgVW5pdmVyc2l0eSBvZiBVbHN0ZXIsIE5vcnRoZXJu

IElyZWxhbmQsIFVLIHZhLmdhdWx0QHVsc3Rlci5hYy51ay48L2F1dGgtYWRkcmVzcz48dGl0bGVz

Pjx0aXRsZT5NZXRhYm9saWMgYW5kIG5ldXJvcHJvdGVjdGl2ZSBlZmZlY3RzIG9mIGRhcGFnbGlm

bG96aW4gYW5kIGxpcmFnbHV0aWRlIGluIGRpYWJldGljIG1pY2U8L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+SiBFbmRvY3Jpbm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjI1NS0y

Njc8L3BhZ2VzPjx2b2x1bWU+MjM0PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGtleXdvcmRz

PjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QmVuemh5ZHJ5bCBDb21wb3VuZHMv

KmFkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZTwva2V5d29yZD48a2V5d29yZD5CbG9vZCBHbHVj

b3NlL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgTWVsbGl0dXMsIEV4cGVy

aW1lbnRhbC8qZHJ1ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkdsdWNhZ29uL21ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y2Fnb24tTGlrZSBQZXB0aWRlIDEvbWV0YWJvbGlzbTwv

a2V5d29yZD48a2V5d29yZD5HbHVjYWdvbi1TZWNyZXRpbmcgQ2VsbHMvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5HbHVjb3NpZGVzLyphZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2U8L2tl

eXdvcmQ+PGtleXdvcmQ+R2x5Y2F0ZWQgSGVtb2dsb2JpbiBBL21ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBBZ2VudHMvKmFk

bWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZTwva2V5d29yZD48a2V5d29yZD5JbnN1bGluL21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXJsZXVraW4tNi9tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPkxpcmFnbHV0aWRlLyphZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2U8L2tleXdv

cmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3Jk

Pk5ldXJvbnMvZHJ1ZyBlZmZlY3RzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9w

cm90ZWN0aXZlIEFnZW50cy8qYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlL21ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+R2xwLTE8L2tleXdvcmQ+PGtleXdvcmQ+ZGFwYWdsaWZsb3ppbjwv

a2V5d29yZD48a2V5d29yZD5kaWFiZXRlczwva2V5d29yZD48a2V5d29yZD5nbHVjYWdvbjwva2V5

d29yZD48a2V5d29yZD5saXJhZ2x1dGlkZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVh

cj4yMDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0

ZXM+PGlzYm4+MTQ3OS02ODA1IChFbGVjdHJvbmljKSYjeEQ7MDAyMi0wNzk1IChMaW5raW5nKTwv

aXNibj48YWNjZXNzaW9uLW51bT4yODYxMTIxMTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRl

ZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yODYxMTIxMTwv

dXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTUz

MC9KT0UtMTctMDI2MzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwv

RW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaWtrYW5lbjwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+

PFJlY051bT4zODEzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MzgyLTM4NTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM4MTM8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkxOTExOSI+MzgxMzwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+VGlra2FuZW4sIElsa2thPC9h

dXRob3I+PGF1dGhvcj5DaGlsdG9uLCBSb2JlcnQ8L2F1dGhvcj48YXV0aG9yPkpvaGFuc2VuLCBP

ZGQgRXJpazwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5Q

b3RlbnRpYWwgcm9sZSBvZiBzb2RpdW0gZ2x1Y29zZSBjb3RyYW5zcG9ydGVyIDIgaW5oaWJpdG9y

cyBpbiB0aGUgdHJlYXRtZW50IG9mIGh5cGVydGVuc2lvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5DdXJyZW50IE9waW5pb24gaW4gTmVwaHJvbG9neSBhbmQgSHlwZXJ0ZW5zaW9uPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjgxLTg2PC9wYWdlcz48dm9sdW1lPjI1PC92b2x1bWU+

PG51bWJlcj4yPC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT4yMDE2LzAzPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHB1Ymxpc2hlcj5PdmlkIFRlY2hu

b2xvZ2llcyAoV29sdGVycyBLbHV3ZXIgSGVhbHRoKTwvcHVibGlzaGVyPjxpc2JuPjEwNjItNDgy

MTwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTA5

Ny9tbmguMDAwMDAwMDAwMDAwMDE5OTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTA5Ny9tbmguMDAwMDAwMDAwMDAwMDE5OTwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+T3R0PC9BdXRob3I+

PFllYXI+MjAxNzwvWWVhcj48UmVjTnVtPjM4OTY8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVy

PjM4OTY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ew

cng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTkyNDM4MCI+

Mzg5Njwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi

PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+T3R0LCBDLjwvYXV0

aG9yPjxhdXRob3I+SnVtYXIsIEEuPC9hdXRob3I+PGF1dGhvcj5TdHJpZXBlLCBLLjwvYXV0aG9y

PjxhdXRob3I+RnJpZWRyaWNoLCBTLjwvYXV0aG9yPjxhdXRob3I+S2FyZywgTS4gVi48L2F1dGhv

cj48YXV0aG9yPkJyYW1sYWdlLCBQLjwvYXV0aG9yPjxhdXRob3I+U2NobWllZGVyLCBSLiBFLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQg

b2YgTmVwaHJvbG9neSBhbmQgSHlwZXJ0ZW5zaW9uLCBGcmllZHJpY2gtQWxleGFuZGVyLVVuaXZl

cnNpdHkgRXJsYW5nZW4tTnVybmJlcmcgKEZBVSksIFVsbWVud2VnIDE4LCA5MTA1NCwgRXJsYW5n

ZW4sIEdlcm1hbnkuJiN4RDtJbnN0aXR1dGUgZm9yIFBoYXJtYWNvbG9neSBhbmQgUHJldmVudGl2

ZSBNZWRpY2luZSwgTWFobG93LCBHZXJtYW55LiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXBocm9sb2d5

IGFuZCBIeXBlcnRlbnNpb24sIEZyaWVkcmljaC1BbGV4YW5kZXItVW5pdmVyc2l0eSBFcmxhbmdl

bi1OdXJuYmVyZyAoRkFVKSwgVWxtZW53ZWcgMTgsIDkxMDU0LCBFcmxhbmdlbiwgR2VybWFueS4g

cm9sYW5kLnNjaG1pZWRlckB1ay1lcmxhbmdlbi5kZS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0

aXRsZT5BIHJhbmRvbWlzZWQgc3R1ZHkgb2YgdGhlIGltcGFjdCBvZiB0aGUgU0dMVDIgaW5oaWJp

dG9yIGRhcGFnbGlmbG96aW4gb24gbWljcm92YXNjdWxhciBhbmQgbWFjcm92YXNjdWxhciBjaXJj

dWxhdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5DYXJkaW92YXNjIERpYWJldG9sPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjI2PC9wYWdlcz48dm9sdW1lPjE2PC92b2x1bWU+

PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdv

cmQ+QmVuemh5ZHJ5bCBDb21wb3VuZHMvcGhhcm1hY29sb2d5Lyp0aGVyYXBldXRpYyB1c2U8L2tl

eXdvcmQ+PGtleXdvcmQ+Qmxvb2QgR2x1Y29zZS9kcnVnIGVmZmVjdHMvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5CbG9vZCBQcmVzc3VyZS8qZHJ1ZyBlZmZlY3RzL3BoeXNpb2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+Q3Jvc3MtT3ZlciBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkRpYWJl

dGVzIE1lbGxpdHVzLCBUeXBlIDIvYmxvb2QvKmRydWcgdGhlcmFweS9waHlzaW9wYXRob2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+RG91YmxlLUJsaW5kIE1ldGhvZDwva2V5d29yZD48a2V5d29yZD5G

ZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y29zaWRlcy9waGFybWFjb2xvZ3kvKnRoZXJhcGV1

dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

biBSZXNpc3RhbmNlL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TGFzZXItRG9wcGxlciBG

bG93bWV0cnkvbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1pY3JvY2lyY3VsYXRpb24vKmRydWcgZWZmZWN0cy9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPk1pY3JvdmVzc2Vscy8qZHJ1ZyBlZmZlY3RzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UHJvc3BlY3RpdmUgU3R1ZGllczwva2V5

d29yZD48a2V5d29yZD5Tb2RpdW0tR2x1Y29zZSBUcmFuc3BvcnRlciAyLyphbnRhZ29uaXN0cyAm

YW1wOyBpbmhpYml0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPipBcnRlcmlhbCByZW1vZGVsbGluZzwv

a2V5d29yZD48a2V5d29yZD4qQmxvb2QgcHJlc3N1cmU8L2tleXdvcmQ+PGtleXdvcmQ+Kkluc3Vs

aW4gcmVzaXN0YW5jZTwva2V5d29yZD48a2V5d29yZD4qUHVsc2Ugd2F2ZSBhbmFseXNpczwva2V5

d29yZD48a2V5d29yZD4qU0dMVDIgaW5oaWJpdG9yczwva2V5d29yZD48a2V5d29yZD4qU2Nhbm5p

bmcgbGFzZXIgRG9wcGxlciBmbG93bWV0cnksIHZhc2N1bGFyIHByb3RlY3Rpb248L2tleXdvcmQ+

PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkZlYiAy

MzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0NzUtMjg0MCAoRWxlY3Ryb25pYykm

I3hEOzE0NzUtMjg0MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjgyMzE4MzE8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMjgyMzE4MzE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3Rv

bTI+UE1DNTMyNDI3MjwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTE4Ni9z

MTI5MzMtMDE3LTA1MTAtMTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRl

PjxDaXRlPjxBdXRob3I+TGluPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48UmVjTnVtPjM4OTc8

L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM4OTc8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5

cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1

YXYiIHRpbWVzdGFtcD0iMTUzNTkyNDUwNCI+Mzg5Nzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYt

dHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxh

dXRob3JzPjxhdXRob3I+TGluLCBCLjwvYXV0aG9yPjxhdXRob3I+S29pYnVjaGksIE4uPC9hdXRo

b3I+PGF1dGhvcj5IYXNlZ2F3YSwgWS48L2F1dGhvcj48YXV0aG9yPlN1ZXRhLCBELjwvYXV0aG9y

PjxhdXRob3I+VG95YW1hLCBLLjwvYXV0aG9yPjxhdXRob3I+VWVrYXdhLCBLLjwvYXV0aG9yPjxh

dXRob3I+TWEsIE0uPC9hdXRob3I+PGF1dGhvcj5OYWthZ2F3YSwgVC48L2F1dGhvcj48YXV0aG9y

Pkt1c2FrYSwgSC48L2F1dGhvcj48YXV0aG9yPktpbS1NaXRzdXlhbWEsIFMuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQaGFybWFj

b2xvZ3kgYW5kIE1vbGVjdWxhciBUaGVyYXBldXRpY3MsIEt1bWFtb3RvIFVuaXZlcnNpdHkgR3Jh

ZHVhdGUgU2Nob29sIG9mIE1lZGljYWwgU2NpZW5jZXMsIDEtMS0xIEhvbmp5bywgS3VtYW1vdG8s

IDg2MC04NTU2LCBKYXBhbi4gcGFya21vb24xOTgyQHlhaG9vLmNvLmpwLiYjeEQ7RGVwYXJ0bWVu

dCBvZiBQaGFybWFjb2xvZ3kgYW5kIE1vbGVjdWxhciBUaGVyYXBldXRpY3MsIEt1bWFtb3RvIFVu

aXZlcnNpdHkgR3JhZHVhdGUgU2Nob29sIG9mIE1lZGljYWwgU2NpZW5jZXMsIDEtMS0xIEhvbmp5

bywgS3VtYW1vdG8sIDg2MC04NTU2LCBKYXBhbi4ga29pYnVjaGktY2lyY0B1bWluLmFjLmpwLiYj

eEQ7RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xvZ3kgYW5kIE1vbGVjdWxhciBUaGVyYXBldXRpY3Ms

IEt1bWFtb3RvIFVuaXZlcnNpdHkgR3JhZHVhdGUgU2Nob29sIG9mIE1lZGljYWwgU2NpZW5jZXMs

IDEtMS0xIEhvbmp5bywgS3VtYW1vdG8sIDg2MC04NTU2LCBKYXBhbi4gZnBtaGFzc2VAeWFob28u

Y28uanAuJiN4RDtEZXBhcnRtZW50IG9mIFBoYXJtYWNvbG9neSBhbmQgTW9sZWN1bGFyIFRoZXJh

cGV1dGljcywgS3VtYW1vdG8gVW5pdmVyc2l0eSBHcmFkdWF0ZSBTY2hvb2wgb2YgTWVkaWNhbCBT

Y2llbmNlcywgMS0xLTEgSG9uanlvLCBLdW1hbW90bywgODYwLTg1NTYsIEphcGFuLiBkYWlzdWtl

c3VldGFAZ21haWwuY29tLiYjeEQ7RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xvZ3kgYW5kIE1vbGVj

dWxhciBUaGVyYXBldXRpY3MsIEt1bWFtb3RvIFVuaXZlcnNpdHkgR3JhZHVhdGUgU2Nob29sIG9m

IE1lZGljYWwgU2NpZW5jZXMsIDEtMS0xIEhvbmp5bywgS3VtYW1vdG8sIDg2MC04NTU2LCBKYXBh

bi4gay10b3lhbWFAa3VtYW1vdG8tdS5hYy5qcC4mI3hEO0RlcGFydG1lbnQgb2YgUGhhcm1hY29s

b2d5IGFuZCBNb2xlY3VsYXIgVGhlcmFwZXV0aWNzLCBLdW1hbW90byBVbml2ZXJzaXR5IEdyYWR1

YXRlIFNjaG9vbCBvZiBNZWRpY2FsIFNjaWVuY2VzLCAxLTEtMSBIb25qeW8sIEt1bWFtb3RvLCA4

NjAtODU1NiwgSmFwYW4uIDEwMXI1MTAyQHN0Lmt1bWFtb3RvLXUuYWMuanAuJiN4RDtEZXBhcnRt

ZW50IG9mIFBoYXJtYWNvbG9neSBhbmQgTW9sZWN1bGFyIFRoZXJhcGV1dGljcywgS3VtYW1vdG8g

VW5pdmVyc2l0eSBHcmFkdWF0ZSBTY2hvb2wgb2YgTWVkaWNhbCBTY2llbmNlcywgMS0xLTEgSG9u

anlvLCBLdW1hbW90bywgODYwLTg1NTYsIEphcGFuLiBtYW1pbmdqaWUxMTI0QHlhaG9vLmNvLmpw

LiYjeEQ7RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xvZ3kgYW5kIE1vbGVjdWxhciBUaGVyYXBldXRp

Y3MsIEt1bWFtb3RvIFVuaXZlcnNpdHkgR3JhZHVhdGUgU2Nob29sIG9mIE1lZGljYWwgU2NpZW5j

ZXMsIDEtMS0xIEhvbmp5bywgS3VtYW1vdG8sIDg2MC04NTU2LCBKYXBhbi4gMTEzcjUxMzNAc3Qu

a3VtYW1vdG8tdS5hYy5qcC4mI3hEO0RlcGFydG1lbnQgb2YgUGhhcm1hY29sb2d5IGFuZCBNb2xl

Y3VsYXIgVGhlcmFwZXV0aWNzLCBLdW1hbW90byBVbml2ZXJzaXR5IEdyYWR1YXRlIFNjaG9vbCBv

ZiBNZWRpY2FsIFNjaWVuY2VzLCAxLTEtMSBIb25qeW8sIEt1bWFtb3RvLCA4NjAtODU1NiwgSmFw

YW4uIGt1c2FrYUBrdW1hbW90by11LmFjLmpwLiYjeEQ7RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xv

Z3kgYW5kIE1vbGVjdWxhciBUaGVyYXBldXRpY3MsIEt1bWFtb3RvIFVuaXZlcnNpdHkgR3JhZHVh

dGUgU2Nob29sIG9mIE1lZGljYWwgU2NpZW5jZXMsIDEtMS0xIEhvbmp5bywgS3VtYW1vdG8sIDg2

MC04NTU2LCBKYXBhbi4gbWl0c3V5YW1AZ3BvLmt1bWFtb3RvLXUuYWMuanAuPC9hdXRoLWFkZHJl

c3M+PHRpdGxlcz48dGl0bGU+R2x5Y2VtaWMgY29udHJvbCB3aXRoIGVtcGFnbGlmbG96aW4sIGEg

bm92ZWwgc2VsZWN0aXZlIFNHTFQyIGluaGliaXRvciwgYW1lbGlvcmF0ZXMgY2FyZGlvdmFzY3Vs

YXIgaW5qdXJ5IGFuZCBjb2duaXRpdmUgZHlzZnVuY3Rpb24gaW4gb2Jlc2UgYW5kIHR5cGUgMiBk

aWFiZXRpYyBtaWNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNhcmRpb3Zhc2MgRGlhYmV0b2w8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTQ4PC9wYWdlcz48dm9sdW1lPjEzPC92

b2x1bWU+PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QmVuemh5

ZHJ5bCBDb21wb3VuZHMvKnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5CbG9vZCBHbHVj

b3NlL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5DYXJkaW92YXNjdWxhciBEaXNlYXNl

cy9ibG9vZC8qZHJ1ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbiBEaXNvcmRl

cnMvKmRydWcgdGhlcmFweS9ldGlvbG9neTwva2V5d29yZD48a2V5d29yZD5EaWFiZXRlcyBNZWxs

aXR1cywgRXhwZXJpbWVudGFsLypkcnVnIHRoZXJhcHkvcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkRpYWJldGVzIE1lbGxpdHVzLCBUeXBlIDIvY29tcGxpY2F0aW9ucy8qZHJ1ZyB0

aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkdsdWNvc2lkZXMvKnBoYXJtYWNvbG9neTwva2V5d29y

ZD48a2V5d29yZD5IeXBvZ2x5Y2VtaWMgQWdlbnRzLypwaGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+

PGtleXdvcmQ+T2Jlc2l0eS8qY29tcGxpY2F0aW9ucy9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+U29kaXVtLUdsdWNvc2UgVHJhbnNwb3J0ZXIgMi9hbnRhZ29uaXN0cyAmYW1wOyBp

bmhpYml0b3JzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT5PY3QgMjY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDc1

LTI4NDAgKEVsZWN0cm9uaWMpJiN4RDsxNDc1LTI4NDAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI1MzQ0Njk0PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI1MzQ0Njk0PC91cmw+PC9yZWxhdGVk

LXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQyMTkwMzE8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjEwLjExODYvczEyOTMzLTAxNC0wMTQ4LTE8L2VsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk1pbGxhcjwvQXV0aG9yPjxZZWFyPjIw

MTc8L1llYXI+PFJlY051bT4zODk4PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zODk4PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzU5MjQ1NzYiPjM4OTg8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1pbGxhciwgUC48L2F1dGhvcj48

YXV0aG9yPlBhdGhhaywgTi48L2F1dGhvcj48YXV0aG9yPlBhcnRoc2FyYXRoeSwgVi48L2F1dGhv

cj48YXV0aG9yPkJqb3Vyc29uLCBBLiBKLjwvYXV0aG9yPjxhdXRob3I+TyZhcG9zO0thbmUsIE0u

PC9hdXRob3I+PGF1dGhvcj5QYXRoYWssIFYuPC9hdXRob3I+PGF1dGhvcj5Nb2ZmZXR0LCBSLiBD

LjwvYXV0aG9yPjxhdXRob3I+RmxhdHQsIFAuIFIuPC9hdXRob3I+PGF1dGhvcj5HYXVsdCwgVi4g

QS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5TQUFEIENl

bnRyZSBmb3IgUGhhcm1hY3kgYW5kIERpYWJldGVzU2Nob29sIG9mIEJpb21lZGljYWwgU2NpZW5j

ZXMsIFVuaXZlcnNpdHkgb2YgVWxzdGVyLCBOb3J0aGVybiBJcmVsYW5kLCBVSy4mI3hEO05vcnRo

ZXJuIElyZWxhbmQgQ2VudHJlIGZvciBTdHJhdGlmaWVkIE1lZGljaW5lVW5pdmVyc2l0eSBvZiBV

bHN0ZXIsIEMtVFJJQyBCdWlsZGluZywgQWx0bmFnZWx2aW4gSG9zcGl0YWwsIE5vcnRoZXJuIEly

ZWxhbmQsIFVLLiYjeEQ7Q2xpbmljYWwgQ2hlbWlzdHJ5IExhYm9yYXRvcnlXZXN0ZXJuIEhlYWx0

aCBhbmQgU29jaWFsIENhcmUgVHJ1c3QsIEFsdG5hZ2VsdmluIEhvc3BpdGFsLCBOb3J0aGVybiBJ

cmVsYW5kLCBVSy4mI3hEO1NBQUQgQ2VudHJlIGZvciBQaGFybWFjeSBhbmQgRGlhYmV0ZXNTY2hv

b2wgb2YgQmlvbWVkaWNhbCBTY2llbmNlcywgVW5pdmVyc2l0eSBvZiBVbHN0ZXIsIE5vcnRoZXJu

IElyZWxhbmQsIFVLIHZhLmdhdWx0QHVsc3Rlci5hYy51ay48L2F1dGgtYWRkcmVzcz48dGl0bGVz

Pjx0aXRsZT5NZXRhYm9saWMgYW5kIG5ldXJvcHJvdGVjdGl2ZSBlZmZlY3RzIG9mIGRhcGFnbGlm

bG96aW4gYW5kIGxpcmFnbHV0aWRlIGluIGRpYWJldGljIG1pY2U8L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+SiBFbmRvY3Jpbm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjI1NS0y

Njc8L3BhZ2VzPjx2b2x1bWU+MjM0PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGtleXdvcmRz

PjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QmVuemh5ZHJ5bCBDb21wb3VuZHMv

KmFkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZTwva2V5d29yZD48a2V5d29yZD5CbG9vZCBHbHVj

b3NlL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgTWVsbGl0dXMsIEV4cGVy

aW1lbnRhbC8qZHJ1ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkdsdWNhZ29uL21ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y2Fnb24tTGlrZSBQZXB0aWRlIDEvbWV0YWJvbGlzbTwv

a2V5d29yZD48a2V5d29yZD5HbHVjYWdvbi1TZWNyZXRpbmcgQ2VsbHMvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5HbHVjb3NpZGVzLyphZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2U8L2tl

eXdvcmQ+PGtleXdvcmQ+R2x5Y2F0ZWQgSGVtb2dsb2JpbiBBL21ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9nbHljZW1pYyBBZ2VudHMvKmFk

bWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZTwva2V5d29yZD48a2V5d29yZD5JbnN1bGluL21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXJsZXVraW4tNi9tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPkxpcmFnbHV0aWRlLyphZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2U8L2tleXdv

cmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3Jk

Pk5ldXJvbnMvZHJ1ZyBlZmZlY3RzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9w

cm90ZWN0aXZlIEFnZW50cy8qYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlL21ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+R2xwLTE8L2tleXdvcmQ+PGtleXdvcmQ+ZGFwYWdsaWZsb3ppbjwv

a2V5d29yZD48a2V5d29yZD5kaWFiZXRlczwva2V5d29yZD48a2V5d29yZD5nbHVjYWdvbjwva2V5

d29yZD48a2V5d29yZD5saXJhZ2x1dGlkZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVh

cj4yMDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0

ZXM+PGlzYm4+MTQ3OS02ODA1IChFbGVjdHJvbmljKSYjeEQ7MDAyMi0wNzk1IChMaW5raW5nKTwv

aXNibj48YWNjZXNzaW9uLW51bT4yODYxMTIxMTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRl

ZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yODYxMTIxMTwv

dXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTUz

MC9KT0UtMTctMDI2MzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwv

RW5kTm90ZT5=

ADDIN EN.CITE.DATA 382-385.To our knowledge, there are no current clinical trials on the use of SGLT2 inhibitors to tackle AD.ConclusionsIn sum, one can hypothesize that, either by ameliorating peripheral insulin action and glucose homeostasis and/or by crossing the blood-brain barrier and exerting similar effects in the central nervous system, anti-T2D drugs from the different classes may represent promising therapeutic approaches to tackle AD (Fig. 5).Figure 5. T2D drugs for treating AD. Strategies to improve insulin actions in AD brains could act by ameliorating peripheral insulin action or cross directly into the CNS to restore glucose homeostasis. Restoring brain cholesterol metabolism by CYP46A1 gene therapyIncreasing evidence demonstrate the role of brain cholesterol in the physiopathology of neurodegenerative disease particularly in Alzheimer’s disease and Huntington’s disease ADDIN EN.CITE <EndNote><Cite><Author>Di Paolo</Author><Year>2011</Year><RecNum>4172</RecNum><DisplayText><style face="superscript">386</style></DisplayText><record><rec-number>4172</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1536776953">4172</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Di Paolo, G.</author><author>Kim, T. W.</author></authors></contributors><auth-address>Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer&apos;s Disease and the Aging Brain, Columbia University Medical Center, 630 West 168th Street, New York, New York 10032, USA. gil.dipaolo@columbia.edu</auth-address><titles><title>Linking lipids to Alzheimer&apos;s disease: cholesterol and beyond</title><secondary-title>Nat Rev Neurosci</secondary-title></titles><pages>284-96</pages><volume>12</volume><number>5</number><keywords><keyword>Alzheimer Disease/drug therapy/*metabolism</keyword><keyword>Amyloid beta-Peptides/metabolism</keyword><keyword>Animals</keyword><keyword>Cholesterol/*metabolism</keyword><keyword>Humans</keyword><keyword>Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use</keyword><keyword>Lipid Metabolism/*physiology</keyword><keyword>*Lipids</keyword><keyword>Models, Biological</keyword><keyword>Signal Transduction/physiology</keyword></keywords><dates><year>2011</year><pub-dates><date>May</date></pub-dates></dates><isbn>1471-0048 (Electronic)&#xD;1471-003X (Linking)</isbn><accession-num>21448224</accession-num><urls><related-urls><url>, ADDIN EN.CITE <EndNote><Cite><Author>Karasinska</Author><Year>2011</Year><RecNum>4320</RecNum><DisplayText><style face="superscript">387</style></DisplayText><record><rec-number>4320</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1540931242">4320</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Karasinska, J. M.</author><author>Hayden, M. R.</author></authors></contributors><auth-address>Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada.</auth-address><titles><title>Cholesterol metabolism in Huntington disease</title><secondary-title>Nat Rev Neurol</secondary-title></titles><periodical><full-title>Nat Rev Neurol</full-title></periodical><pages>561-72</pages><volume>7</volume><number>10</number><keywords><keyword>Animals</keyword><keyword>Brain/*metabolism/pathology</keyword><keyword>Cholesterol/*metabolism</keyword><keyword>Humans</keyword><keyword>Huntington Disease/*metabolism/pathology</keyword><keyword>Nerve Degeneration/*metabolism/pathology</keyword></keywords><dates><year>2011</year><pub-dates><date>Sep 6</date></pub-dates></dates><isbn>1759-4766 (Electronic)&#xD;1759-4758 (Linking)</isbn><accession-num>21894212</accession-num><urls><related-urls><url>. Brain contains a particularly high portion of total body cholesterol, since our brain represents 2% of our body weight, but contains 25% of total cholesterol. Beside the important (70%) myelin fraction, brain cholesterol is a major constituent of neuronal membranes and plays crucial role in synaptic function and neuronal survival.Increasing arguments link brain cholesterol metabolism and AD. Tangles of Tau are observed In Niemann Pick-C, a genetic disease of cholesterol metabolism, confirming the direct connection between dysfunction of cholesterol in the brain and the tangles of Tau. The role of ApoE, the main cholesterol transporter in the brain, and of the ApoE4 allele has been long recognized as the main risk factor (after age) for Alzheimer’s disease6. More recently, GWAS analysis have identified several genes of lipid metabolism, like SORL, ABCA7 and CLU in association with ADPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Kb25lczwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl

Y051bT4yMDY1PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDY1PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ3Nzk5NjEiPjIwNjU8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkpvbmVzLCBMLjwvYXV0aG9yPjxhdXRob3I+

SG9sbWFucywgUC4gQS48L2F1dGhvcj48YXV0aG9yPkhhbXNoZXJlLCBNLiBMLjwvYXV0aG9yPjxh

dXRob3I+SGFyb2xkLCBELjwvYXV0aG9yPjxhdXRob3I+TW9za3ZpbmEsIFYuPC9hdXRob3I+PGF1

dGhvcj5JdmFub3YsIEQuPC9hdXRob3I+PGF1dGhvcj5Qb2NrbGluZ3RvbiwgQS48L2F1dGhvcj48

YXV0aG9yPkFicmFoYW0sIFIuPC9hdXRob3I+PGF1dGhvcj5Ib2xsaW5nd29ydGgsIFAuPC9hdXRo

b3I+PGF1dGhvcj5TaW1zLCBSLjwvYXV0aG9yPjxhdXRob3I+R2VycmlzaCwgQS48L2F1dGhvcj48

YXV0aG9yPlBhaHdhLCBKLiBTLjwvYXV0aG9yPjxhdXRob3I+Sm9uZXMsIE4uPC9hdXRob3I+PGF1

dGhvcj5TdHJldHRvbiwgQS48L2F1dGhvcj48YXV0aG9yPk1vcmdhbiwgQS4gUi48L2F1dGhvcj48

YXV0aG9yPkxvdmVzdG9uZSwgUy48L2F1dGhvcj48YXV0aG9yPlBvd2VsbCwgSi48L2F1dGhvcj48

YXV0aG9yPlByb2l0c2ksIFAuPC9hdXRob3I+PGF1dGhvcj5MdXB0b24sIE0uIEsuPC9hdXRob3I+

PGF1dGhvcj5CcmF5bmUsIEMuPC9hdXRob3I+PGF1dGhvcj5SdWJpbnN6dGVpbiwgRC4gQy48L2F1

dGhvcj48YXV0aG9yPkdpbGwsIE0uPC9hdXRob3I+PGF1dGhvcj5MYXdsb3IsIEIuPC9hdXRob3I+

PGF1dGhvcj5MeW5jaCwgQS48L2F1dGhvcj48YXV0aG9yPk1vcmdhbiwgSy48L2F1dGhvcj48YXV0

aG9yPkJyb3duLCBLLiBTLjwvYXV0aG9yPjxhdXRob3I+UGFzc21vcmUsIFAuIEEuPC9hdXRob3I+

PGF1dGhvcj5DcmFpZywgRC48L2F1dGhvcj48YXV0aG9yPk1jR3Vpbm5lc3MsIEIuPC9hdXRob3I+

PGF1dGhvcj5Ub2RkLCBTLjwvYXV0aG9yPjxhdXRob3I+SG9sbWVzLCBDLjwvYXV0aG9yPjxhdXRo

b3I+TWFubiwgRC48L2F1dGhvcj48YXV0aG9yPlNtaXRoLCBBLiBELjwvYXV0aG9yPjxhdXRob3I+

TG92ZSwgUy48L2F1dGhvcj48YXV0aG9yPktlaG9lLCBQLiBHLjwvYXV0aG9yPjxhdXRob3I+TWVh

ZCwgUy48L2F1dGhvcj48YXV0aG9yPkZveCwgTi48L2F1dGhvcj48YXV0aG9yPlJvc3NvciwgTS48

L2F1dGhvcj48YXV0aG9yPkNvbGxpbmdlLCBKLjwvYXV0aG9yPjxhdXRob3I+TWFpZXIsIFcuPC9h

dXRob3I+PGF1dGhvcj5KZXNzZW4sIEYuPC9hdXRob3I+PGF1dGhvcj5TY2h1cm1hbm4sIEIuPC9h

dXRob3I+PGF1dGhvcj5IZXVuLCBSLjwvYXV0aG9yPjxhdXRob3I+S29sc2NoLCBILjwvYXV0aG9y

PjxhdXRob3I+dmFuIGRlbiBCdXNzY2hlLCBILjwvYXV0aG9yPjxhdXRob3I+SGV1c2VyLCBJLjwv

YXV0aG9yPjxhdXRob3I+UGV0ZXJzLCBPLjwvYXV0aG9yPjxhdXRob3I+S29ybmh1YmVyLCBKLjwv

YXV0aG9yPjxhdXRob3I+V2lsdGZhbmcsIEouPC9hdXRob3I+PGF1dGhvcj5EaWNoZ2FucywgTS48

L2F1dGhvcj48YXV0aG9yPkZyb2xpY2gsIEwuPC9hdXRob3I+PGF1dGhvcj5IYW1wZWwsIEguPC9h

dXRob3I+PGF1dGhvcj5IdWxsLCBNLjwvYXV0aG9yPjxhdXRob3I+UnVqZXNjdSwgRC48L2F1dGhv

cj48YXV0aG9yPkdvYXRlLCBBLiBNLjwvYXV0aG9yPjxhdXRob3I+S2F1d2UsIEouIFMuPC9hdXRo

b3I+PGF1dGhvcj5DcnVjaGFnYSwgQy48L2F1dGhvcj48YXV0aG9yPk5vd290bnksIFAuPC9hdXRo

b3I+PGF1dGhvcj5Nb3JyaXMsIEouIEMuPC9hdXRob3I+PGF1dGhvcj5NYXlvLCBLLjwvYXV0aG9y

PjxhdXRob3I+TGl2aW5nc3RvbiwgRy48L2F1dGhvcj48YXV0aG9yPkJhc3MsIE4uIEouPC9hdXRo

b3I+PGF1dGhvcj5HdXJsaW5nLCBILjwvYXV0aG9yPjxhdXRob3I+TWNRdWlsbGluLCBBLjwvYXV0

aG9yPjxhdXRob3I+R3dpbGxpYW0sIFIuPC9hdXRob3I+PGF1dGhvcj5EZWxvdWthcywgUC48L2F1

dGhvcj48YXV0aG9yPkFsLUNoYWxhYmksIEEuPC9hdXRob3I+PGF1dGhvcj5TaGF3LCBDLiBFLjwv

YXV0aG9yPjxhdXRob3I+U2luZ2xldG9uLCBBLiBCLjwvYXV0aG9yPjxhdXRob3I+R3VlcnJlaXJv

LCBSLjwvYXV0aG9yPjxhdXRob3I+TXVobGVpc2VuLCBULiBXLjwvYXV0aG9yPjxhdXRob3I+Tm90

aGVuLCBNLiBNLjwvYXV0aG9yPjxhdXRob3I+TW9lYnVzLCBTLjwvYXV0aG9yPjxhdXRob3I+Sm9j

a2VsLCBLLiBILjwvYXV0aG9yPjxhdXRob3I+S2xvcHAsIE4uPC9hdXRob3I+PGF1dGhvcj5XaWNo

bWFubiwgSC4gRS48L2F1dGhvcj48YXV0aG9yPlJ1dGhlciwgRS48L2F1dGhvcj48YXV0aG9yPkNh

cnJhc3F1aWxsbywgTS4gTS48L2F1dGhvcj48YXV0aG9yPlBhbmtyYXR6LCBWLiBTLjwvYXV0aG9y

PjxhdXRob3I+WW91bmtpbiwgUy4gRy48L2F1dGhvcj48YXV0aG9yPkhhcmR5LCBKLjwvYXV0aG9y

PjxhdXRob3I+TyZhcG9zO0Rvbm92YW4sIE0uIEMuPC9hdXRob3I+PGF1dGhvcj5Pd2VuLCBNLiBK

LjwvYXV0aG9yPjxhdXRob3I+V2lsbGlhbXMsIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp

YnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQc3ljaG9sb2dpY2FsIE1lZGljaW5l

IGFuZCBOZXVyb2xvZ3ksIFNjaG9vbCBvZiBNZWRpY2luZSwgQ2FyZGlmZiBVbml2ZXJzaXR5LCBN

ZWRpY2FsIFJlc2VhcmNoIENvdW5jaWwgQ2VudHJlIGZvciBOZXVyb3BzeWNoaWF0cmljIEdlbmV0

aWNzIGFuZCBHZW5vbWljcywgQ2FyZGlmZiwgVW5pdGVkIEtpbmdkb20uPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+R2VuZXRpYyBldmlkZW5jZSBpbXBsaWNhdGVzIHRoZSBpbW11bmUgc3lz

dGVtIGFuZCBjaG9sZXN0ZXJvbCBtZXRhYm9saXNtIGluIHRoZSBhZXRpb2xvZ3kgb2YgQWx6aGVp

bWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlBMb1MgT25lPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UExvUyBPbmU8L2Z1

bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz5lMTM5NTA8L3BhZ2VzPjx2b2x1bWU+NTwvdm9s

dW1lPjxudW1iZXI+MTE8L251bWJlcj48ZWRpdGlvbj4yMDEwLzExLzE5PC9lZGl0aW9uPjxrZXl3

b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qZ2VuZXRpY3MvaW1tdW5vbG9neS9tZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWlucyBFL2dlbmV0aWNzL21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGVzdGVyb2wvKm1ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+Q2hyb21vc29tZSBNYXBwaW5nPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmV0aWMgUHJl

ZGlzcG9zaXRpb24gdG8gRGlzZWFzZS9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5HZW5vbWUs

IEh1bWFuPC9rZXl3b3JkPjxrZXl3b3JkPipHZW5vbWUtV2lkZSBBc3NvY2lhdGlvbiBTdHVkeTwv

a2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5lIFN5c3RlbS8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5Qb2x5bW9ycGhpc20sIFNpbmdsZSBOdWNsZW90

aWRlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTA8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT5Ob3YgMTU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xOTMyLTYyMDMg

KEVsZWN0cm9uaWMpJiN4RDsxOTMyLTYyMDMgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVt

PjIxMDg1NTcwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczov

L3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMTA4NTU3MDwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48Y3VzdG9tMj5QTUMyOTgxNTI2PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNl

LW51bT4xMC4xMzcxL2pvdXJuYWwucG9uZS4wMDEzOTUwPC9lbGVjdHJvbmljLXJlc291cmNlLW51

bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Kb25lczwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl

Y051bT4yMDY1PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDY1PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ3Nzk5NjEiPjIwNjU8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkpvbmVzLCBMLjwvYXV0aG9yPjxhdXRob3I+

SG9sbWFucywgUC4gQS48L2F1dGhvcj48YXV0aG9yPkhhbXNoZXJlLCBNLiBMLjwvYXV0aG9yPjxh

dXRob3I+SGFyb2xkLCBELjwvYXV0aG9yPjxhdXRob3I+TW9za3ZpbmEsIFYuPC9hdXRob3I+PGF1

dGhvcj5JdmFub3YsIEQuPC9hdXRob3I+PGF1dGhvcj5Qb2NrbGluZ3RvbiwgQS48L2F1dGhvcj48

YXV0aG9yPkFicmFoYW0sIFIuPC9hdXRob3I+PGF1dGhvcj5Ib2xsaW5nd29ydGgsIFAuPC9hdXRo

b3I+PGF1dGhvcj5TaW1zLCBSLjwvYXV0aG9yPjxhdXRob3I+R2VycmlzaCwgQS48L2F1dGhvcj48

YXV0aG9yPlBhaHdhLCBKLiBTLjwvYXV0aG9yPjxhdXRob3I+Sm9uZXMsIE4uPC9hdXRob3I+PGF1

dGhvcj5TdHJldHRvbiwgQS48L2F1dGhvcj48YXV0aG9yPk1vcmdhbiwgQS4gUi48L2F1dGhvcj48

YXV0aG9yPkxvdmVzdG9uZSwgUy48L2F1dGhvcj48YXV0aG9yPlBvd2VsbCwgSi48L2F1dGhvcj48

YXV0aG9yPlByb2l0c2ksIFAuPC9hdXRob3I+PGF1dGhvcj5MdXB0b24sIE0uIEsuPC9hdXRob3I+

PGF1dGhvcj5CcmF5bmUsIEMuPC9hdXRob3I+PGF1dGhvcj5SdWJpbnN6dGVpbiwgRC4gQy48L2F1

dGhvcj48YXV0aG9yPkdpbGwsIE0uPC9hdXRob3I+PGF1dGhvcj5MYXdsb3IsIEIuPC9hdXRob3I+

PGF1dGhvcj5MeW5jaCwgQS48L2F1dGhvcj48YXV0aG9yPk1vcmdhbiwgSy48L2F1dGhvcj48YXV0

aG9yPkJyb3duLCBLLiBTLjwvYXV0aG9yPjxhdXRob3I+UGFzc21vcmUsIFAuIEEuPC9hdXRob3I+

PGF1dGhvcj5DcmFpZywgRC48L2F1dGhvcj48YXV0aG9yPk1jR3Vpbm5lc3MsIEIuPC9hdXRob3I+

PGF1dGhvcj5Ub2RkLCBTLjwvYXV0aG9yPjxhdXRob3I+SG9sbWVzLCBDLjwvYXV0aG9yPjxhdXRo

b3I+TWFubiwgRC48L2F1dGhvcj48YXV0aG9yPlNtaXRoLCBBLiBELjwvYXV0aG9yPjxhdXRob3I+

TG92ZSwgUy48L2F1dGhvcj48YXV0aG9yPktlaG9lLCBQLiBHLjwvYXV0aG9yPjxhdXRob3I+TWVh

ZCwgUy48L2F1dGhvcj48YXV0aG9yPkZveCwgTi48L2F1dGhvcj48YXV0aG9yPlJvc3NvciwgTS48

L2F1dGhvcj48YXV0aG9yPkNvbGxpbmdlLCBKLjwvYXV0aG9yPjxhdXRob3I+TWFpZXIsIFcuPC9h

dXRob3I+PGF1dGhvcj5KZXNzZW4sIEYuPC9hdXRob3I+PGF1dGhvcj5TY2h1cm1hbm4sIEIuPC9h

dXRob3I+PGF1dGhvcj5IZXVuLCBSLjwvYXV0aG9yPjxhdXRob3I+S29sc2NoLCBILjwvYXV0aG9y

PjxhdXRob3I+dmFuIGRlbiBCdXNzY2hlLCBILjwvYXV0aG9yPjxhdXRob3I+SGV1c2VyLCBJLjwv

YXV0aG9yPjxhdXRob3I+UGV0ZXJzLCBPLjwvYXV0aG9yPjxhdXRob3I+S29ybmh1YmVyLCBKLjwv

YXV0aG9yPjxhdXRob3I+V2lsdGZhbmcsIEouPC9hdXRob3I+PGF1dGhvcj5EaWNoZ2FucywgTS48

L2F1dGhvcj48YXV0aG9yPkZyb2xpY2gsIEwuPC9hdXRob3I+PGF1dGhvcj5IYW1wZWwsIEguPC9h

dXRob3I+PGF1dGhvcj5IdWxsLCBNLjwvYXV0aG9yPjxhdXRob3I+UnVqZXNjdSwgRC48L2F1dGhv

cj48YXV0aG9yPkdvYXRlLCBBLiBNLjwvYXV0aG9yPjxhdXRob3I+S2F1d2UsIEouIFMuPC9hdXRo

b3I+PGF1dGhvcj5DcnVjaGFnYSwgQy48L2F1dGhvcj48YXV0aG9yPk5vd290bnksIFAuPC9hdXRo

b3I+PGF1dGhvcj5Nb3JyaXMsIEouIEMuPC9hdXRob3I+PGF1dGhvcj5NYXlvLCBLLjwvYXV0aG9y

PjxhdXRob3I+TGl2aW5nc3RvbiwgRy48L2F1dGhvcj48YXV0aG9yPkJhc3MsIE4uIEouPC9hdXRo

b3I+PGF1dGhvcj5HdXJsaW5nLCBILjwvYXV0aG9yPjxhdXRob3I+TWNRdWlsbGluLCBBLjwvYXV0

aG9yPjxhdXRob3I+R3dpbGxpYW0sIFIuPC9hdXRob3I+PGF1dGhvcj5EZWxvdWthcywgUC48L2F1

dGhvcj48YXV0aG9yPkFsLUNoYWxhYmksIEEuPC9hdXRob3I+PGF1dGhvcj5TaGF3LCBDLiBFLjwv

YXV0aG9yPjxhdXRob3I+U2luZ2xldG9uLCBBLiBCLjwvYXV0aG9yPjxhdXRob3I+R3VlcnJlaXJv

LCBSLjwvYXV0aG9yPjxhdXRob3I+TXVobGVpc2VuLCBULiBXLjwvYXV0aG9yPjxhdXRob3I+Tm90

aGVuLCBNLiBNLjwvYXV0aG9yPjxhdXRob3I+TW9lYnVzLCBTLjwvYXV0aG9yPjxhdXRob3I+Sm9j

a2VsLCBLLiBILjwvYXV0aG9yPjxhdXRob3I+S2xvcHAsIE4uPC9hdXRob3I+PGF1dGhvcj5XaWNo

bWFubiwgSC4gRS48L2F1dGhvcj48YXV0aG9yPlJ1dGhlciwgRS48L2F1dGhvcj48YXV0aG9yPkNh

cnJhc3F1aWxsbywgTS4gTS48L2F1dGhvcj48YXV0aG9yPlBhbmtyYXR6LCBWLiBTLjwvYXV0aG9y

PjxhdXRob3I+WW91bmtpbiwgUy4gRy48L2F1dGhvcj48YXV0aG9yPkhhcmR5LCBKLjwvYXV0aG9y

PjxhdXRob3I+TyZhcG9zO0Rvbm92YW4sIE0uIEMuPC9hdXRob3I+PGF1dGhvcj5Pd2VuLCBNLiBK

LjwvYXV0aG9yPjxhdXRob3I+V2lsbGlhbXMsIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp

YnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQc3ljaG9sb2dpY2FsIE1lZGljaW5l

IGFuZCBOZXVyb2xvZ3ksIFNjaG9vbCBvZiBNZWRpY2luZSwgQ2FyZGlmZiBVbml2ZXJzaXR5LCBN

ZWRpY2FsIFJlc2VhcmNoIENvdW5jaWwgQ2VudHJlIGZvciBOZXVyb3BzeWNoaWF0cmljIEdlbmV0

aWNzIGFuZCBHZW5vbWljcywgQ2FyZGlmZiwgVW5pdGVkIEtpbmdkb20uPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+R2VuZXRpYyBldmlkZW5jZSBpbXBsaWNhdGVzIHRoZSBpbW11bmUgc3lz

dGVtIGFuZCBjaG9sZXN0ZXJvbCBtZXRhYm9saXNtIGluIHRoZSBhZXRpb2xvZ3kgb2YgQWx6aGVp

bWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlBMb1MgT25lPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UExvUyBPbmU8L2Z1

bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz5lMTM5NTA8L3BhZ2VzPjx2b2x1bWU+NTwvdm9s

dW1lPjxudW1iZXI+MTE8L251bWJlcj48ZWRpdGlvbj4yMDEwLzExLzE5PC9lZGl0aW9uPjxrZXl3

b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qZ2VuZXRpY3MvaW1tdW5vbG9neS9tZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWlucyBFL2dlbmV0aWNzL21ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGVzdGVyb2wvKm1ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+Q2hyb21vc29tZSBNYXBwaW5nPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmV0aWMgUHJl

ZGlzcG9zaXRpb24gdG8gRGlzZWFzZS9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5HZW5vbWUs

IEh1bWFuPC9rZXl3b3JkPjxrZXl3b3JkPipHZW5vbWUtV2lkZSBBc3NvY2lhdGlvbiBTdHVkeTwv

a2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5lIFN5c3RlbS8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5Qb2x5bW9ycGhpc20sIFNpbmdsZSBOdWNsZW90

aWRlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTA8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT5Ob3YgMTU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xOTMyLTYyMDMg

KEVsZWN0cm9uaWMpJiN4RDsxOTMyLTYyMDMgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVt

PjIxMDg1NTcwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczov

L3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMTA4NTU3MDwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48Y3VzdG9tMj5QTUMyOTgxNTI2PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNl

LW51bT4xMC4xMzcxL2pvdXJuYWwucG9uZS4wMDEzOTUwPC9lbGVjdHJvbmljLXJlc291cmNlLW51

bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 44. Cholesterol increased concentration has been evidenced in the brain of AD patients. The role of statins (inhibitors of HMGCoA reductase key enzyme of cholesterol synthesis) is still debated. However, a recent retrospective study on 400 000 patient receiving long term treatments by statins evidenced a link between a decreased frequency of Alzheimer’s disease to chronic administration of statins, a link varying upon sex, ethnicity and molecules PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaXNzaW1vcG91bG9zPC9BdXRob3I+PFllYXI+MjAxNzwv

WWVhcj48UmVjTnVtPjQzMjU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVy

c2NyaXB0Ij4zODg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40MzI1

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDA5MzQ3MjQiPjQzMjU8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlppc3NpbW9wb3Vsb3MsIEou

IE0uPC9hdXRob3I+PGF1dGhvcj5CYXJ0aG9sZCwgRC48L2F1dGhvcj48YXV0aG9yPkJyaW50b24s

IFIuIEQuPC9hdXRob3I+PGF1dGhvcj5Kb3ljZSwgRy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5MZW9uYXJkIEQuIFNjaGFlZmZlciBDZW50ZXIgZm9yIEhl

YWx0aCBQb2xpY3kgYW5kIEVjb25vbWljcywgVW5pdmVyc2l0eSBvZiBTb3V0aGVybiBDYWxpZm9y

bmlhLCBMb3MgQW5nZWxlcy4mI3hEO0xlb25hcmQgRC4gU2NoYWVmZmVyIENlbnRlciBmb3IgSGVh

bHRoIFBvbGljeSBhbmQgRWNvbm9taWNzLCBVbml2ZXJzaXR5IG9mIFNvdXRoZXJuIENhbGlmb3Ju

aWEsIExvcyBBbmdlbGVzMkNlbnRlciBmb3IgSW5ub3ZhdGlvbiBpbiBCcmFpbiBTY2llbmNlLCBV

bml2ZXJzaXR5IG9mIEFyaXpvbmEgSGVhbHRoIFNjaWVuY2VzLCBUdWNzb24uPC9hdXRoLWFkZHJl

c3M+PHRpdGxlcz48dGl0bGU+U2V4IGFuZCBSYWNlIERpZmZlcmVuY2VzIGluIHRoZSBBc3NvY2lh

dGlvbiBCZXR3ZWVuIFN0YXRpbiBVc2UgYW5kIHRoZSBJbmNpZGVuY2Ugb2YgQWx6aGVpbWVyIERp

c2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SkFNQSBOZXVyb2w8L3NlY29uZGFyeS10aXRs

ZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KQU1BIE5ldXJvbDwvZnVsbC10aXRs

ZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIyNS0yMzI8L3BhZ2VzPjx2b2x1bWU+NzQ8L3ZvbHVtZT48

bnVtYmVyPjI8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWZyaWNhbiBDb250aW5lbnRhbCBB

bmNlc3RyeSBHcm91cDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFn

ZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPipBbHpoZWltZXIgRGlzZWFzZS9lcGlk

ZW1pb2xvZ3kvZXRobm9sb2d5L3ByZXZlbnRpb24gJmFtcDsgY29udHJvbDwva2V5d29yZD48a2V5

d29yZD5Bc2lhbiBBbWVyaWNhbnM8L2tleXdvcmQ+PGtleXdvcmQ+RXVyb3BlYW4gQ29udGluZW50

YWwgQW5jZXN0cnkgR3JvdXA8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3

b3JkPkhpc3BhbmljIEFtZXJpY2Fuczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+

PGtleXdvcmQ+SHlkcm94eW1ldGh5bGdsdXRhcnlsLUNvQSBSZWR1Y3Rhc2UgSW5oaWJpdG9ycy8q

dGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkluY2lkZW5jZTwva2V5d29yZD48a2V5

d29yZD5Mb25naXR1ZGluYWwgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3Jk

PjxrZXl3b3JkPk1lZGljYXJlL3N0YXRpc3RpY3MgJmFtcDsgbnVtZXJpY2FsIGRhdGE8L2tleXdv

cmQ+PGtleXdvcmQ+UHJvcG9ydGlvbmFsIEhhemFyZHMgTW9kZWxzPC9rZXl3b3JkPjxrZXl3b3Jk

PlBzeWNoaWF0cmljIFN0YXR1cyBSYXRpbmcgU2NhbGVzPC9rZXl3b3JkPjxrZXl3b3JkPlJldHJv

c3BlY3RpdmUgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD4qU2V4IENoYXJhY3RlcmlzdGljczwv

a2V5d29yZD48a2V5d29yZD5Vbml0ZWQgU3RhdGVzL2VwaWRlbWlvbG9neTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RmViIDE8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4yMTY4LTYxNTcgKEVsZWN0cm9uaWMpJiN4RDsy

MTY4LTYxNDkgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3OTQyNzI4PC9hY2Nlc3Np

b24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5n

b3YvcHVibWVkLzI3OTQyNzI4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBN

QzU2NDYzNTc8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDEvamFtYW5l

dXJvbC4yMDE2LjM3ODM8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48

L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaXNzaW1vcG91bG9zPC9BdXRob3I+PFllYXI+MjAxNzwv

WWVhcj48UmVjTnVtPjQzMjU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVy

c2NyaXB0Ij4zODg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40MzI1

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDA5MzQ3MjQiPjQzMjU8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlppc3NpbW9wb3Vsb3MsIEou

IE0uPC9hdXRob3I+PGF1dGhvcj5CYXJ0aG9sZCwgRC48L2F1dGhvcj48YXV0aG9yPkJyaW50b24s

IFIuIEQuPC9hdXRob3I+PGF1dGhvcj5Kb3ljZSwgRy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5MZW9uYXJkIEQuIFNjaGFlZmZlciBDZW50ZXIgZm9yIEhl

YWx0aCBQb2xpY3kgYW5kIEVjb25vbWljcywgVW5pdmVyc2l0eSBvZiBTb3V0aGVybiBDYWxpZm9y

bmlhLCBMb3MgQW5nZWxlcy4mI3hEO0xlb25hcmQgRC4gU2NoYWVmZmVyIENlbnRlciBmb3IgSGVh

bHRoIFBvbGljeSBhbmQgRWNvbm9taWNzLCBVbml2ZXJzaXR5IG9mIFNvdXRoZXJuIENhbGlmb3Ju

aWEsIExvcyBBbmdlbGVzMkNlbnRlciBmb3IgSW5ub3ZhdGlvbiBpbiBCcmFpbiBTY2llbmNlLCBV

bml2ZXJzaXR5IG9mIEFyaXpvbmEgSGVhbHRoIFNjaWVuY2VzLCBUdWNzb24uPC9hdXRoLWFkZHJl

c3M+PHRpdGxlcz48dGl0bGU+U2V4IGFuZCBSYWNlIERpZmZlcmVuY2VzIGluIHRoZSBBc3NvY2lh

dGlvbiBCZXR3ZWVuIFN0YXRpbiBVc2UgYW5kIHRoZSBJbmNpZGVuY2Ugb2YgQWx6aGVpbWVyIERp

c2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SkFNQSBOZXVyb2w8L3NlY29uZGFyeS10aXRs

ZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KQU1BIE5ldXJvbDwvZnVsbC10aXRs

ZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIyNS0yMzI8L3BhZ2VzPjx2b2x1bWU+NzQ8L3ZvbHVtZT48

bnVtYmVyPjI8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWZyaWNhbiBDb250aW5lbnRhbCBB

bmNlc3RyeSBHcm91cDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFn

ZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPipBbHpoZWltZXIgRGlzZWFzZS9lcGlk

ZW1pb2xvZ3kvZXRobm9sb2d5L3ByZXZlbnRpb24gJmFtcDsgY29udHJvbDwva2V5d29yZD48a2V5

d29yZD5Bc2lhbiBBbWVyaWNhbnM8L2tleXdvcmQ+PGtleXdvcmQ+RXVyb3BlYW4gQ29udGluZW50

YWwgQW5jZXN0cnkgR3JvdXA8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3

b3JkPkhpc3BhbmljIEFtZXJpY2Fuczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+

PGtleXdvcmQ+SHlkcm94eW1ldGh5bGdsdXRhcnlsLUNvQSBSZWR1Y3Rhc2UgSW5oaWJpdG9ycy8q

dGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkluY2lkZW5jZTwva2V5d29yZD48a2V5

d29yZD5Mb25naXR1ZGluYWwgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3Jk

PjxrZXl3b3JkPk1lZGljYXJlL3N0YXRpc3RpY3MgJmFtcDsgbnVtZXJpY2FsIGRhdGE8L2tleXdv

cmQ+PGtleXdvcmQ+UHJvcG9ydGlvbmFsIEhhemFyZHMgTW9kZWxzPC9rZXl3b3JkPjxrZXl3b3Jk

PlBzeWNoaWF0cmljIFN0YXR1cyBSYXRpbmcgU2NhbGVzPC9rZXl3b3JkPjxrZXl3b3JkPlJldHJv

c3BlY3RpdmUgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD4qU2V4IENoYXJhY3RlcmlzdGljczwv

a2V5d29yZD48a2V5d29yZD5Vbml0ZWQgU3RhdGVzL2VwaWRlbWlvbG9neTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RmViIDE8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4yMTY4LTYxNTcgKEVsZWN0cm9uaWMpJiN4RDsy

MTY4LTYxNDkgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3OTQyNzI4PC9hY2Nlc3Np

b24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5n

b3YvcHVibWVkLzI3OTQyNzI4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBN

QzU2NDYzNTc8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDEvamFtYW5l

dXJvbC4yMDE2LjM3ODM8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48

L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 388. Yet, the discussion on statins and cognitive decline in AD remains open PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZXRlazwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl

Y051bT40MzI4PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

Mzg5PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDMyODwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTQzNzc3MDM5Ij40MzI4PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5QZXRlaywgQi48L2F1dGhvcj48YXV0aG9y

PlZpbGxhLUxvcGV6LCBNLjwvYXV0aG9yPjxhdXRob3I+TG9lcmEtVmFsZW5jaWEsIFIuPC9hdXRo

b3I+PGF1dGhvcj5HZXJlbnUsIEcuPC9hdXRob3I+PGF1dGhvcj5XaW5ibGFkLCBCLjwvYXV0aG9y

PjxhdXRob3I+S3JhbWJlcmdlciwgTS4gRy48L2F1dGhvcj48YXV0aG9yPklzbWFpbCwgTS4gQS48

L2F1dGhvcj48YXV0aG9yPkVyaWtzZG90dGVyLCBNLjwvYXV0aG9yPjxhdXRob3I+R2FyY2lhLVB0

YWNlaywgUy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5E

aXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBD

YXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9s

bSwgU3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIFVuaXZlcnNpdHkgTWVkaWNh

bCBDZW50cmUsIExqdWJsamFuYSwgU2xvdmVuaWEuJiN4RDtVbml2ZXJzaXR5IG9mIExqdWJsamFu

YSwgTGp1YmxqYW5hLCBTbG92ZW5pYS4mI3hEO0RpdmlzaW9uIG9mIENsaW5pY2FsIEdlcmlhdHJp

Y3MsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5

LCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7Q2VudGVyIGZv

ciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0cmljcywgRGVwYXJ0

bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIEthcm9saW5z

a2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJv

c2NpZW5jZXMsIEJpb2Rvbm9zdGlhIEhlYWx0aCBSZXNlYXJjaCBJbnN0aXR1dGUsIFNhbiBTZWJh

c3RpYW4sIFNwYWluLiYjeEQ7Q2VudGVyIGZvciBOZXR3b3JrZWQgQmlvbWVkaWNhbCBSZXNlYXJj

aCBpbiBOZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcywgQ0lCRVJORUQsIEhlYWx0aCBJbnN0aXR1

dGUgQ2FybG9zIElJSSwgTWluaXN0cnkgb2YgRWNvbm9teSBhbmQgQ29tcGV0aXRpdmVuZXNzLCBN

YWRyaWQsIFNwYWluLiYjeEQ7RGVwYXJ0bWVudCBvZiBHZXJpYXRyaWMgTWVkaWNpbmUsIEthcm9s

aW5za2EgVW5pdmVyc2l0eSBIb3NwaXRhbCwgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtUaGVtZSBO

ZXVybywgRGlzZWFzZXMgb2YgdGhlIE5lcnZvdXMgU3lzdGVtIHBhdGllbnQgZmxvdywgS2Fyb2xp

bnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIdWRkaW5nZSwgU3dlZGVuLiYjeEQ7RGVwYXJ0bWVu

dCBvZiBJbnRlcm5hbCBNZWRpY2luZSwgTmV1cm9sb2d5IFNlY3Rpb24sIFNvZGVyc2p1a2h1c2V0

LCBTdG9ja2hvbG0sIFN3ZWRlbi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Db25uZWN0

aW5nIHRoZSBicmFpbiBjaG9sZXN0ZXJvbCBhbmQgcmVuaW4tYW5naW90ZW5zaW4gc3lzdGVtczog

cG90ZW50aWFsIHJvbGUgb2Ygc3RhdGlucyBhbmQgUkFTLW1vZGlmeWluZyBtZWRpY2F0aW9ucyBp

biBkZW1lbnRpYTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEludGVybiBNZWQ8L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIEludGVybiBNZWQ8L2Z1

bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz42MjAtNjQyPC9wYWdlcz48dm9sdW1lPjI4NDwv

dm9sdW1lPjxudW1iZXI+NjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBv

cztzIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+YW50aWh5cGVydGVuc2l2ZSBkcnVnczwva2V5

d29yZD48a2V5d29yZD5jaG9sZXN0ZXJvbDwva2V5d29yZD48a2V5d29yZD5kZW1lbnRpYTwva2V5

d29yZD48a2V5d29yZD5oeXBlcnRlbnNpb248L2tleXdvcmQ+PGtleXdvcmQ+c3RhdGluczwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

RGVjPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTM2NS0yNzk2IChFbGVjdHJvbmlj

KSYjeEQ7MDk1NC02ODIwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4zMDI2NDkxMDwv

YWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5s

bS5uaWguZ292L3B1Ym1lZC8zMDI2NDkxMDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTExMS9qb2ltLjEyODM4PC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZXRlazwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl

Y051bT40MzI4PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

Mzg5PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDMyODwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTQzNzc3MDM5Ij40MzI4PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5QZXRlaywgQi48L2F1dGhvcj48YXV0aG9y

PlZpbGxhLUxvcGV6LCBNLjwvYXV0aG9yPjxhdXRob3I+TG9lcmEtVmFsZW5jaWEsIFIuPC9hdXRo

b3I+PGF1dGhvcj5HZXJlbnUsIEcuPC9hdXRob3I+PGF1dGhvcj5XaW5ibGFkLCBCLjwvYXV0aG9y

PjxhdXRob3I+S3JhbWJlcmdlciwgTS4gRy48L2F1dGhvcj48YXV0aG9yPklzbWFpbCwgTS4gQS48

L2F1dGhvcj48YXV0aG9yPkVyaWtzZG90dGVyLCBNLjwvYXV0aG9yPjxhdXRob3I+R2FyY2lhLVB0

YWNlaywgUy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5E

aXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBD

YXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9s

bSwgU3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIFVuaXZlcnNpdHkgTWVkaWNh

bCBDZW50cmUsIExqdWJsamFuYSwgU2xvdmVuaWEuJiN4RDtVbml2ZXJzaXR5IG9mIExqdWJsamFu

YSwgTGp1YmxqYW5hLCBTbG92ZW5pYS4mI3hEO0RpdmlzaW9uIG9mIENsaW5pY2FsIEdlcmlhdHJp

Y3MsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5

LCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7Q2VudGVyIGZv

ciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0cmljcywgRGVwYXJ0

bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIEthcm9saW5z

a2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJv

c2NpZW5jZXMsIEJpb2Rvbm9zdGlhIEhlYWx0aCBSZXNlYXJjaCBJbnN0aXR1dGUsIFNhbiBTZWJh

c3RpYW4sIFNwYWluLiYjeEQ7Q2VudGVyIGZvciBOZXR3b3JrZWQgQmlvbWVkaWNhbCBSZXNlYXJj

aCBpbiBOZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcywgQ0lCRVJORUQsIEhlYWx0aCBJbnN0aXR1

dGUgQ2FybG9zIElJSSwgTWluaXN0cnkgb2YgRWNvbm9teSBhbmQgQ29tcGV0aXRpdmVuZXNzLCBN

YWRyaWQsIFNwYWluLiYjeEQ7RGVwYXJ0bWVudCBvZiBHZXJpYXRyaWMgTWVkaWNpbmUsIEthcm9s

aW5za2EgVW5pdmVyc2l0eSBIb3NwaXRhbCwgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtUaGVtZSBO

ZXVybywgRGlzZWFzZXMgb2YgdGhlIE5lcnZvdXMgU3lzdGVtIHBhdGllbnQgZmxvdywgS2Fyb2xp

bnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIdWRkaW5nZSwgU3dlZGVuLiYjeEQ7RGVwYXJ0bWVu

dCBvZiBJbnRlcm5hbCBNZWRpY2luZSwgTmV1cm9sb2d5IFNlY3Rpb24sIFNvZGVyc2p1a2h1c2V0

LCBTdG9ja2hvbG0sIFN3ZWRlbi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Db25uZWN0

aW5nIHRoZSBicmFpbiBjaG9sZXN0ZXJvbCBhbmQgcmVuaW4tYW5naW90ZW5zaW4gc3lzdGVtczog

cG90ZW50aWFsIHJvbGUgb2Ygc3RhdGlucyBhbmQgUkFTLW1vZGlmeWluZyBtZWRpY2F0aW9ucyBp

biBkZW1lbnRpYTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEludGVybiBNZWQ8L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIEludGVybiBNZWQ8L2Z1

bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz42MjAtNjQyPC9wYWdlcz48dm9sdW1lPjI4NDwv

dm9sdW1lPjxudW1iZXI+NjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXImYXBv

cztzIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+YW50aWh5cGVydGVuc2l2ZSBkcnVnczwva2V5

d29yZD48a2V5d29yZD5jaG9sZXN0ZXJvbDwva2V5d29yZD48a2V5d29yZD5kZW1lbnRpYTwva2V5

d29yZD48a2V5d29yZD5oeXBlcnRlbnNpb248L2tleXdvcmQ+PGtleXdvcmQ+c3RhdGluczwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

RGVjPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTM2NS0yNzk2IChFbGVjdHJvbmlj

KSYjeEQ7MDk1NC02ODIwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4zMDI2NDkxMDwv

YWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5s

bS5uaWguZ292L3B1Ym1lZC8zMDI2NDkxMDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTExMS9qb2ltLjEyODM4PC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 389. Cholesterol is directly associated with plaques and tangles. In vitro and in vivo studies have shown that increased cholesterol content in membranes is associated with increased A-beta production. Conversely, decreased cholesterol in the membranes favors the non-amyloidogenic pathway of APP processing ADDIN EN.CITE <EndNote><Cite><Author>Bjorkhem</Author><Year>2004</Year><RecNum>4322</RecNum><DisplayText><style face="superscript">390</style></DisplayText><record><rec-number>4322</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1540931335">4322</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bjorkhem, I.</author><author>Meaney, S.</author></authors></contributors><auth-address>Division of Clinical Chemistry, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden. ingemar.bjorkhem@hs.se</auth-address><titles><title>Brain cholesterol: long secret life behind a barrier</title><secondary-title>Arterioscler Thromb Vasc Biol</secondary-title></titles><periodical><full-title>Arterioscler Thromb Vasc Biol</full-title></periodical><pages>806-15</pages><volume>24</volume><number>5</number><keywords><keyword>Animals</keyword><keyword>*Blood-Brain Barrier</keyword><keyword>Brain/cytology/*metabolism</keyword><keyword>Cholesterol/*metabolism</keyword><keyword>Homeostasis</keyword><keyword>Humans</keyword><keyword>Hydroxycholesterols/metabolism</keyword><keyword>Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology/therapeutic use</keyword><keyword>Membrane Lipids/*metabolism</keyword><keyword>Myelin Sheath/metabolism/physiology</keyword><keyword>Nerve Degeneration/drug therapy/metabolism/prevention &amp; control</keyword><keyword>Neuroprotective Agents/pharmacology/therapeutic use</keyword><keyword>Rats</keyword><keyword>Receptors, Cytoplasmic and Nuclear/metabolism</keyword></keywords><dates><year>2004</year><pub-dates><date>May</date></pub-dates></dates><isbn>1524-4636 (Electronic)&#xD;1079-5642 (Linking)</isbn><accession-num>14764421</accession-num><urls><related-urls><url> cannot cross the Blood brain barrier (BBB) and brain cholesterol is produced in situ, mostly by astrocytes in adults. It is then transported to neurons by APOE, which are the major consumers of the generated cholesterol. To some extent, cholesterol is also produced by synthesis in neurons and this is an important part of the brain cholesterol homeostasis. Cholesterol is excreted from the brain mostly after transformation into 24-hydroxycholesterol (24-OH Chol), that can freely cross the BBB and is metabolized in the liver. 24-OH Chol is produced by CYP46A1, a cytochrome enzyme specifically expressed in the brain PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MdW5kPC9BdXRob3I+PFllYXI+MTk5OTwvWWVhcj48UmVj

TnVtPjQyMTE8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4z

OTEsMzkyPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDIxMTwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2Nzc3Mzk2Ij40MjExPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5MdW5kLCBFLiBHLjwvYXV0aG9yPjxh

dXRob3I+R3VpbGV5YXJkbywgSi4gTS48L2F1dGhvcj48YXV0aG9yPlJ1c3NlbGwsIEQuIFcuPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBv

ZiBNb2xlY3VsYXIgR2VuZXRpY3MsIFVuaXZlcnNpdHkgb2YgVGV4YXMgU291dGh3ZXN0ZXJuIE1l

ZGljYWwgQ2VudGVyLCA1MzIzIEhhcnJ5IEhpbmVzIEJvdWxldmFyZCwgRGFsbGFzLCBUWCA3NTIz

NS05MDQ2LCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Y0ROQSBjbG9uaW5nIG9m

IGNob2xlc3Rlcm9sIDI0LWh5ZHJveHlsYXNlLCBhIG1lZGlhdG9yIG9mIGNob2xlc3Rlcm9sIGhv

bWVvc3Rhc2lzIGluIHRoZSBicmFpbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Qcm9jIE5hdGwg

QWNhZCBTY2kgVSBTIEE8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVs

bC10aXRsZT5Qcm9jIE5hdGwgQWNhZCBTY2kgVSBTIEE8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz43MjM4LTQzPC9wYWdlcz48dm9sdW1lPjk2PC92b2x1bWU+PG51bWJlcj4xMzwvbnVt

YmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbWlubyBBY2lkIFNlcXVlbmNlPC9rZXl3b3JkPjxrZXl3

b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKm1ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+Q2hvbGVzdGVyb2wvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q2xvbmlu

ZywgTW9sZWN1bGFyPC9rZXl3b3JkPjxrZXl3b3JkPkN5dG9jaHJvbWUgUC00NTAgRW56eW1lIFN5

c3RlbS9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5ETkEsIENvbXBsZW1lbnRhcnkvZ2VuZXRp

Y3MvaXNvbGF0aW9uICZhbXA7IHB1cmlmaWNhdGlvbjwva2V5d29yZD48a2V5d29yZD5Ib21lb3N0

YXNpczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5

d29yZD48a2V5d29yZD5Nb2xlY3VsYXIgU2VxdWVuY2UgRGF0YTwva2V5d29yZD48a2V5d29yZD5P

cmdhbiBTcGVjaWZpY2l0eTwva2V5d29yZD48a2V5d29yZD5TZXF1ZW5jZSBBbGlnbm1lbnQ8L2tl

eXdvcmQ+PGtleXdvcmQ+U3Rlcm9pZCBIeWRyb3h5bGFzZXMvKmdlbmV0aWNzL21ldGFib2xpc208

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MTk5OTwveWVhcj48cHViLWRhdGVzPjxk

YXRlPkp1biAyMjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMjctODQyNCAoUHJp

bnQpJiN4RDswMDI3LTg0MjQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjEwMzc3Mzk4

PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmku

bmxtLm5paC5nb3YvcHVibWVkLzEwMzc3Mzk4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxj

dXN0b20yPlBNQzIyMDY0PC9jdXN0b20yPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkJq

b3JraGVtPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48UmVjTnVtPjQxOTg8L1JlY051bT48cmVj

b3JkPjxyZWMtbnVtYmVyPjQxOTg8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFt

cD0iMTUzNjc3NzAzOCI+NDE5ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+QmpvcmtoZW0sIEkuPC9hdXRob3I+PGF1dGhvcj5EaWN6ZmFsdXN5LCBVLjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT4yNChTKSwyNS1lcG94eWNob2xl

c3Rlcm9sLS1hIHBvdGVudGlhbCBmcmllbmQ8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QXJ0ZXJp

b3NjbGVyIFRocm9tYiBWYXNjIEJpb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9k

aWNhbD48ZnVsbC10aXRsZT5BcnRlcmlvc2NsZXIgVGhyb21iIFZhc2MgQmlvbDwvZnVsbC10aXRs

ZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIyMDktMTA8L3BhZ2VzPjx2b2x1bWU+MjQ8L3ZvbHVtZT48

bnVtYmVyPjEyPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtl

eXdvcmQ+Q2hvbGVzdGVyb2wvKmFuYWxvZ3MgJmFtcDsgZGVyaXZhdGl2ZXMvKnRoZXJhcGV1dGlj

IHVzZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAwNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPkRlYzwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjE1MjQtNDYzNiAoRWxlY3Ryb25pYykmI3hEOzEwNzktNTY0MiAoTGlua2lu

Zyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTU1NzY2NDQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJl

bGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTU1NzY2

NDQ8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEw

LjExNjEvMDEuQVRWLjAwMDAxNDg3MDQuNzI0ODEuMjg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MdW5kPC9BdXRob3I+PFllYXI+MTk5OTwvWWVhcj48UmVj

TnVtPjQyMTE8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4z

OTEsMzkyPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDIxMTwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2Nzc3Mzk2Ij40MjExPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5MdW5kLCBFLiBHLjwvYXV0aG9yPjxh

dXRob3I+R3VpbGV5YXJkbywgSi4gTS48L2F1dGhvcj48YXV0aG9yPlJ1c3NlbGwsIEQuIFcuPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBv

ZiBNb2xlY3VsYXIgR2VuZXRpY3MsIFVuaXZlcnNpdHkgb2YgVGV4YXMgU291dGh3ZXN0ZXJuIE1l

ZGljYWwgQ2VudGVyLCA1MzIzIEhhcnJ5IEhpbmVzIEJvdWxldmFyZCwgRGFsbGFzLCBUWCA3NTIz

NS05MDQ2LCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Y0ROQSBjbG9uaW5nIG9m

IGNob2xlc3Rlcm9sIDI0LWh5ZHJveHlsYXNlLCBhIG1lZGlhdG9yIG9mIGNob2xlc3Rlcm9sIGhv

bWVvc3Rhc2lzIGluIHRoZSBicmFpbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Qcm9jIE5hdGwg

QWNhZCBTY2kgVSBTIEE8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVs

bC10aXRsZT5Qcm9jIE5hdGwgQWNhZCBTY2kgVSBTIEE8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz43MjM4LTQzPC9wYWdlcz48dm9sdW1lPjk2PC92b2x1bWU+PG51bWJlcj4xMzwvbnVt

YmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbWlubyBBY2lkIFNlcXVlbmNlPC9rZXl3b3JkPjxrZXl3

b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKm1ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+Q2hvbGVzdGVyb2wvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q2xvbmlu

ZywgTW9sZWN1bGFyPC9rZXl3b3JkPjxrZXl3b3JkPkN5dG9jaHJvbWUgUC00NTAgRW56eW1lIFN5

c3RlbS9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5ETkEsIENvbXBsZW1lbnRhcnkvZ2VuZXRp

Y3MvaXNvbGF0aW9uICZhbXA7IHB1cmlmaWNhdGlvbjwva2V5d29yZD48a2V5d29yZD5Ib21lb3N0

YXNpczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5

d29yZD48a2V5d29yZD5Nb2xlY3VsYXIgU2VxdWVuY2UgRGF0YTwva2V5d29yZD48a2V5d29yZD5P

cmdhbiBTcGVjaWZpY2l0eTwva2V5d29yZD48a2V5d29yZD5TZXF1ZW5jZSBBbGlnbm1lbnQ8L2tl

eXdvcmQ+PGtleXdvcmQ+U3Rlcm9pZCBIeWRyb3h5bGFzZXMvKmdlbmV0aWNzL21ldGFib2xpc208

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MTk5OTwveWVhcj48cHViLWRhdGVzPjxk

YXRlPkp1biAyMjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMjctODQyNCAoUHJp

bnQpJiN4RDswMDI3LTg0MjQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjEwMzc3Mzk4

PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmku

bmxtLm5paC5nb3YvcHVibWVkLzEwMzc3Mzk4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxj

dXN0b20yPlBNQzIyMDY0PC9jdXN0b20yPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkJq

b3JraGVtPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48UmVjTnVtPjQxOTg8L1JlY051bT48cmVj

b3JkPjxyZWMtbnVtYmVyPjQxOTg8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFt

cD0iMTUzNjc3NzAzOCI+NDE5ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+QmpvcmtoZW0sIEkuPC9hdXRob3I+PGF1dGhvcj5EaWN6ZmFsdXN5LCBVLjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT4yNChTKSwyNS1lcG94eWNob2xl

c3Rlcm9sLS1hIHBvdGVudGlhbCBmcmllbmQ8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QXJ0ZXJp

b3NjbGVyIFRocm9tYiBWYXNjIEJpb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9k

aWNhbD48ZnVsbC10aXRsZT5BcnRlcmlvc2NsZXIgVGhyb21iIFZhc2MgQmlvbDwvZnVsbC10aXRs

ZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIyMDktMTA8L3BhZ2VzPjx2b2x1bWU+MjQ8L3ZvbHVtZT48

bnVtYmVyPjEyPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtl

eXdvcmQ+Q2hvbGVzdGVyb2wvKmFuYWxvZ3MgJmFtcDsgZGVyaXZhdGl2ZXMvKnRoZXJhcGV1dGlj

IHVzZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAwNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPkRlYzwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjE1MjQtNDYzNiAoRWxlY3Ryb25pYykmI3hEOzEwNzktNTY0MiAoTGlua2lu

Zyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTU1NzY2NDQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJl

bGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTU1NzY2

NDQ8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEw

LjExNjEvMDEuQVRWLjAwMDAxNDg3MDQuNzI0ODEuMjg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 391,392. CYP46A1 is a key enzyme of brain cholesterol metabolism. Not only CYP46A1 allows most cholesterol efflux from the brain, it also activates the whole pathway of cholesterol metabolism, the so-called mevalonate pathway (Fig. 6) and represents an important stress response factor to noxious stimuli like aging, toxic protein aggregates, disease conditions like AD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb2Rlcm88L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

ZWNOdW0+NDMyMzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjM5MywzOTQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40MzIzPC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDA5MzEzNjUiPjQzMjM8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNvZGVybywgQS4gTy48L2F1dGhv

cj48YXV0aG9yPlRyb3ZvLCBMLjwvYXV0aG9yPjxhdXRob3I+SWFubmlsbGksIEYuPC9hdXRob3I+

PGF1dGhvcj5WYW4gVmVsZGhvdmVuLCBQLjwvYXV0aG9yPjxhdXRob3I+RG90dGksIEMuIEcuPC9h

dXRob3I+PGF1dGhvcj5NYXJ0aW4sIE0uIEcuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjxhdXRoLWFkZHJlc3M+VklCIERlcGFydG1lbnQgb2YgTW9sZWN1bGFyIGFuZCBEZXZlbG9w

bWVudGFsIEdlbmV0aWNzLCBLVSBMZXV2ZW4sIExldXZlbiwgQmVsZ2l1bS48L2F1dGgtYWRkcmVz

cz48dGl0bGVzPjx0aXRsZT5SZWd1bGF0aW9uIG9mIHR5cm9zaW5lIGtpbmFzZSBCIGFjdGl2aXR5

IGJ5IHRoZSBDeXA0Ni9jaG9sZXN0ZXJvbCBsb3NzIHBhdGh3YXkgaW4gbWF0dXJlIGhpcHBvY2Ft

cGFsIG5ldXJvbnM6IHJlbGV2YW5jZSBmb3IgbmV1cm9uYWwgc3Vydml2YWwgdW5kZXIgc3RyZXNz

IGFuZCBpbiBhZ2luZzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIE5ldXJvY2hlbTwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9jaGVtPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NzQ3LTU1PC9wYWdlcz48dm9sdW1lPjExNjwv

dm9sdW1lPjxudW1iZXI+NTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD4qQWdpbmc8L2tleXdv

cmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5DZWxsIERlYXRoL3BoeXNpb2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGVzdGVyb2wvKm1ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+Q2hvbGVzdGVyb2wgMjQtSHlkcm94eWxhc2U8L2tleXdvcmQ+PGtleXdvcmQ+SGlwcG9j

YW1wdXMvKmN5dG9sb2d5L2Vuenltb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3

b3JkPjxrZXl3b3JkPk1vZGVscywgQmlvbG9naWNhbDwva2V5d29yZD48a2V5d29yZD5OZXVyb25z

Lyplbnp5bW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk94aWRhdGl2ZSBTdHJlc3MvcGh5c2lvbG9n

eTwva2V5d29yZD48a2V5d29yZD5Qcm90ZWluLVR5cm9zaW5lIEtpbmFzZXMvKm1ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+U2lnbmFsIFRyYW5zZHVjdGlvbi8qcGh5c2lvbG9neTwva2V5d29y

ZD48a2V5d29yZD5TdGVyb2lkIEh5ZHJveHlsYXNlcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5TdHJlc3MsIFBoeXNpb2xvZ2ljYWwvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

VXAtUmVndWxhdGlvbi9waHlzaW9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFy

PjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48aXNibj4xNDcxLTQxNTkgKEVsZWN0cm9uaWMpJiN4RDswMDIyLTMwNDIgKExpbmtpbmcpPC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjIxMjE0NTY4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIxMjE0NTY4PC91

cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTEx

L2ouMTQ3MS00MTU5LjIwMTAuMDcwNzkueDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNv

cmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+THV0am9oYW5uPC9BdXRob3I+PFllYXI+MTk5NjwvWWVh

cj48UmVjTnVtPjQyMTQ8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjQyMTQ8L3JlYy1udW1i

ZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBo

cGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjc3NzQ1NCI+NDIxNDwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+THV0am9oYW5uLCBELjwvYXV0aG9yPjxhdXRo

b3I+QnJldWVyLCBPLjwvYXV0aG9yPjxhdXRob3I+QWhsYm9yZywgRy48L2F1dGhvcj48YXV0aG9y

Pk5lbm5lc21vLCBJLjwvYXV0aG9yPjxhdXRob3I+U2lkZW4sIEEuPC9hdXRob3I+PGF1dGhvcj5E

aWN6ZmFsdXN5LCBVLjwvYXV0aG9yPjxhdXRob3I+QmpvcmtoZW0sIEkuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGl2aXNpb24gb2YgQ2xpbmljYWwgQ2hl

bWlzdHJ5LCBLYXJvbGluc2thIEluc3RpdHV0ZSwgSHVkZGluZ2UgVW5pdmVyc2l0eSBIb3NwaXRh

bCwgU3dlZGVuLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNob2xlc3Rlcm9sIGhvbWVv

c3Rhc2lzIGluIGh1bWFuIGJyYWluOiBldmlkZW5jZSBmb3IgYW4gYWdlLWRlcGVuZGVudCBmbHV4

IG9mIDI0Uy1oeWRyb3h5Y2hvbGVzdGVyb2wgZnJvbSB0aGUgYnJhaW4gaW50byB0aGUgY2lyY3Vs

YXRpb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UHJvYyBOYXRs

IEFjYWQgU2NpIFUgUyBBPC9mdWxsLXRpdGxlPjxhYmJyLTE+UHJvY2VlZGluZ3Mgb2YgdGhlIE5h

dGlvbmFsIEFjYWRlbXkgb2YgU2NpZW5jZXMgb2YgdGhlIFVuaXRlZCBTdGF0ZXMgb2YgQW1lcmlj

YTwvYWJici0xPjwvcGVyaW9kaWNhbD48cGFnZXM+OTc5OS04MDQ8L3BhZ2VzPjx2b2x1bWU+OTM8

L3ZvbHVtZT48bnVtYmVyPjE4PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkb2xlc2NlbnQ8

L2tleXdvcmQ+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48

a2V5d29yZD5BZ2luZy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3

b3JkPjxrZXl3b3JkPkJyYWluLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkNoaWxkPC9r

ZXl3b3JkPjxrZXl3b3JkPkNoaWxkLCBQcmVzY2hvb2w8L2tleXdvcmQ+PGtleXdvcmQ+Q2lyY2Fk

aWFuIFJoeXRobTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+Kkhv

bWVvc3Rhc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IeWRy

b3h5Y2hvbGVzdGVyb2xzL2Jsb29kL2NlcmVicm9zcGluYWwgZmx1aWQvKm1ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+SW5mYW50PC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtl

eXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+T3h5Z2VuPC9rZXl3b3JkPjxrZXl3

b3JkPlJhdHM8L2tleXdvcmQ+PGtleXdvcmQ+UmVmZXJlbmNlIFZhbHVlczwva2V5d29yZD48a2V5

d29yZD5TdGVyZW9pc29tZXJpc208L2tleXdvcmQ+PGtleXdvcmQ+VGlzc3VlIERpc3RyaWJ1dGlv

bjwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk2PC95ZWFyPjxwdWItZGF0ZXM+

PGRhdGU+U2VwIDM8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDI3LTg0MjQgKFBy

aW50KSYjeEQ7MDAyNy04NDI0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT44NzkwNDEx

PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmku

bmxtLm5paC5nb3YvcHVibWVkLzg3OTA0MTE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1

c3RvbTI+UE1DMzg1MDk8L2N1c3RvbTI+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb2Rlcm88L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

ZWNOdW0+NDMyMzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjM5MywzOTQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40MzIzPC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDA5MzEzNjUiPjQzMjM8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNvZGVybywgQS4gTy48L2F1dGhv

cj48YXV0aG9yPlRyb3ZvLCBMLjwvYXV0aG9yPjxhdXRob3I+SWFubmlsbGksIEYuPC9hdXRob3I+

PGF1dGhvcj5WYW4gVmVsZGhvdmVuLCBQLjwvYXV0aG9yPjxhdXRob3I+RG90dGksIEMuIEcuPC9h

dXRob3I+PGF1dGhvcj5NYXJ0aW4sIE0uIEcuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjxhdXRoLWFkZHJlc3M+VklCIERlcGFydG1lbnQgb2YgTW9sZWN1bGFyIGFuZCBEZXZlbG9w

bWVudGFsIEdlbmV0aWNzLCBLVSBMZXV2ZW4sIExldXZlbiwgQmVsZ2l1bS48L2F1dGgtYWRkcmVz

cz48dGl0bGVzPjx0aXRsZT5SZWd1bGF0aW9uIG9mIHR5cm9zaW5lIGtpbmFzZSBCIGFjdGl2aXR5

IGJ5IHRoZSBDeXA0Ni9jaG9sZXN0ZXJvbCBsb3NzIHBhdGh3YXkgaW4gbWF0dXJlIGhpcHBvY2Ft

cGFsIG5ldXJvbnM6IHJlbGV2YW5jZSBmb3IgbmV1cm9uYWwgc3Vydml2YWwgdW5kZXIgc3RyZXNz

IGFuZCBpbiBhZ2luZzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIE5ldXJvY2hlbTwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9jaGVtPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NzQ3LTU1PC9wYWdlcz48dm9sdW1lPjExNjwv

dm9sdW1lPjxudW1iZXI+NTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD4qQWdpbmc8L2tleXdv

cmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5DZWxsIERlYXRoL3BoeXNpb2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGVzdGVyb2wvKm1ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+Q2hvbGVzdGVyb2wgMjQtSHlkcm94eWxhc2U8L2tleXdvcmQ+PGtleXdvcmQ+SGlwcG9j

YW1wdXMvKmN5dG9sb2d5L2Vuenltb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3

b3JkPjxrZXl3b3JkPk1vZGVscywgQmlvbG9naWNhbDwva2V5d29yZD48a2V5d29yZD5OZXVyb25z

Lyplbnp5bW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk94aWRhdGl2ZSBTdHJlc3MvcGh5c2lvbG9n

eTwva2V5d29yZD48a2V5d29yZD5Qcm90ZWluLVR5cm9zaW5lIEtpbmFzZXMvKm1ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+U2lnbmFsIFRyYW5zZHVjdGlvbi8qcGh5c2lvbG9neTwva2V5d29y

ZD48a2V5d29yZD5TdGVyb2lkIEh5ZHJveHlsYXNlcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5TdHJlc3MsIFBoeXNpb2xvZ2ljYWwvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

VXAtUmVndWxhdGlvbi9waHlzaW9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFy

PjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48aXNibj4xNDcxLTQxNTkgKEVsZWN0cm9uaWMpJiN4RDswMDIyLTMwNDIgKExpbmtpbmcpPC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjIxMjE0NTY4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIxMjE0NTY4PC91

cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTEx

L2ouMTQ3MS00MTU5LjIwMTAuMDcwNzkueDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNv

cmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+THV0am9oYW5uPC9BdXRob3I+PFllYXI+MTk5NjwvWWVh

cj48UmVjTnVtPjQyMTQ8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjQyMTQ8L3JlYy1udW1i

ZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBo

cGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjc3NzQ1NCI+NDIxNDwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+THV0am9oYW5uLCBELjwvYXV0aG9yPjxhdXRo

b3I+QnJldWVyLCBPLjwvYXV0aG9yPjxhdXRob3I+QWhsYm9yZywgRy48L2F1dGhvcj48YXV0aG9y

Pk5lbm5lc21vLCBJLjwvYXV0aG9yPjxhdXRob3I+U2lkZW4sIEEuPC9hdXRob3I+PGF1dGhvcj5E

aWN6ZmFsdXN5LCBVLjwvYXV0aG9yPjxhdXRob3I+QmpvcmtoZW0sIEkuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGl2aXNpb24gb2YgQ2xpbmljYWwgQ2hl

bWlzdHJ5LCBLYXJvbGluc2thIEluc3RpdHV0ZSwgSHVkZGluZ2UgVW5pdmVyc2l0eSBIb3NwaXRh

bCwgU3dlZGVuLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNob2xlc3Rlcm9sIGhvbWVv

c3Rhc2lzIGluIGh1bWFuIGJyYWluOiBldmlkZW5jZSBmb3IgYW4gYWdlLWRlcGVuZGVudCBmbHV4

IG9mIDI0Uy1oeWRyb3h5Y2hvbGVzdGVyb2wgZnJvbSB0aGUgYnJhaW4gaW50byB0aGUgY2lyY3Vs

YXRpb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UHJvYyBOYXRs

IEFjYWQgU2NpIFUgUyBBPC9mdWxsLXRpdGxlPjxhYmJyLTE+UHJvY2VlZGluZ3Mgb2YgdGhlIE5h

dGlvbmFsIEFjYWRlbXkgb2YgU2NpZW5jZXMgb2YgdGhlIFVuaXRlZCBTdGF0ZXMgb2YgQW1lcmlj

YTwvYWJici0xPjwvcGVyaW9kaWNhbD48cGFnZXM+OTc5OS04MDQ8L3BhZ2VzPjx2b2x1bWU+OTM8

L3ZvbHVtZT48bnVtYmVyPjE4PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkb2xlc2NlbnQ8

L2tleXdvcmQ+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48

a2V5d29yZD5BZ2luZy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3

b3JkPjxrZXl3b3JkPkJyYWluLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkNoaWxkPC9r

ZXl3b3JkPjxrZXl3b3JkPkNoaWxkLCBQcmVzY2hvb2w8L2tleXdvcmQ+PGtleXdvcmQ+Q2lyY2Fk

aWFuIFJoeXRobTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+Kkhv

bWVvc3Rhc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IeWRy

b3h5Y2hvbGVzdGVyb2xzL2Jsb29kL2NlcmVicm9zcGluYWwgZmx1aWQvKm1ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+SW5mYW50PC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtl

eXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+T3h5Z2VuPC9rZXl3b3JkPjxrZXl3

b3JkPlJhdHM8L2tleXdvcmQ+PGtleXdvcmQ+UmVmZXJlbmNlIFZhbHVlczwva2V5d29yZD48a2V5

d29yZD5TdGVyZW9pc29tZXJpc208L2tleXdvcmQ+PGtleXdvcmQ+VGlzc3VlIERpc3RyaWJ1dGlv

bjwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk2PC95ZWFyPjxwdWItZGF0ZXM+

PGRhdGU+U2VwIDM8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDI3LTg0MjQgKFBy

aW50KSYjeEQ7MDAyNy04NDI0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT44NzkwNDEx

PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmku

bmxtLm5paC5nb3YvcHVibWVkLzg3OTA0MTE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1

c3RvbTI+UE1DMzg1MDk8L2N1c3RvbTI+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 393,394. CYP46A1 was shown in response to stress, to induce the relocation of Trkb in plasma membranes, leading to its activation and to postsynaptic stress response signaling, a pathway that could be associated with improved cognition and synaptic plasticity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb2Rlcm88L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

ZWNOdW0+NDMyMzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjM5Mzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQzMjM8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0MDkzMTM2NSI+NDMyMzwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U29kZXJvLCBBLiBPLjwvYXV0aG9yPjxh

dXRob3I+VHJvdm8sIEwuPC9hdXRob3I+PGF1dGhvcj5JYW5uaWxsaSwgRi48L2F1dGhvcj48YXV0

aG9yPlZhbiBWZWxkaG92ZW4sIFAuPC9hdXRob3I+PGF1dGhvcj5Eb3R0aSwgQy4gRy48L2F1dGhv

cj48YXV0aG9yPk1hcnRpbiwgTS4gRy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+

PGF1dGgtYWRkcmVzcz5WSUIgRGVwYXJ0bWVudCBvZiBNb2xlY3VsYXIgYW5kIERldmVsb3BtZW50

YWwgR2VuZXRpY3MsIEtVIExldXZlbiwgTGV1dmVuLCBCZWxnaXVtLjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPlJlZ3VsYXRpb24gb2YgdHlyb3NpbmUga2luYXNlIEIgYWN0aXZpdHkgYnkg

dGhlIEN5cDQ2L2Nob2xlc3Rlcm9sIGxvc3MgcGF0aHdheSBpbiBtYXR1cmUgaGlwcG9jYW1wYWwg

bmV1cm9uczogcmVsZXZhbmNlIGZvciBuZXVyb25hbCBzdXJ2aXZhbCB1bmRlciBzdHJlc3MgYW5k

IGluIGFnaW5nPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogTmV1cm9jaGVtPC9zZWNvbmRhcnkt

dGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBOZXVyb2NoZW08L2Z1bGwt

dGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz43NDctNTU8L3BhZ2VzPjx2b2x1bWU+MTE2PC92b2x1

bWU+PG51bWJlcj41PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPipBZ2luZzwva2V5d29yZD48

a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgRGVhdGgvcGh5c2lvbG9neTwv

a2V5d29yZD48a2V5d29yZD5DaG9sZXN0ZXJvbC8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29y

ZD5DaG9sZXN0ZXJvbCAyNC1IeWRyb3h5bGFzZTwva2V5d29yZD48a2V5d29yZD5IaXBwb2NhbXB1

cy8qY3l0b2xvZ3kvZW56eW1vbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+

PGtleXdvcmQ+TW9kZWxzLCBCaW9sb2dpY2FsPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbnMvKmVu

enltb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+T3hpZGF0aXZlIFN0cmVzcy9waHlzaW9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPlByb3RlaW4tVHlyb3NpbmUgS2luYXNlcy8qbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5TaWduYWwgVHJhbnNkdWN0aW9uLypwaHlzaW9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPlN0ZXJvaWQgSHlkcm94eWxhc2VzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

PlN0cmVzcywgUGh5c2lvbG9naWNhbC8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5VcC1S

ZWd1bGF0aW9uL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAx

MTwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1hcjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxp

c2JuPjE0NzEtNDE1OSAoRWxlY3Ryb25pYykmI3hEOzAwMjItMzA0MiAoTGlua2luZyk8L2lzYm4+

PGFjY2Vzc2lvbi1udW0+MjEyMTQ1Njg8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJs

cz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjEyMTQ1Njg8L3VybD48

L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExMTEvai4x

NDcxLTQxNTkuMjAxMC4wNzA3OS54PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48

L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb2Rlcm88L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

ZWNOdW0+NDMyMzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjM5Mzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQzMjM8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0MDkzMTM2NSI+NDMyMzwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U29kZXJvLCBBLiBPLjwvYXV0aG9yPjxh

dXRob3I+VHJvdm8sIEwuPC9hdXRob3I+PGF1dGhvcj5JYW5uaWxsaSwgRi48L2F1dGhvcj48YXV0

aG9yPlZhbiBWZWxkaG92ZW4sIFAuPC9hdXRob3I+PGF1dGhvcj5Eb3R0aSwgQy4gRy48L2F1dGhv

cj48YXV0aG9yPk1hcnRpbiwgTS4gRy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+

PGF1dGgtYWRkcmVzcz5WSUIgRGVwYXJ0bWVudCBvZiBNb2xlY3VsYXIgYW5kIERldmVsb3BtZW50

YWwgR2VuZXRpY3MsIEtVIExldXZlbiwgTGV1dmVuLCBCZWxnaXVtLjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPlJlZ3VsYXRpb24gb2YgdHlyb3NpbmUga2luYXNlIEIgYWN0aXZpdHkgYnkg

dGhlIEN5cDQ2L2Nob2xlc3Rlcm9sIGxvc3MgcGF0aHdheSBpbiBtYXR1cmUgaGlwcG9jYW1wYWwg

bmV1cm9uczogcmVsZXZhbmNlIGZvciBuZXVyb25hbCBzdXJ2aXZhbCB1bmRlciBzdHJlc3MgYW5k

IGluIGFnaW5nPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogTmV1cm9jaGVtPC9zZWNvbmRhcnkt

dGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBOZXVyb2NoZW08L2Z1bGwt

dGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz43NDctNTU8L3BhZ2VzPjx2b2x1bWU+MTE2PC92b2x1

bWU+PG51bWJlcj41PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPipBZ2luZzwva2V5d29yZD48

a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgRGVhdGgvcGh5c2lvbG9neTwv

a2V5d29yZD48a2V5d29yZD5DaG9sZXN0ZXJvbC8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29y

ZD5DaG9sZXN0ZXJvbCAyNC1IeWRyb3h5bGFzZTwva2V5d29yZD48a2V5d29yZD5IaXBwb2NhbXB1

cy8qY3l0b2xvZ3kvZW56eW1vbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+

PGtleXdvcmQ+TW9kZWxzLCBCaW9sb2dpY2FsPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbnMvKmVu

enltb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+T3hpZGF0aXZlIFN0cmVzcy9waHlzaW9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPlByb3RlaW4tVHlyb3NpbmUgS2luYXNlcy8qbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5TaWduYWwgVHJhbnNkdWN0aW9uLypwaHlzaW9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPlN0ZXJvaWQgSHlkcm94eWxhc2VzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

PlN0cmVzcywgUGh5c2lvbG9naWNhbC8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5VcC1S

ZWd1bGF0aW9uL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAx

MTwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1hcjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxp

c2JuPjE0NzEtNDE1OSAoRWxlY3Ryb25pYykmI3hEOzAwMjItMzA0MiAoTGlua2luZyk8L2lzYm4+

PGFjY2Vzc2lvbi1udW0+MjEyMTQ1Njg8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJs

cz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjEyMTQ1Njg8L3VybD48

L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExMTEvai4x

NDcxLTQxNTkuMjAxMC4wNzA3OS54PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48

L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 393. Figure 6. The mevalonate pathway of cholesterol metabolism: roles in neuronal functions.The decrease in CYP46A1 function in normal mouse hippocampus, using AAV- CYP46A1 shRNA delivery is associated with cholesterol accumulation in cell membranes and strong neuronal toxicity leading to severe endoplasmic reticulum stress and neuronal death with hippocampal atrophy. Interestingly a reduction of only 30 to 50% in CYP46 levels induces amyloid beta accumulation and hyperphosphorylation of Tau protein in the hippocampus, a phenotype resembling Alzheimer’s disease. CYP46A1 inhibition in AD mice with amyloid pathology leads to accelerated toxicity with major amyloid accumulation, rapid neuronal death, and seizures, evidencing the toxic loop between cholesterol metabolism impairment and amyloid productionPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdXJsb3Q8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS

ZWNOdW0+NDIxODwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjM5NSwzOTY8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40MjE4PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzY3Nzc1MjIiPjQyMTg8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJ1cmxvdCwgTS4gQS48L2F1dGhv

cj48YXV0aG9yPkJyYXVkZWF1LCBKLjwvYXV0aG9yPjxhdXRob3I+TWljaGFlbHNlbi1QcmV1c3Nl

LCBLLjwvYXV0aG9yPjxhdXRob3I+UG90aWVyLCBCLjwvYXV0aG9yPjxhdXRob3I+QXljaXJpZXgs

IFMuPC9hdXRob3I+PGF1dGhvcj5WYXJpbiwgSi48L2F1dGhvcj48YXV0aG9yPkdhdXRpZXIsIEIu

PC9hdXRob3I+PGF1dGhvcj5EamVsdGksIEYuPC9hdXRob3I+PGF1dGhvcj5BdWRyYWluLCBNLjwv

YXV0aG9yPjxhdXRob3I+RGF1cGhpbm90LCBMLjwvYXV0aG9yPjxhdXRob3I+RmVybmFuZGV6LUdv

bWV6LCBGLiBKLjwvYXV0aG9yPjxhdXRob3I+Q2FpbGxpZXJleiwgUi48L2F1dGhvcj48YXV0aG9y

PkxhcHJldm90ZSwgTy48L2F1dGhvcj48YXV0aG9yPkJpZWNoZSwgSS48L2F1dGhvcj48YXV0aG9y

PkF1emVpbCwgTi48L2F1dGhvcj48YXV0aG9yPlBvdGllciwgTS4gQy48L2F1dGhvcj48YXV0aG9y

PkR1dGFyLCBQLjwvYXV0aG9yPjxhdXRob3I+S29ydGUsIE0uPC9hdXRob3I+PGF1dGhvcj5CdWVl

LCBMLjwvYXV0aG9yPjxhdXRob3I+Qmx1bSwgRC48L2F1dGhvcj48YXV0aG9yPkNhcnRpZXIsIE4u

PC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+SU5TRVJNIFUx

MTY5L01JUkNlbiBDRUEsIEZvbnRlbmF5IGF1eCBSb3NlcyA5MjI2NSwgRnJhbmNlLCBVbml2ZXJz

aXRlIFBhcmlzLVN1ZCwgVW5pdmVyc2l0ZSBQYXJpcy1TYWNsYXksIE9yc2F5IDkxNDAwLCBGcmFu

Y2UsIFVuaXZlcnNpdGUgUGFyaXMgRGVzY2FydGVzLCBQYXJpcyA3NTAwNiwgRnJhbmNlLiYjeEQ7

SU5TRVJNIFUxMTY5L01JUkNlbiBDRUEsIEZvbnRlbmF5IGF1eCBSb3NlcyA5MjI2NSwgRnJhbmNl

LCBVbml2ZXJzaXRlIFBhcmlzLVN1ZCwgVW5pdmVyc2l0ZSBQYXJpcy1TYWNsYXksIE9yc2F5IDkx

NDAwLCBGcmFuY2UuJiN4RDtEaXZpc2lvbiBvZiBDZWxsdWxhciBOZXVyb2Jpb2xvZ3ksIFpvb2xv

Z2ljYWwgSW5zdGl0dXRlLCBVbml2ZXJzaXR5IG9mIEJyYXVuc2Nod2VpZywgQnJhdW5zY2h3ZWln

IDM4MTA2LCBHZXJtYW55LCBBRyBOSU5ELCBIWkksIEluaG9mZmVuc3RyYXNzZSA3LCBCcmF1bnNj

aHdlaWcgRC0zODEyNCwgR2VybWFueS4mI3hEO0NlbnRyZSBkZSBQc3ljaGlhdHJpZSBldCBOZXVy

b3NjaWVuY2VzLCBVbml2ZXJzaXRlIFBhcmlzIERlc2NhcnRlcywgU29yYm9ubmUgUGFyaXMgQ2l0

ZSwgSU5TRVJNIFVNUlM4OTQsIFBhcmlzIDc1MDE0LCBGcmFuY2UuJiN4RDtDaGltaWUtVG94aWNv

bG9naWUgQW5hbHl0aXF1ZSBldCBDZWxsdWxhaXJlLCBFQSA0NDYzIGFuZC4mI3hEO0VBNzMzMSwg

VW5pdmVyc2l0ZSBQYXJpcyBEZXNjYXJ0ZXMsIFNvcmJvbm5lIFBhcmlzIENpdGUsIEZhY3VsdGUg

ZGVzIFNjaWVuY2VzIFBoYXJtYWNldXRpcXVlcyBldCBCaW9sb2dpcXVlcywgUGFyaXMgNzUwMDYs

IEZyYW5jZS4mI3hEO0lDTSwgSG9waXRhbCBQaXRpZS1TYWxwZXRyaWVyZSwgQ05SUyBVTVI3MjI1

LCBJTlNFUk0gVU1SUzk3NSwgVVBNQywgUGFyaXMgNzUwMTMsIEZyYW5jZS4mI3hEO1VuaXZlcnNp

dGUgZGUgTGlsbGUsIFVEU0wsIExpbGxlIDU5MDQ1LCBGcmFuY2UsIElOU0VSTSBVTVIxMTcyLCBK

ZWFuLVBpZXJyZSBBdWJlcnQgUmVzZWFyY2ggQ2VudHJlLCBMaWxsZSA1OTA0NSwgRnJhbmNlIGFu

ZC4mI3hEO1VuaXZlcnNpdGUgZGUgTGlsbGUsIFVEU0wsIExpbGxlIDU5MDQ1LCBGcmFuY2UsIElO

U0VSTSBVTVIxMTcyLCBKZWFuLVBpZXJyZSBBdWJlcnQgUmVzZWFyY2ggQ2VudHJlLCBMaWxsZSA1

OTA0NSwgRnJhbmNlIGFuZCBDSFJVLUxpbGxlLCBGYWN1bHRlIGRlIE1lZGVjaW5lLCBMaWxsZSA1

OTAzNywgRnJhbmNlLiYjeEQ7SU5TRVJNIFUxMTY5L01JUkNlbiBDRUEsIEZvbnRlbmF5IGF1eCBS

b3NlcyA5MjI2NSwgRnJhbmNlLCBVbml2ZXJzaXRlIFBhcmlzLVN1ZCwgVW5pdmVyc2l0ZSBQYXJp

cy1TYWNsYXksIE9yc2F5IDkxNDAwLCBGcmFuY2UsIG5hdGhhbGllLmNhcnRpZXJAaW5zZXJtLmZy

LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNob2xlc3Rlcm9sIDI0LWh5ZHJveHlsYXNl

IGRlZmVjdCBpcyBpbXBsaWNhdGVkIGluIG1lbW9yeSBpbXBhaXJtZW50cyBhc3NvY2lhdGVkIHdp

dGggQWx6aGVpbWVyLWxpa2UgVGF1IHBhdGhvbG9neTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5I

dW0gTW9sIEdlbmV0PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwt

dGl0bGU+SHVtIE1vbCBHZW5ldDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjU5NjUt

NzY8L3BhZ2VzPjx2b2x1bWU+MjQ8L3ZvbHVtZT48bnVtYmVyPjIxPC9udW1iZXI+PGtleXdvcmRz

PjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2Vuenltb2xvZ3kvZ2VuZXRpY3MvcGF0aG9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGVzdGVyb2wg

MjQtSHlkcm94eWxhc2U8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFuaW1hbDwv

a2V5d29yZD48a2V5d29yZD5HbGlvc2lzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SGlw

cG9jYW1wdXMvZW56eW1vbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtl

eXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1l

bW9yeSBEaXNvcmRlcnMvKmVuenltb2xvZ3kvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+TWlj

ZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFuc2dlbmljPC9rZXl3b3JkPjxrZXl3b3JkPlBo

b3NwaG9yeWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5TdGVyb2lkIEh5ZHJveHlsYXNlcy9nZW5l

dGljcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5UYXVvcGF0aGllcy9nZW5ldGljcy8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD50YXUgUHJvdGVpbnM8L2tleXdvcmQ+PC9rZXl3

b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdiAxPC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ2MC0yMDgzIChFbGVjdHJvbmljKSYjeEQ7MDk2

NC02OTA2IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNjM1ODc4MDwvYWNjZXNzaW9u

LW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292

L3B1Ym1lZC8yNjM1ODc4MDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+MTAuMTA5My9obWcvZGR2MjY4PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48

L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5EamVsdGk8L0F1dGhvcj48WWVhcj4yMDE1PC9Z

ZWFyPjxSZWNOdW0+NDIxOTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+NDIxOTwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2Nzc3NTIyIj40MjE5PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5EamVsdGksIEYuPC9hdXRob3I+PGF1dGhv

cj5CcmF1ZGVhdSwgSi48L2F1dGhvcj48YXV0aG9yPkh1ZHJ5LCBFLjwvYXV0aG9yPjxhdXRob3I+

RGhlbmFpbiwgTS48L2F1dGhvcj48YXV0aG9yPlZhcmluLCBKLjwvYXV0aG9yPjxhdXRob3I+Qmll

Y2hlLCBJLjwvYXV0aG9yPjxhdXRob3I+TWFycXVlciwgQy48L2F1dGhvcj48YXV0aG9yPkNoYWxp

LCBGLjwvYXV0aG9yPjxhdXRob3I+QXljaXJpZXgsIFMuPC9hdXRob3I+PGF1dGhvcj5BdXplaWws

IE4uPC9hdXRob3I+PGF1dGhvcj5BbHZlcywgUy48L2F1dGhvcj48YXV0aG9yPkxhbmd1aSwgRC48

L2F1dGhvcj48YXV0aG9yPlBvdGllciwgTS4gQy48L2F1dGhvcj48YXV0aG9yPkxhcHJldm90ZSwg

Ty48L2F1dGhvcj48YXV0aG9yPlZpZGF1ZCwgTS48L2F1dGhvcj48YXV0aG9yPkR1eWNrYWVydHMs

IEMuPC9hdXRob3I+PGF1dGhvcj5NaWxlcywgUi48L2F1dGhvcj48YXV0aG9yPkF1Ym91cmcsIFAu

PC9hdXRob3I+PGF1dGhvcj5DYXJ0aWVyLCBOLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPjEgSU5TRVJNIFUxMTY5IExlIEtyZW1saW4tQmljZXRyZSBhbmQg

VW5pdmVyc2l0ZSBQYXJpcy1TdWQsIDkxNDAwIE9yc2F5LCBGcmFuY2UuJiN4RDsyIENOUlMgVVJB

MjIxMCBNSVJDZW4gQ0VBIEZvbnRlbmF5IGF1eCBSb3NlcyA5MjI2NSwgYW5kIFVuaXZlcnNpdGUg

UGFyaXMtU3VkLCA5MTQwMCBPcnNheSwgRnJhbmNlLiYjeEQ7MyBFQTczMzEsIFVuaXZlcnNpdGUg

UGFyaXMgRGVzY2FydGVzIFNvcmJvbm5lIFBhcmlzIENpdGUsIEZhY3VsdGUgZGVzIFNjaWVuY2Vz

IFBoYXJtYWNldXRpcXVlcyBldCBCaW9sb2dpcXVlcywgNzUwMDYgUGFyaXMsIEZyYW5jZS4mI3hE

OzQgVU1SIFMxMTI3LCBhbmQgSU5TRVJNIFUxMTI3LCBhbmQgQ05SUyBVTVI3MjI1LCBhbmQgSUNN

LCBTb3Jib25uZSBVbml2ZXJzaXRlLCBVUE1DIFVuaXYgUGFyaXMgMDYgNzUwMTMsIFBhcmlzLCBG

cmFuY2UuJiN4RDs1IENoaW1pZS1Ub3hpY29sb2dpZSBBbmFseXRpcXVlIGV0IENlbGx1bGFpcmUs

IEVBIDQ0NjMsIFVuaXZlcnNpdGUgUGFyaXMgRGVzY2FydGVzLCBTb3Jib25uZSBQYXJpcyBDaXRl

LCBGYWN1bHRlIGRlcyBTY2llbmNlcyBQaGFybWFjZXV0aXF1ZXMgZXQgQmlvbG9naXF1ZXMsIDc1

MDA2IFBhcmlzLCBGcmFuY2UuJiN4RDsxIElOU0VSTSBVMTE2OSBMZSBLcmVtbGluLUJpY2V0cmUg

YW5kIFVuaXZlcnNpdGUgUGFyaXMtU3VkLCA5MTQwMCBPcnNheSwgRnJhbmNlIG5hdGhhbGllLmNh

cnRpZXJAaW5zZXJtLmZyLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNZUDQ2QTEgaW5o

aWJpdGlvbiwgYnJhaW4gY2hvbGVzdGVyb2wgYWNjdW11bGF0aW9uIGFuZCBuZXVyb2RlZ2VuZXJh

dGlvbiBwYXZlIHRoZSB3YXkgZm9yIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5CcmFpbjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPkJyYWluPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjM4My05

ODwvcGFnZXM+PHZvbHVtZT4xMzg8L3ZvbHVtZT48bnVtYmVyPlB0IDg8L251bWJlcj48a2V5d29y

ZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW15

bG9pZCBiZXRhLVByb3RlaW4gUHJlY3Vyc29yL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+

QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CcmFpbi8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5DaG9sZXN0ZXJvbC8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0ZXJv

bCAyNC1IeWRyb3h5bGFzZTwva2V5d29yZD48a2V5d29yZD5Fbnp5bWUgSW5oaWJpdG9ycy8qcGhh

cm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5Ib21l

b3N0YXNpcy9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIEluYnJlZCBDNTdCTDwv

a2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFuc2dlbmljPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJv

bnMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5TdGVyb2lkIEh5ZHJveHlsYXNlcy8qYW50

YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9yczwva2V5d29yZD48a2V5d29yZD4yNFMtaHlkcm94eWNo

b2xlc3Rlcm9sPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5

d29yZD48a2V5d29yZD5DeXA0NmExPC9rZXl3b3JkPjxrZXl3b3JkPmNob2xlc3Rlcm9sPC9rZXl3

b3JkPjxrZXl3b3JkPm5ldXJvZGVnZW5lcmF0aW9uPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVz

Pjx5ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+

PC9kYXRlcz48aXNibj4xNDYwLTIxNTYgKEVsZWN0cm9uaWMpJiN4RDswMDA2LTg5NTAgKExpbmtp

bmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2MTQxNDkyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxy

ZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI2MTQx

NDkyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4x

MC4xMDkzL2JyYWluL2F3djE2NjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9D

aXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdXJsb3Q8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS

ZWNOdW0+NDIxODwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjM5NSwzOTY8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40MjE4PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzY3Nzc1MjIiPjQyMTg8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJ1cmxvdCwgTS4gQS48L2F1dGhv

cj48YXV0aG9yPkJyYXVkZWF1LCBKLjwvYXV0aG9yPjxhdXRob3I+TWljaGFlbHNlbi1QcmV1c3Nl

LCBLLjwvYXV0aG9yPjxhdXRob3I+UG90aWVyLCBCLjwvYXV0aG9yPjxhdXRob3I+QXljaXJpZXgs

IFMuPC9hdXRob3I+PGF1dGhvcj5WYXJpbiwgSi48L2F1dGhvcj48YXV0aG9yPkdhdXRpZXIsIEIu

PC9hdXRob3I+PGF1dGhvcj5EamVsdGksIEYuPC9hdXRob3I+PGF1dGhvcj5BdWRyYWluLCBNLjwv

YXV0aG9yPjxhdXRob3I+RGF1cGhpbm90LCBMLjwvYXV0aG9yPjxhdXRob3I+RmVybmFuZGV6LUdv

bWV6LCBGLiBKLjwvYXV0aG9yPjxhdXRob3I+Q2FpbGxpZXJleiwgUi48L2F1dGhvcj48YXV0aG9y

PkxhcHJldm90ZSwgTy48L2F1dGhvcj48YXV0aG9yPkJpZWNoZSwgSS48L2F1dGhvcj48YXV0aG9y

PkF1emVpbCwgTi48L2F1dGhvcj48YXV0aG9yPlBvdGllciwgTS4gQy48L2F1dGhvcj48YXV0aG9y

PkR1dGFyLCBQLjwvYXV0aG9yPjxhdXRob3I+S29ydGUsIE0uPC9hdXRob3I+PGF1dGhvcj5CdWVl

LCBMLjwvYXV0aG9yPjxhdXRob3I+Qmx1bSwgRC48L2F1dGhvcj48YXV0aG9yPkNhcnRpZXIsIE4u

PC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+SU5TRVJNIFUx

MTY5L01JUkNlbiBDRUEsIEZvbnRlbmF5IGF1eCBSb3NlcyA5MjI2NSwgRnJhbmNlLCBVbml2ZXJz

aXRlIFBhcmlzLVN1ZCwgVW5pdmVyc2l0ZSBQYXJpcy1TYWNsYXksIE9yc2F5IDkxNDAwLCBGcmFu

Y2UsIFVuaXZlcnNpdGUgUGFyaXMgRGVzY2FydGVzLCBQYXJpcyA3NTAwNiwgRnJhbmNlLiYjeEQ7

SU5TRVJNIFUxMTY5L01JUkNlbiBDRUEsIEZvbnRlbmF5IGF1eCBSb3NlcyA5MjI2NSwgRnJhbmNl

LCBVbml2ZXJzaXRlIFBhcmlzLVN1ZCwgVW5pdmVyc2l0ZSBQYXJpcy1TYWNsYXksIE9yc2F5IDkx

NDAwLCBGcmFuY2UuJiN4RDtEaXZpc2lvbiBvZiBDZWxsdWxhciBOZXVyb2Jpb2xvZ3ksIFpvb2xv

Z2ljYWwgSW5zdGl0dXRlLCBVbml2ZXJzaXR5IG9mIEJyYXVuc2Nod2VpZywgQnJhdW5zY2h3ZWln

IDM4MTA2LCBHZXJtYW55LCBBRyBOSU5ELCBIWkksIEluaG9mZmVuc3RyYXNzZSA3LCBCcmF1bnNj

aHdlaWcgRC0zODEyNCwgR2VybWFueS4mI3hEO0NlbnRyZSBkZSBQc3ljaGlhdHJpZSBldCBOZXVy

b3NjaWVuY2VzLCBVbml2ZXJzaXRlIFBhcmlzIERlc2NhcnRlcywgU29yYm9ubmUgUGFyaXMgQ2l0

ZSwgSU5TRVJNIFVNUlM4OTQsIFBhcmlzIDc1MDE0LCBGcmFuY2UuJiN4RDtDaGltaWUtVG94aWNv

bG9naWUgQW5hbHl0aXF1ZSBldCBDZWxsdWxhaXJlLCBFQSA0NDYzIGFuZC4mI3hEO0VBNzMzMSwg

VW5pdmVyc2l0ZSBQYXJpcyBEZXNjYXJ0ZXMsIFNvcmJvbm5lIFBhcmlzIENpdGUsIEZhY3VsdGUg

ZGVzIFNjaWVuY2VzIFBoYXJtYWNldXRpcXVlcyBldCBCaW9sb2dpcXVlcywgUGFyaXMgNzUwMDYs

IEZyYW5jZS4mI3hEO0lDTSwgSG9waXRhbCBQaXRpZS1TYWxwZXRyaWVyZSwgQ05SUyBVTVI3MjI1

LCBJTlNFUk0gVU1SUzk3NSwgVVBNQywgUGFyaXMgNzUwMTMsIEZyYW5jZS4mI3hEO1VuaXZlcnNp

dGUgZGUgTGlsbGUsIFVEU0wsIExpbGxlIDU5MDQ1LCBGcmFuY2UsIElOU0VSTSBVTVIxMTcyLCBK

ZWFuLVBpZXJyZSBBdWJlcnQgUmVzZWFyY2ggQ2VudHJlLCBMaWxsZSA1OTA0NSwgRnJhbmNlIGFu

ZC4mI3hEO1VuaXZlcnNpdGUgZGUgTGlsbGUsIFVEU0wsIExpbGxlIDU5MDQ1LCBGcmFuY2UsIElO

U0VSTSBVTVIxMTcyLCBKZWFuLVBpZXJyZSBBdWJlcnQgUmVzZWFyY2ggQ2VudHJlLCBMaWxsZSA1

OTA0NSwgRnJhbmNlIGFuZCBDSFJVLUxpbGxlLCBGYWN1bHRlIGRlIE1lZGVjaW5lLCBMaWxsZSA1

OTAzNywgRnJhbmNlLiYjeEQ7SU5TRVJNIFUxMTY5L01JUkNlbiBDRUEsIEZvbnRlbmF5IGF1eCBS

b3NlcyA5MjI2NSwgRnJhbmNlLCBVbml2ZXJzaXRlIFBhcmlzLVN1ZCwgVW5pdmVyc2l0ZSBQYXJp

cy1TYWNsYXksIE9yc2F5IDkxNDAwLCBGcmFuY2UsIG5hdGhhbGllLmNhcnRpZXJAaW5zZXJtLmZy

LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNob2xlc3Rlcm9sIDI0LWh5ZHJveHlsYXNl

IGRlZmVjdCBpcyBpbXBsaWNhdGVkIGluIG1lbW9yeSBpbXBhaXJtZW50cyBhc3NvY2lhdGVkIHdp

dGggQWx6aGVpbWVyLWxpa2UgVGF1IHBhdGhvbG9neTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5I

dW0gTW9sIEdlbmV0PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwt

dGl0bGU+SHVtIE1vbCBHZW5ldDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjU5NjUt

NzY8L3BhZ2VzPjx2b2x1bWU+MjQ8L3ZvbHVtZT48bnVtYmVyPjIxPC9udW1iZXI+PGtleXdvcmRz

PjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2Vuenltb2xvZ3kvZ2VuZXRpY3MvcGF0aG9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGVzdGVyb2wg

MjQtSHlkcm94eWxhc2U8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFuaW1hbDwv

a2V5d29yZD48a2V5d29yZD5HbGlvc2lzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SGlw

cG9jYW1wdXMvZW56eW1vbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtl

eXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1l

bW9yeSBEaXNvcmRlcnMvKmVuenltb2xvZ3kvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+TWlj

ZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFuc2dlbmljPC9rZXl3b3JkPjxrZXl3b3JkPlBo

b3NwaG9yeWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5TdGVyb2lkIEh5ZHJveHlsYXNlcy9nZW5l

dGljcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5UYXVvcGF0aGllcy9nZW5ldGljcy8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD50YXUgUHJvdGVpbnM8L2tleXdvcmQ+PC9rZXl3

b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdiAxPC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ2MC0yMDgzIChFbGVjdHJvbmljKSYjeEQ7MDk2

NC02OTA2IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNjM1ODc4MDwvYWNjZXNzaW9u

LW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292

L3B1Ym1lZC8yNjM1ODc4MDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+MTAuMTA5My9obWcvZGR2MjY4PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48

L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5EamVsdGk8L0F1dGhvcj48WWVhcj4yMDE1PC9Z

ZWFyPjxSZWNOdW0+NDIxOTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+NDIxOTwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2Nzc3NTIyIj40MjE5PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5EamVsdGksIEYuPC9hdXRob3I+PGF1dGhv

cj5CcmF1ZGVhdSwgSi48L2F1dGhvcj48YXV0aG9yPkh1ZHJ5LCBFLjwvYXV0aG9yPjxhdXRob3I+

RGhlbmFpbiwgTS48L2F1dGhvcj48YXV0aG9yPlZhcmluLCBKLjwvYXV0aG9yPjxhdXRob3I+Qmll

Y2hlLCBJLjwvYXV0aG9yPjxhdXRob3I+TWFycXVlciwgQy48L2F1dGhvcj48YXV0aG9yPkNoYWxp

LCBGLjwvYXV0aG9yPjxhdXRob3I+QXljaXJpZXgsIFMuPC9hdXRob3I+PGF1dGhvcj5BdXplaWws

IE4uPC9hdXRob3I+PGF1dGhvcj5BbHZlcywgUy48L2F1dGhvcj48YXV0aG9yPkxhbmd1aSwgRC48

L2F1dGhvcj48YXV0aG9yPlBvdGllciwgTS4gQy48L2F1dGhvcj48YXV0aG9yPkxhcHJldm90ZSwg

Ty48L2F1dGhvcj48YXV0aG9yPlZpZGF1ZCwgTS48L2F1dGhvcj48YXV0aG9yPkR1eWNrYWVydHMs

IEMuPC9hdXRob3I+PGF1dGhvcj5NaWxlcywgUi48L2F1dGhvcj48YXV0aG9yPkF1Ym91cmcsIFAu

PC9hdXRob3I+PGF1dGhvcj5DYXJ0aWVyLCBOLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPjEgSU5TRVJNIFUxMTY5IExlIEtyZW1saW4tQmljZXRyZSBhbmQg

VW5pdmVyc2l0ZSBQYXJpcy1TdWQsIDkxNDAwIE9yc2F5LCBGcmFuY2UuJiN4RDsyIENOUlMgVVJB

MjIxMCBNSVJDZW4gQ0VBIEZvbnRlbmF5IGF1eCBSb3NlcyA5MjI2NSwgYW5kIFVuaXZlcnNpdGUg

UGFyaXMtU3VkLCA5MTQwMCBPcnNheSwgRnJhbmNlLiYjeEQ7MyBFQTczMzEsIFVuaXZlcnNpdGUg

UGFyaXMgRGVzY2FydGVzIFNvcmJvbm5lIFBhcmlzIENpdGUsIEZhY3VsdGUgZGVzIFNjaWVuY2Vz

IFBoYXJtYWNldXRpcXVlcyBldCBCaW9sb2dpcXVlcywgNzUwMDYgUGFyaXMsIEZyYW5jZS4mI3hE

OzQgVU1SIFMxMTI3LCBhbmQgSU5TRVJNIFUxMTI3LCBhbmQgQ05SUyBVTVI3MjI1LCBhbmQgSUNN

LCBTb3Jib25uZSBVbml2ZXJzaXRlLCBVUE1DIFVuaXYgUGFyaXMgMDYgNzUwMTMsIFBhcmlzLCBG

cmFuY2UuJiN4RDs1IENoaW1pZS1Ub3hpY29sb2dpZSBBbmFseXRpcXVlIGV0IENlbGx1bGFpcmUs

IEVBIDQ0NjMsIFVuaXZlcnNpdGUgUGFyaXMgRGVzY2FydGVzLCBTb3Jib25uZSBQYXJpcyBDaXRl

LCBGYWN1bHRlIGRlcyBTY2llbmNlcyBQaGFybWFjZXV0aXF1ZXMgZXQgQmlvbG9naXF1ZXMsIDc1

MDA2IFBhcmlzLCBGcmFuY2UuJiN4RDsxIElOU0VSTSBVMTE2OSBMZSBLcmVtbGluLUJpY2V0cmUg

YW5kIFVuaXZlcnNpdGUgUGFyaXMtU3VkLCA5MTQwMCBPcnNheSwgRnJhbmNlIG5hdGhhbGllLmNh

cnRpZXJAaW5zZXJtLmZyLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNZUDQ2QTEgaW5o

aWJpdGlvbiwgYnJhaW4gY2hvbGVzdGVyb2wgYWNjdW11bGF0aW9uIGFuZCBuZXVyb2RlZ2VuZXJh

dGlvbiBwYXZlIHRoZSB3YXkgZm9yIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5CcmFpbjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPkJyYWluPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjM4My05

ODwvcGFnZXM+PHZvbHVtZT4xMzg8L3ZvbHVtZT48bnVtYmVyPlB0IDg8L251bWJlcj48a2V5d29y

ZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW15

bG9pZCBiZXRhLVByb3RlaW4gUHJlY3Vyc29yL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+

QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CcmFpbi8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5DaG9sZXN0ZXJvbC8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0ZXJv

bCAyNC1IeWRyb3h5bGFzZTwva2V5d29yZD48a2V5d29yZD5Fbnp5bWUgSW5oaWJpdG9ycy8qcGhh

cm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5Ib21l

b3N0YXNpcy9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIEluYnJlZCBDNTdCTDwv

a2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFuc2dlbmljPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJv

bnMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5TdGVyb2lkIEh5ZHJveHlsYXNlcy8qYW50

YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9yczwva2V5d29yZD48a2V5d29yZD4yNFMtaHlkcm94eWNo

b2xlc3Rlcm9sPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5

d29yZD48a2V5d29yZD5DeXA0NmExPC9rZXl3b3JkPjxrZXl3b3JkPmNob2xlc3Rlcm9sPC9rZXl3

b3JkPjxrZXl3b3JkPm5ldXJvZGVnZW5lcmF0aW9uPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVz

Pjx5ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+

PC9kYXRlcz48aXNibj4xNDYwLTIxNTYgKEVsZWN0cm9uaWMpJiN4RDswMDA2LTg5NTAgKExpbmtp

bmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2MTQxNDkyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxy

ZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI2MTQx

NDkyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4x

MC4xMDkzL2JyYWluL2F3djE2NjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9D

aXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 395,396. On the contrary, CYP46 overexpression in AD models improves cognition and decreases pathology in the brain. Injection of an AAV vector coding for the enzyme CYP46A1 restores cholesterol metabolism, decreases amyloid beta accumulation and plaque formation in the different AD models PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWRyeTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl

Y051bT40MjQ0PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

Mzk1LDM5Nzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQyNDQ8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjc3ODA0MiI+NDI0NDwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SHVkcnksIEUuPC9hdXRob3I+PGF1

dGhvcj5WYW4gRGFtLCBELjwvYXV0aG9yPjxhdXRob3I+S3VsaWssIFcuPC9hdXRob3I+PGF1dGhv

cj5EZSBEZXluLCBQLiBQLjwvYXV0aG9yPjxhdXRob3I+U3RldCwgRi4gUy48L2F1dGhvcj48YXV0

aG9yPkFob3VhbnNvdSwgTy48L2F1dGhvcj48YXV0aG9yPkJlbnJhaXNzLCBBLjwvYXV0aG9yPjxh

dXRob3I+RGVsYWNvdXJ0ZSwgQS48L2F1dGhvcj48YXV0aG9yPkJvdWduZXJlcywgUC48L2F1dGhv

cj48YXV0aG9yPkF1Ym91cmcsIFAuPC9hdXRob3I+PGF1dGhvcj5DYXJ0aWVyLCBOLjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPklOU0VSTSBVNzQ1LCBVbml2

ZXJzaXR5IFBhcmlzIERlc2NhcnRlcywgRmFjdWx0ZSBkZXMgU2NpZW5jZXMgUGhhcm1hY2V1dGlx

dWVzIGV0IEJpb2xvZ2lxdWVzLCBQYXJpcywgRnJhbmNlLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+

PHRpdGxlPkFkZW5vLWFzc29jaWF0ZWQgdmlydXMgZ2VuZSB0aGVyYXB5IHdpdGggY2hvbGVzdGVy

b2wgMjQtaHlkcm94eWxhc2UgcmVkdWNlcyB0aGUgYW15bG9pZCBwYXRob2xvZ3kgYmVmb3JlIG9y

IGFmdGVyIHRoZSBvbnNldCBvZiBhbXlsb2lkIHBsYXF1ZXMgaW4gbW91c2UgbW9kZWxzIG9mIEFs

emhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Nb2wgVGhlcjwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz40NC01MzwvcGFnZXM+PHZvbHVtZT4xODwv

dm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlz

ZWFzZS9tZXRhYm9saXNtLyp0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQvKm1ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CbG90dGlu

ZywgV2VzdGVybjwva2V5d29yZD48a2V5d29yZD5DZWxsIExpbmU8L2tleXdvcmQ+PGtleXdvcmQ+

Q2hvbGVzdGVyb2wgMjQtSHlkcm94eWxhc2U8L2tleXdvcmQ+PGtleXdvcmQ+RGVwZW5kb3ZpcnVz

LypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5Fbnp5bWUtTGlua2VkIEltbXVub3NvcmJlbnQg

QXNzYXk8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXRpYyBUaGVyYXB5LyptZXRob2RzPC9rZXl3b3Jk

PjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IeWRyb3h5Y2hvbGVzdGVyb2xzL21l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vaGlzdG9jaGVtaXN0cnk8L2tleXdvcmQ+

PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFuc2dlbmljPC9rZXl3b3Jk

PjxrZXl3b3JkPlJldmVyc2UgVHJhbnNjcmlwdGFzZSBQb2x5bWVyYXNlIENoYWluIFJlYWN0aW9u

PC9rZXl3b3JkPjxrZXl3b3JkPlN0ZXJvaWQgSHlkcm94eWxhc2VzL2dlbmV0aWNzLypwaHlzaW9s

b2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTA8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT5KYW48L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTI1LTAwMjQgKEVs

ZWN0cm9uaWMpJiN4RDsxNTI1LTAwMTYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjE5

NjU0NTY5PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3

Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE5NjU0NTY5PC91cmw+PC9yZWxhdGVkLXVybHM+PC91

cmxzPjxjdXN0b20yPlBNQzI4MzkyMTk8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjEwLjEwMzgvbXQuMjAwOS4xNzU8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48Q2l0ZT48QXV0aG9yPkJ1cmxvdDwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJlY051

bT40MjE4PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj40MjE4PC9yZWMtbnVtYmVyPjxmb3Jl

aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRz

enpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzY3Nzc1MjIiPjQyMTg8L2tleT48L2ZvcmVpZ24ta2V5

cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1

dG9ycz48YXV0aG9ycz48YXV0aG9yPkJ1cmxvdCwgTS4gQS48L2F1dGhvcj48YXV0aG9yPkJyYXVk

ZWF1LCBKLjwvYXV0aG9yPjxhdXRob3I+TWljaGFlbHNlbi1QcmV1c3NlLCBLLjwvYXV0aG9yPjxh

dXRob3I+UG90aWVyLCBCLjwvYXV0aG9yPjxhdXRob3I+QXljaXJpZXgsIFMuPC9hdXRob3I+PGF1

dGhvcj5WYXJpbiwgSi48L2F1dGhvcj48YXV0aG9yPkdhdXRpZXIsIEIuPC9hdXRob3I+PGF1dGhv

cj5EamVsdGksIEYuPC9hdXRob3I+PGF1dGhvcj5BdWRyYWluLCBNLjwvYXV0aG9yPjxhdXRob3I+

RGF1cGhpbm90LCBMLjwvYXV0aG9yPjxhdXRob3I+RmVybmFuZGV6LUdvbWV6LCBGLiBKLjwvYXV0

aG9yPjxhdXRob3I+Q2FpbGxpZXJleiwgUi48L2F1dGhvcj48YXV0aG9yPkxhcHJldm90ZSwgTy48

L2F1dGhvcj48YXV0aG9yPkJpZWNoZSwgSS48L2F1dGhvcj48YXV0aG9yPkF1emVpbCwgTi48L2F1

dGhvcj48YXV0aG9yPlBvdGllciwgTS4gQy48L2F1dGhvcj48YXV0aG9yPkR1dGFyLCBQLjwvYXV0

aG9yPjxhdXRob3I+S29ydGUsIE0uPC9hdXRob3I+PGF1dGhvcj5CdWVlLCBMLjwvYXV0aG9yPjxh

dXRob3I+Qmx1bSwgRC48L2F1dGhvcj48YXV0aG9yPkNhcnRpZXIsIE4uPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+SU5TRVJNIFUxMTY5L01JUkNlbiBDRUEs

IEZvbnRlbmF5IGF1eCBSb3NlcyA5MjI2NSwgRnJhbmNlLCBVbml2ZXJzaXRlIFBhcmlzLVN1ZCwg

VW5pdmVyc2l0ZSBQYXJpcy1TYWNsYXksIE9yc2F5IDkxNDAwLCBGcmFuY2UsIFVuaXZlcnNpdGUg

UGFyaXMgRGVzY2FydGVzLCBQYXJpcyA3NTAwNiwgRnJhbmNlLiYjeEQ7SU5TRVJNIFUxMTY5L01J

UkNlbiBDRUEsIEZvbnRlbmF5IGF1eCBSb3NlcyA5MjI2NSwgRnJhbmNlLCBVbml2ZXJzaXRlIFBh

cmlzLVN1ZCwgVW5pdmVyc2l0ZSBQYXJpcy1TYWNsYXksIE9yc2F5IDkxNDAwLCBGcmFuY2UuJiN4

RDtEaXZpc2lvbiBvZiBDZWxsdWxhciBOZXVyb2Jpb2xvZ3ksIFpvb2xvZ2ljYWwgSW5zdGl0dXRl

LCBVbml2ZXJzaXR5IG9mIEJyYXVuc2Nod2VpZywgQnJhdW5zY2h3ZWlnIDM4MTA2LCBHZXJtYW55

LCBBRyBOSU5ELCBIWkksIEluaG9mZmVuc3RyYXNzZSA3LCBCcmF1bnNjaHdlaWcgRC0zODEyNCwg

R2VybWFueS4mI3hEO0NlbnRyZSBkZSBQc3ljaGlhdHJpZSBldCBOZXVyb3NjaWVuY2VzLCBVbml2

ZXJzaXRlIFBhcmlzIERlc2NhcnRlcywgU29yYm9ubmUgUGFyaXMgQ2l0ZSwgSU5TRVJNIFVNUlM4

OTQsIFBhcmlzIDc1MDE0LCBGcmFuY2UuJiN4RDtDaGltaWUtVG94aWNvbG9naWUgQW5hbHl0aXF1

ZSBldCBDZWxsdWxhaXJlLCBFQSA0NDYzIGFuZC4mI3hEO0VBNzMzMSwgVW5pdmVyc2l0ZSBQYXJp

cyBEZXNjYXJ0ZXMsIFNvcmJvbm5lIFBhcmlzIENpdGUsIEZhY3VsdGUgZGVzIFNjaWVuY2VzIFBo

YXJtYWNldXRpcXVlcyBldCBCaW9sb2dpcXVlcywgUGFyaXMgNzUwMDYsIEZyYW5jZS4mI3hEO0lD

TSwgSG9waXRhbCBQaXRpZS1TYWxwZXRyaWVyZSwgQ05SUyBVTVI3MjI1LCBJTlNFUk0gVU1SUzk3

NSwgVVBNQywgUGFyaXMgNzUwMTMsIEZyYW5jZS4mI3hEO1VuaXZlcnNpdGUgZGUgTGlsbGUsIFVE

U0wsIExpbGxlIDU5MDQ1LCBGcmFuY2UsIElOU0VSTSBVTVIxMTcyLCBKZWFuLVBpZXJyZSBBdWJl

cnQgUmVzZWFyY2ggQ2VudHJlLCBMaWxsZSA1OTA0NSwgRnJhbmNlIGFuZC4mI3hEO1VuaXZlcnNp

dGUgZGUgTGlsbGUsIFVEU0wsIExpbGxlIDU5MDQ1LCBGcmFuY2UsIElOU0VSTSBVTVIxMTcyLCBK

ZWFuLVBpZXJyZSBBdWJlcnQgUmVzZWFyY2ggQ2VudHJlLCBMaWxsZSA1OTA0NSwgRnJhbmNlIGFu

ZCBDSFJVLUxpbGxlLCBGYWN1bHRlIGRlIE1lZGVjaW5lLCBMaWxsZSA1OTAzNywgRnJhbmNlLiYj

eEQ7SU5TRVJNIFUxMTY5L01JUkNlbiBDRUEsIEZvbnRlbmF5IGF1eCBSb3NlcyA5MjI2NSwgRnJh

bmNlLCBVbml2ZXJzaXRlIFBhcmlzLVN1ZCwgVW5pdmVyc2l0ZSBQYXJpcy1TYWNsYXksIE9yc2F5

IDkxNDAwLCBGcmFuY2UsIG5hdGhhbGllLmNhcnRpZXJAaW5zZXJtLmZyLjwvYXV0aC1hZGRyZXNz

Pjx0aXRsZXM+PHRpdGxlPkNob2xlc3Rlcm9sIDI0LWh5ZHJveHlsYXNlIGRlZmVjdCBpcyBpbXBs

aWNhdGVkIGluIG1lbW9yeSBpbXBhaXJtZW50cyBhc3NvY2lhdGVkIHdpdGggQWx6aGVpbWVyLWxp

a2UgVGF1IHBhdGhvbG9neTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5IdW0gTW9sIEdlbmV0PC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SHVtIE1vbCBH

ZW5ldDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjU5NjUtNzY8L3BhZ2VzPjx2b2x1

bWU+MjQ8L3ZvbHVtZT48bnVtYmVyPjIxPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhl

aW1lciBEaXNlYXNlL2Vuenltb2xvZ3kvZ2VuZXRpY3MvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGVzdGVyb2wgMjQtSHlkcm94eWxhc2U8

L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFuaW1hbDwva2V5d29yZD48a2V5d29y

ZD5HbGlvc2lzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SGlwcG9jYW1wdXMvZW56eW1v

bG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNo

b2xlc3Rlcm9scy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1lbW9yeSBEaXNvcmRlcnMv

KmVuenltb2xvZ3kvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5

d29yZD5NaWNlLCBUcmFuc2dlbmljPC9rZXl3b3JkPjxrZXl3b3JkPlBob3NwaG9yeWxhdGlvbjwv

a2V5d29yZD48a2V5d29yZD5TdGVyb2lkIEh5ZHJveHlsYXNlcy9nZW5ldGljcy8qbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5UYXVvcGF0aGllcy9nZW5ldGljcy8qbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD50YXUgUHJvdGVpbnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdiAxPC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PGlzYm4+MTQ2MC0yMDgzIChFbGVjdHJvbmljKSYjeEQ7MDk2NC02OTA2IChMaW5raW5n

KTwvaXNibj48YWNjZXNzaW9uLW51bT4yNjM1ODc4MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVs

YXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjM1ODc4

MDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu

MTA5My9obWcvZGR2MjY4PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+

PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWRyeTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl

Y051bT40MjQ0PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

Mzk1LDM5Nzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQyNDQ8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjc3ODA0MiI+NDI0NDwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SHVkcnksIEUuPC9hdXRob3I+PGF1

dGhvcj5WYW4gRGFtLCBELjwvYXV0aG9yPjxhdXRob3I+S3VsaWssIFcuPC9hdXRob3I+PGF1dGhv

cj5EZSBEZXluLCBQLiBQLjwvYXV0aG9yPjxhdXRob3I+U3RldCwgRi4gUy48L2F1dGhvcj48YXV0

aG9yPkFob3VhbnNvdSwgTy48L2F1dGhvcj48YXV0aG9yPkJlbnJhaXNzLCBBLjwvYXV0aG9yPjxh

dXRob3I+RGVsYWNvdXJ0ZSwgQS48L2F1dGhvcj48YXV0aG9yPkJvdWduZXJlcywgUC48L2F1dGhv

cj48YXV0aG9yPkF1Ym91cmcsIFAuPC9hdXRob3I+PGF1dGhvcj5DYXJ0aWVyLCBOLjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPklOU0VSTSBVNzQ1LCBVbml2

ZXJzaXR5IFBhcmlzIERlc2NhcnRlcywgRmFjdWx0ZSBkZXMgU2NpZW5jZXMgUGhhcm1hY2V1dGlx

dWVzIGV0IEJpb2xvZ2lxdWVzLCBQYXJpcywgRnJhbmNlLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+

PHRpdGxlPkFkZW5vLWFzc29jaWF0ZWQgdmlydXMgZ2VuZSB0aGVyYXB5IHdpdGggY2hvbGVzdGVy

b2wgMjQtaHlkcm94eWxhc2UgcmVkdWNlcyB0aGUgYW15bG9pZCBwYXRob2xvZ3kgYmVmb3JlIG9y

IGFmdGVyIHRoZSBvbnNldCBvZiBhbXlsb2lkIHBsYXF1ZXMgaW4gbW91c2UgbW9kZWxzIG9mIEFs

emhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Nb2wgVGhlcjwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz40NC01MzwvcGFnZXM+PHZvbHVtZT4xODwv

dm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlz

ZWFzZS9tZXRhYm9saXNtLyp0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQvKm1ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CbG90dGlu

ZywgV2VzdGVybjwva2V5d29yZD48a2V5d29yZD5DZWxsIExpbmU8L2tleXdvcmQ+PGtleXdvcmQ+

Q2hvbGVzdGVyb2wgMjQtSHlkcm94eWxhc2U8L2tleXdvcmQ+PGtleXdvcmQ+RGVwZW5kb3ZpcnVz

LypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5Fbnp5bWUtTGlua2VkIEltbXVub3NvcmJlbnQg

QXNzYXk8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXRpYyBUaGVyYXB5LyptZXRob2RzPC9rZXl3b3Jk

PjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IeWRyb3h5Y2hvbGVzdGVyb2xzL21l

dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vaGlzdG9jaGVtaXN0cnk8L2tleXdvcmQ+

PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFuc2dlbmljPC9rZXl3b3Jk

PjxrZXl3b3JkPlJldmVyc2UgVHJhbnNjcmlwdGFzZSBQb2x5bWVyYXNlIENoYWluIFJlYWN0aW9u

PC9rZXl3b3JkPjxrZXl3b3JkPlN0ZXJvaWQgSHlkcm94eWxhc2VzL2dlbmV0aWNzLypwaHlzaW9s

b2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTA8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT5KYW48L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTI1LTAwMjQgKEVs

ZWN0cm9uaWMpJiN4RDsxNTI1LTAwMTYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjE5

NjU0NTY5PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3

Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE5NjU0NTY5PC91cmw+PC9yZWxhdGVkLXVybHM+PC91

cmxzPjxjdXN0b20yPlBNQzI4MzkyMTk8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjEwLjEwMzgvbXQuMjAwOS4xNzU8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48Q2l0ZT48QXV0aG9yPkJ1cmxvdDwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJlY051

bT40MjE4PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj40MjE4PC9yZWMtbnVtYmVyPjxmb3Jl

aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRz

enpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzY3Nzc1MjIiPjQyMTg8L2tleT48L2ZvcmVpZ24ta2V5

cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1

dG9ycz48YXV0aG9ycz48YXV0aG9yPkJ1cmxvdCwgTS4gQS48L2F1dGhvcj48YXV0aG9yPkJyYXVk

ZWF1LCBKLjwvYXV0aG9yPjxhdXRob3I+TWljaGFlbHNlbi1QcmV1c3NlLCBLLjwvYXV0aG9yPjxh

dXRob3I+UG90aWVyLCBCLjwvYXV0aG9yPjxhdXRob3I+QXljaXJpZXgsIFMuPC9hdXRob3I+PGF1

dGhvcj5WYXJpbiwgSi48L2F1dGhvcj48YXV0aG9yPkdhdXRpZXIsIEIuPC9hdXRob3I+PGF1dGhv

cj5EamVsdGksIEYuPC9hdXRob3I+PGF1dGhvcj5BdWRyYWluLCBNLjwvYXV0aG9yPjxhdXRob3I+

RGF1cGhpbm90LCBMLjwvYXV0aG9yPjxhdXRob3I+RmVybmFuZGV6LUdvbWV6LCBGLiBKLjwvYXV0

aG9yPjxhdXRob3I+Q2FpbGxpZXJleiwgUi48L2F1dGhvcj48YXV0aG9yPkxhcHJldm90ZSwgTy48

L2F1dGhvcj48YXV0aG9yPkJpZWNoZSwgSS48L2F1dGhvcj48YXV0aG9yPkF1emVpbCwgTi48L2F1

dGhvcj48YXV0aG9yPlBvdGllciwgTS4gQy48L2F1dGhvcj48YXV0aG9yPkR1dGFyLCBQLjwvYXV0

aG9yPjxhdXRob3I+S29ydGUsIE0uPC9hdXRob3I+PGF1dGhvcj5CdWVlLCBMLjwvYXV0aG9yPjxh

dXRob3I+Qmx1bSwgRC48L2F1dGhvcj48YXV0aG9yPkNhcnRpZXIsIE4uPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+SU5TRVJNIFUxMTY5L01JUkNlbiBDRUEs

IEZvbnRlbmF5IGF1eCBSb3NlcyA5MjI2NSwgRnJhbmNlLCBVbml2ZXJzaXRlIFBhcmlzLVN1ZCwg

VW5pdmVyc2l0ZSBQYXJpcy1TYWNsYXksIE9yc2F5IDkxNDAwLCBGcmFuY2UsIFVuaXZlcnNpdGUg

UGFyaXMgRGVzY2FydGVzLCBQYXJpcyA3NTAwNiwgRnJhbmNlLiYjeEQ7SU5TRVJNIFUxMTY5L01J

UkNlbiBDRUEsIEZvbnRlbmF5IGF1eCBSb3NlcyA5MjI2NSwgRnJhbmNlLCBVbml2ZXJzaXRlIFBh

cmlzLVN1ZCwgVW5pdmVyc2l0ZSBQYXJpcy1TYWNsYXksIE9yc2F5IDkxNDAwLCBGcmFuY2UuJiN4

RDtEaXZpc2lvbiBvZiBDZWxsdWxhciBOZXVyb2Jpb2xvZ3ksIFpvb2xvZ2ljYWwgSW5zdGl0dXRl

LCBVbml2ZXJzaXR5IG9mIEJyYXVuc2Nod2VpZywgQnJhdW5zY2h3ZWlnIDM4MTA2LCBHZXJtYW55

LCBBRyBOSU5ELCBIWkksIEluaG9mZmVuc3RyYXNzZSA3LCBCcmF1bnNjaHdlaWcgRC0zODEyNCwg

R2VybWFueS4mI3hEO0NlbnRyZSBkZSBQc3ljaGlhdHJpZSBldCBOZXVyb3NjaWVuY2VzLCBVbml2

ZXJzaXRlIFBhcmlzIERlc2NhcnRlcywgU29yYm9ubmUgUGFyaXMgQ2l0ZSwgSU5TRVJNIFVNUlM4

OTQsIFBhcmlzIDc1MDE0LCBGcmFuY2UuJiN4RDtDaGltaWUtVG94aWNvbG9naWUgQW5hbHl0aXF1

ZSBldCBDZWxsdWxhaXJlLCBFQSA0NDYzIGFuZC4mI3hEO0VBNzMzMSwgVW5pdmVyc2l0ZSBQYXJp

cyBEZXNjYXJ0ZXMsIFNvcmJvbm5lIFBhcmlzIENpdGUsIEZhY3VsdGUgZGVzIFNjaWVuY2VzIFBo

YXJtYWNldXRpcXVlcyBldCBCaW9sb2dpcXVlcywgUGFyaXMgNzUwMDYsIEZyYW5jZS4mI3hEO0lD

TSwgSG9waXRhbCBQaXRpZS1TYWxwZXRyaWVyZSwgQ05SUyBVTVI3MjI1LCBJTlNFUk0gVU1SUzk3

NSwgVVBNQywgUGFyaXMgNzUwMTMsIEZyYW5jZS4mI3hEO1VuaXZlcnNpdGUgZGUgTGlsbGUsIFVE

U0wsIExpbGxlIDU5MDQ1LCBGcmFuY2UsIElOU0VSTSBVTVIxMTcyLCBKZWFuLVBpZXJyZSBBdWJl

cnQgUmVzZWFyY2ggQ2VudHJlLCBMaWxsZSA1OTA0NSwgRnJhbmNlIGFuZC4mI3hEO1VuaXZlcnNp

dGUgZGUgTGlsbGUsIFVEU0wsIExpbGxlIDU5MDQ1LCBGcmFuY2UsIElOU0VSTSBVTVIxMTcyLCBK

ZWFuLVBpZXJyZSBBdWJlcnQgUmVzZWFyY2ggQ2VudHJlLCBMaWxsZSA1OTA0NSwgRnJhbmNlIGFu

ZCBDSFJVLUxpbGxlLCBGYWN1bHRlIGRlIE1lZGVjaW5lLCBMaWxsZSA1OTAzNywgRnJhbmNlLiYj

eEQ7SU5TRVJNIFUxMTY5L01JUkNlbiBDRUEsIEZvbnRlbmF5IGF1eCBSb3NlcyA5MjI2NSwgRnJh

bmNlLCBVbml2ZXJzaXRlIFBhcmlzLVN1ZCwgVW5pdmVyc2l0ZSBQYXJpcy1TYWNsYXksIE9yc2F5

IDkxNDAwLCBGcmFuY2UsIG5hdGhhbGllLmNhcnRpZXJAaW5zZXJtLmZyLjwvYXV0aC1hZGRyZXNz

Pjx0aXRsZXM+PHRpdGxlPkNob2xlc3Rlcm9sIDI0LWh5ZHJveHlsYXNlIGRlZmVjdCBpcyBpbXBs

aWNhdGVkIGluIG1lbW9yeSBpbXBhaXJtZW50cyBhc3NvY2lhdGVkIHdpdGggQWx6aGVpbWVyLWxp

a2UgVGF1IHBhdGhvbG9neTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5IdW0gTW9sIEdlbmV0PC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SHVtIE1vbCBH

ZW5ldDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjU5NjUtNzY8L3BhZ2VzPjx2b2x1

bWU+MjQ8L3ZvbHVtZT48bnVtYmVyPjIxPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhl

aW1lciBEaXNlYXNlL2Vuenltb2xvZ3kvZ2VuZXRpY3MvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGVzdGVyb2wgMjQtSHlkcm94eWxhc2U8

L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFuaW1hbDwva2V5d29yZD48a2V5d29y

ZD5HbGlvc2lzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SGlwcG9jYW1wdXMvZW56eW1v

bG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNo

b2xlc3Rlcm9scy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1lbW9yeSBEaXNvcmRlcnMv

KmVuenltb2xvZ3kvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5

d29yZD5NaWNlLCBUcmFuc2dlbmljPC9rZXl3b3JkPjxrZXl3b3JkPlBob3NwaG9yeWxhdGlvbjwv

a2V5d29yZD48a2V5d29yZD5TdGVyb2lkIEh5ZHJveHlsYXNlcy9nZW5ldGljcy8qbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5UYXVvcGF0aGllcy9nZW5ldGljcy8qbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD50YXUgUHJvdGVpbnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdiAxPC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PGlzYm4+MTQ2MC0yMDgzIChFbGVjdHJvbmljKSYjeEQ7MDk2NC02OTA2IChMaW5raW5n

KTwvaXNibj48YWNjZXNzaW9uLW51bT4yNjM1ODc4MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVs

YXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjM1ODc4

MDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu

MTA5My9obWcvZGR2MjY4PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+

PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 395,397 (Fig. 7) . Importantly, this beneficial effect of AAV-CYP46A1 delivery is demonstrated not only in three different amyloid models but also in Tau22 mice 328 . Dendritic spine density are restored, together with electrophysiological parameters (LTC), contributing to the correction of memory deficits in these mice. In parallel, results from studies in Huntington mouse model demonstrated that overexpressing CYP46A1 restores deficient cholesterol metabolism, behavior deficits and neuropathological hallmaks confirming the link between brain cholesterol impairment and neuronal functionPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3Vzc2ljYXVsdDwvQXV0aG9yPjxZZWFyPjIwMTY8L1ll

YXI+PFJlY051bT40MjA5PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNj

cmlwdCI+Mzk4PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDIwOTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2Nzc3MjU5Ij40MjA5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Cb3Vzc2ljYXVsdCwgTC48L2F1

dGhvcj48YXV0aG9yPkFsdmVzLCBTLjwvYXV0aG9yPjxhdXRob3I+TGFtYXppZXJlLCBBLjwvYXV0

aG9yPjxhdXRob3I+UGxhbnF1ZXMsIEEuPC9hdXRob3I+PGF1dGhvcj5IZWNrLCBOLjwvYXV0aG9y

PjxhdXRob3I+TW91bW5lLCBMLjwvYXV0aG9yPjxhdXRob3I+RGVzcHJlcywgRy48L2F1dGhvcj48

YXV0aG9yPkJvbHRlLCBTLjwvYXV0aG9yPjxhdXRob3I+SHUsIEEuPC9hdXRob3I+PGF1dGhvcj5Q

YWdlcywgQy48L2F1dGhvcj48YXV0aG9yPkdhbHZhbiwgTC48L2F1dGhvcj48YXV0aG9yPlBpZ3Vl

dCwgRi48L2F1dGhvcj48YXV0aG9yPkF1Ym91cmcsIFAuPC9hdXRob3I+PGF1dGhvcj5DYXJ0aWVy

LCBOLjwvYXV0aG9yPjxhdXRob3I+Q2Fib2NoZSwgSi48L2F1dGhvcj48YXV0aG9yPkJldHVpbmcs

IFMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+MSBOZXVy

b25hbCBTaWduYWxpbmcgYW5kIEdlbmUgUmVndWxhdGlvbiwgTmV1cm9zY2llbmNlcyBQYXJpcyBT

ZWluZSwgSW5zdGl0dXRlIG9mIEJpb2xvZ3kgUGFyaXMtU2VpbmUsIFNvcmJvbm5lIFVuaXZlcnNp

dGVzLCBVUE1DIFVuaXZlcnNpdGUgUGllcnJlIGV0IE1hcmllIEN1cmllLVBhcmlzIDYsIElOU0VS

TS9VTVItUyAxMTMwLCBDTlJTL1VNUiA4MjQ2LCA3NTAwNSBQYXJpcywgRnJhbmNlLiYjeEQ7MiBJ

TlNFUk0gVTExNjksIExlIEtyZW1saW4tQmljZXRyZSwgTUlSQ0VOIENFQSBhbmQgVW5pdmVyc2l0

ZSBQYXJpcy1TdWQsIFVuaXZlcnNpdGUgUGFyaXMgU2FjbGF5LCA5MTQwMCBPcnNheSwgRnJhbmNl

LiYjeEQ7MyBMYWJvcmF0b3J5IG9mIE1hc3MgU3BlY3Ryb21ldHJ5LCBJTlNFUk0gRVJMIDExNTcs

IENOUlMgVU1SIDcyMDMgTEJNLCBTb3Jib25uZSBVbml2ZXJzaXRlcy0gVW5pdmVyc2l0ZSBQaWVy

cmUgZXQgTWFyaWUgQ3VyaWUtUGFyaXMgNiwgQ0hVIFNhaW50LUFudG9pbmUsIDc1MDEyIFBhcmlz

LCBGcmFuY2UuJiN4RDsxIE5ldXJvbmFsIFNpZ25hbGluZyBhbmQgR2VuZSBSZWd1bGF0aW9uLCBO

ZXVyb3NjaWVuY2VzIFBhcmlzIFNlaW5lLCBJbnN0aXR1dGUgb2YgQmlvbG9neSBQYXJpcy1TZWlu

ZSwgU29yYm9ubmUgVW5pdmVyc2l0ZXMsIFVQTUMgVW5pdmVyc2l0ZSBQaWVycmUgZXQgTWFyaWUg

Q3VyaWUtUGFyaXMgNiwgSU5TRVJNL1VNUi1TIDExMzAsIENOUlMvVU1SIDgyNDYsIDc1MDA1IFBh

cmlzLCBGcmFuY2UgNCBEZXZlbG9wbWVudCBhbmQgTmV1cm9waGFybWFjb2xvZ3ksIENlbnRlciBm

b3IgSW50ZXJkaXNjaXBsaW5hcnkgUmVzZWFyY2ggaW4gQmlvbG9neSwgSU5TRVJNIENOUlMgNzE0

MS4gQ29sbGVnZSBkZSBGcmFuY2UuJiN4RDs1IENlbGx1bGFyIEltYWdpbmcgRmFjaWxpdHksIElu

c3RpdHV0ZSBvZiBCaW9sb2d5IFBhcmlzLVNlaW5lIENOUlMgRlIsIFNvcmJvbm5lIFVuaXZlcnNp

dGVzLCBVUE1DIFVuaXZlcnNpdGUgUGllcnJlIGV0IE1hcmllIEN1cmllLVBhcmlzIDYsIFBhcmlz

LCBGcmFuY2UuJiN4RDsxIE5ldXJvbmFsIFNpZ25hbGluZyBhbmQgR2VuZSBSZWd1bGF0aW9uLCBO

ZXVyb3NjaWVuY2VzIFBhcmlzIFNlaW5lLCBJbnN0aXR1dGUgb2YgQmlvbG9neSBQYXJpcy1TZWlu

ZSwgU29yYm9ubmUgVW5pdmVyc2l0ZXMsIFVQTUMgVW5pdmVyc2l0ZSBQaWVycmUgZXQgTWFyaWUg

Q3VyaWUtUGFyaXMgNiwgSU5TRVJNL1VNUi1TIDExMzAsIENOUlMvVU1SIDgyNDYsIDc1MDA1IFBh

cmlzLCBGcmFuY2UgNiBMYWJvcmF0b3J5IG9mIEV4cGVyaW1lbnRhbCBOZXVyb2xvZ3ksIFVuaXZl

cnNpdGUgTGlicmUgZGUgQnJ1eGVsbGVzLCBCZWxnaXVtLiYjeEQ7NyBTZW1lbCBJbnN0aXR1dGUs

IFVuaXZlcnNpdHkgQ2FsaWZvcm5pYSBMb3MgQW5nZWxlcywgTG9zIEFuZ2VsZXMsIFVTQS4mI3hE

OzggRGVwYXJ0bWVudCBvZiBUcmFuc2xhdGlvbmFsIE1lZGljaW5lIGFuZCBOZXVyb2dlbmV0aWNz

LCBJbnN0aXR1dCBkZSBHZW5ldGlxdWUgZXQgZGUgQmlvbG9naWUgTW9sZWN1bGFpcmUgZXQgQ2Vs

bHVsYWlyZSAoSUdCTUMpLCBVTVIgNzEwNCBDTlJTL1VkUywgSU5TRVJNIFU5NjQsIEJQIDEwMTQy

LCA2NzQwNCBJbGxraXJjaCBDZWRleCwgRnJhbmNlLiYjeEQ7MSBOZXVyb25hbCBTaWduYWxpbmcg

YW5kIEdlbmUgUmVndWxhdGlvbiwgTmV1cm9zY2llbmNlcyBQYXJpcyBTZWluZSwgSW5zdGl0dXRl

IG9mIEJpb2xvZ3kgUGFyaXMtU2VpbmUsIFNvcmJvbm5lIFVuaXZlcnNpdGVzLCBVUE1DIFVuaXZl

cnNpdGUgUGllcnJlIGV0IE1hcmllIEN1cmllLVBhcmlzIDYsIElOU0VSTS9VTVItUyAxMTMwLCBD

TlJTL1VNUiA4MjQ2LCA3NTAwNSBQYXJpcywgRnJhbmNlIGpvY2VseW5lLmNhYm9jaGVAdXBtYy5m

ciBzYW5kcmluZS5iZXR1aW5nQHVwbWMuZnIuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+

Q1lQNDZBMSwgdGhlIHJhdGUtbGltaXRpbmcgZW56eW1lIGZvciBjaG9sZXN0ZXJvbCBkZWdyYWRh

dGlvbiwgaXMgbmV1cm9wcm90ZWN0aXZlIGluIEh1bnRpbmd0b24mYXBvcztzIGRpc2Vhc2U8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+QnJhaW48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5CcmFpbjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2Vz

Pjk1My03MDwvcGFnZXM+PHZvbHVtZT4xMzk8L3ZvbHVtZT48bnVtYmVyPlB0IDM8L251bWJlcj48

a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zl

cjwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGxzLCBDdWx0

dXJlZDwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBDb3J0ZXgvbWV0YWJvbGlzbS9wYXRob2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGVzdGVyb2wvKm1ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+Q2hvbGVzdGVyb2wgMjQtSHlkcm94eWxhc2U8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxl

PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IdW50aW5ndG9uIERp

c2Vhc2UvKmVuenltb2xvZ3kvcGF0aG9sb2d5LypwcmV2ZW50aW9uICZhbXA7IGNvbnRyb2w8L2tl

eXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3

b3JkPk1pY2UsIEluYnJlZCBDNTdCTDwva2V5d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQ0JB

PC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlN0ZXJvaWQg

SHlkcm94eWxhc2VzLypiaW9zeW50aGVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+Q3lwNDZhMTwva2V5

d29yZD48a2V5d29yZD5IdW50aW5ndG9uJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3Jk

PmNob2xlc3Rlcm9sPC9rZXl3b3JkPjxrZXl3b3JkPm5ldXJvcHJvdGVjdGlvbjwva2V5d29yZD48

a2V5d29yZD5zdHJpYXR1bTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95

ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWFyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+

MTQ2MC0yMTU2IChFbGVjdHJvbmljKSYjeEQ7MDAwNi04OTUwIChMaW5raW5nKTwvaXNibj48YWNj

ZXNzaW9uLW51bT4yNjkxMjYzNDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1

cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjkxMjYzNDwvdXJsPjwvcmVs

YXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NzY2Mzc2PC9jdXN0b20yPjxlbGVjdHJvbmlj

LXJlc291cmNlLW51bT4xMC4xMDkzL2JyYWluL2F3djM4NDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3Vzc2ljYXVsdDwvQXV0aG9yPjxZZWFyPjIwMTY8L1ll

YXI+PFJlY051bT40MjA5PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNj

cmlwdCI+Mzk4PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDIwOTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2Nzc3MjU5Ij40MjA5PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Cb3Vzc2ljYXVsdCwgTC48L2F1

dGhvcj48YXV0aG9yPkFsdmVzLCBTLjwvYXV0aG9yPjxhdXRob3I+TGFtYXppZXJlLCBBLjwvYXV0

aG9yPjxhdXRob3I+UGxhbnF1ZXMsIEEuPC9hdXRob3I+PGF1dGhvcj5IZWNrLCBOLjwvYXV0aG9y

PjxhdXRob3I+TW91bW5lLCBMLjwvYXV0aG9yPjxhdXRob3I+RGVzcHJlcywgRy48L2F1dGhvcj48

YXV0aG9yPkJvbHRlLCBTLjwvYXV0aG9yPjxhdXRob3I+SHUsIEEuPC9hdXRob3I+PGF1dGhvcj5Q

YWdlcywgQy48L2F1dGhvcj48YXV0aG9yPkdhbHZhbiwgTC48L2F1dGhvcj48YXV0aG9yPlBpZ3Vl

dCwgRi48L2F1dGhvcj48YXV0aG9yPkF1Ym91cmcsIFAuPC9hdXRob3I+PGF1dGhvcj5DYXJ0aWVy

LCBOLjwvYXV0aG9yPjxhdXRob3I+Q2Fib2NoZSwgSi48L2F1dGhvcj48YXV0aG9yPkJldHVpbmcs

IFMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+MSBOZXVy

b25hbCBTaWduYWxpbmcgYW5kIEdlbmUgUmVndWxhdGlvbiwgTmV1cm9zY2llbmNlcyBQYXJpcyBT

ZWluZSwgSW5zdGl0dXRlIG9mIEJpb2xvZ3kgUGFyaXMtU2VpbmUsIFNvcmJvbm5lIFVuaXZlcnNp

dGVzLCBVUE1DIFVuaXZlcnNpdGUgUGllcnJlIGV0IE1hcmllIEN1cmllLVBhcmlzIDYsIElOU0VS

TS9VTVItUyAxMTMwLCBDTlJTL1VNUiA4MjQ2LCA3NTAwNSBQYXJpcywgRnJhbmNlLiYjeEQ7MiBJ

TlNFUk0gVTExNjksIExlIEtyZW1saW4tQmljZXRyZSwgTUlSQ0VOIENFQSBhbmQgVW5pdmVyc2l0

ZSBQYXJpcy1TdWQsIFVuaXZlcnNpdGUgUGFyaXMgU2FjbGF5LCA5MTQwMCBPcnNheSwgRnJhbmNl

LiYjeEQ7MyBMYWJvcmF0b3J5IG9mIE1hc3MgU3BlY3Ryb21ldHJ5LCBJTlNFUk0gRVJMIDExNTcs

IENOUlMgVU1SIDcyMDMgTEJNLCBTb3Jib25uZSBVbml2ZXJzaXRlcy0gVW5pdmVyc2l0ZSBQaWVy

cmUgZXQgTWFyaWUgQ3VyaWUtUGFyaXMgNiwgQ0hVIFNhaW50LUFudG9pbmUsIDc1MDEyIFBhcmlz

LCBGcmFuY2UuJiN4RDsxIE5ldXJvbmFsIFNpZ25hbGluZyBhbmQgR2VuZSBSZWd1bGF0aW9uLCBO

ZXVyb3NjaWVuY2VzIFBhcmlzIFNlaW5lLCBJbnN0aXR1dGUgb2YgQmlvbG9neSBQYXJpcy1TZWlu

ZSwgU29yYm9ubmUgVW5pdmVyc2l0ZXMsIFVQTUMgVW5pdmVyc2l0ZSBQaWVycmUgZXQgTWFyaWUg

Q3VyaWUtUGFyaXMgNiwgSU5TRVJNL1VNUi1TIDExMzAsIENOUlMvVU1SIDgyNDYsIDc1MDA1IFBh

cmlzLCBGcmFuY2UgNCBEZXZlbG9wbWVudCBhbmQgTmV1cm9waGFybWFjb2xvZ3ksIENlbnRlciBm

b3IgSW50ZXJkaXNjaXBsaW5hcnkgUmVzZWFyY2ggaW4gQmlvbG9neSwgSU5TRVJNIENOUlMgNzE0

MS4gQ29sbGVnZSBkZSBGcmFuY2UuJiN4RDs1IENlbGx1bGFyIEltYWdpbmcgRmFjaWxpdHksIElu

c3RpdHV0ZSBvZiBCaW9sb2d5IFBhcmlzLVNlaW5lIENOUlMgRlIsIFNvcmJvbm5lIFVuaXZlcnNp

dGVzLCBVUE1DIFVuaXZlcnNpdGUgUGllcnJlIGV0IE1hcmllIEN1cmllLVBhcmlzIDYsIFBhcmlz

LCBGcmFuY2UuJiN4RDsxIE5ldXJvbmFsIFNpZ25hbGluZyBhbmQgR2VuZSBSZWd1bGF0aW9uLCBO

ZXVyb3NjaWVuY2VzIFBhcmlzIFNlaW5lLCBJbnN0aXR1dGUgb2YgQmlvbG9neSBQYXJpcy1TZWlu

ZSwgU29yYm9ubmUgVW5pdmVyc2l0ZXMsIFVQTUMgVW5pdmVyc2l0ZSBQaWVycmUgZXQgTWFyaWUg

Q3VyaWUtUGFyaXMgNiwgSU5TRVJNL1VNUi1TIDExMzAsIENOUlMvVU1SIDgyNDYsIDc1MDA1IFBh

cmlzLCBGcmFuY2UgNiBMYWJvcmF0b3J5IG9mIEV4cGVyaW1lbnRhbCBOZXVyb2xvZ3ksIFVuaXZl

cnNpdGUgTGlicmUgZGUgQnJ1eGVsbGVzLCBCZWxnaXVtLiYjeEQ7NyBTZW1lbCBJbnN0aXR1dGUs

IFVuaXZlcnNpdHkgQ2FsaWZvcm5pYSBMb3MgQW5nZWxlcywgTG9zIEFuZ2VsZXMsIFVTQS4mI3hE

OzggRGVwYXJ0bWVudCBvZiBUcmFuc2xhdGlvbmFsIE1lZGljaW5lIGFuZCBOZXVyb2dlbmV0aWNz

LCBJbnN0aXR1dCBkZSBHZW5ldGlxdWUgZXQgZGUgQmlvbG9naWUgTW9sZWN1bGFpcmUgZXQgQ2Vs

bHVsYWlyZSAoSUdCTUMpLCBVTVIgNzEwNCBDTlJTL1VkUywgSU5TRVJNIFU5NjQsIEJQIDEwMTQy

LCA2NzQwNCBJbGxraXJjaCBDZWRleCwgRnJhbmNlLiYjeEQ7MSBOZXVyb25hbCBTaWduYWxpbmcg

YW5kIEdlbmUgUmVndWxhdGlvbiwgTmV1cm9zY2llbmNlcyBQYXJpcyBTZWluZSwgSW5zdGl0dXRl

IG9mIEJpb2xvZ3kgUGFyaXMtU2VpbmUsIFNvcmJvbm5lIFVuaXZlcnNpdGVzLCBVUE1DIFVuaXZl

cnNpdGUgUGllcnJlIGV0IE1hcmllIEN1cmllLVBhcmlzIDYsIElOU0VSTS9VTVItUyAxMTMwLCBD

TlJTL1VNUiA4MjQ2LCA3NTAwNSBQYXJpcywgRnJhbmNlIGpvY2VseW5lLmNhYm9jaGVAdXBtYy5m

ciBzYW5kcmluZS5iZXR1aW5nQHVwbWMuZnIuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+

Q1lQNDZBMSwgdGhlIHJhdGUtbGltaXRpbmcgZW56eW1lIGZvciBjaG9sZXN0ZXJvbCBkZWdyYWRh

dGlvbiwgaXMgbmV1cm9wcm90ZWN0aXZlIGluIEh1bnRpbmd0b24mYXBvcztzIGRpc2Vhc2U8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+QnJhaW48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5CcmFpbjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2Vz

Pjk1My03MDwvcGFnZXM+PHZvbHVtZT4xMzk8L3ZvbHVtZT48bnVtYmVyPlB0IDM8L251bWJlcj48

a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zl

cjwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGxzLCBDdWx0

dXJlZDwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBDb3J0ZXgvbWV0YWJvbGlzbS9wYXRob2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGVzdGVyb2wvKm1ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+Q2hvbGVzdGVyb2wgMjQtSHlkcm94eWxhc2U8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxl

PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IdW50aW5ndG9uIERp

c2Vhc2UvKmVuenltb2xvZ3kvcGF0aG9sb2d5LypwcmV2ZW50aW9uICZhbXA7IGNvbnRyb2w8L2tl

eXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3

b3JkPk1pY2UsIEluYnJlZCBDNTdCTDwva2V5d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQ0JB

PC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlN0ZXJvaWQg

SHlkcm94eWxhc2VzLypiaW9zeW50aGVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+Q3lwNDZhMTwva2V5

d29yZD48a2V5d29yZD5IdW50aW5ndG9uJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3Jk

PmNob2xlc3Rlcm9sPC9rZXl3b3JkPjxrZXl3b3JkPm5ldXJvcHJvdGVjdGlvbjwva2V5d29yZD48

a2V5d29yZD5zdHJpYXR1bTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95

ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWFyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+

MTQ2MC0yMTU2IChFbGVjdHJvbmljKSYjeEQ7MDAwNi04OTUwIChMaW5raW5nKTwvaXNibj48YWNj

ZXNzaW9uLW51bT4yNjkxMjYzNDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1

cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjkxMjYzNDwvdXJsPjwvcmVs

YXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0NzY2Mzc2PC9jdXN0b20yPjxlbGVjdHJvbmlj

LXJlc291cmNlLW51bT4xMC4xMDkzL2JyYWluL2F3djM4NDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 398. Figure 7. Gene therapy on CYP46A1. The first panel shows the site of injection with the viral vector carrying an overexpressing copy of CYP46A1 for gene therapy. Neuronal transfection of CYP46A1 can be detected (green) in neurons in the hippocampus (red) as shown by the upper pannels. After gene therapy treatment with CYP46A1, amyloid plaques in the hippocampus are reduced. 219075top00A gene therapy approach based on AAV-CYP46A1 brain delivery is thus a potentially powerful strategy, acting both on the amyloid and the Tau hallmarks of the disease. Feasibility and safety of the procedure were demonstrated in monkey brain (unpublished results). Improvement of AAV vectors able to efficiently target brain neurons after intrathecal or intravenous injection should help the development of such therapeutic approaches. Increased 24-OH cholesterol in CSF could be evaluated as a biomarker of mechanism to evidence the efficacy of the therapy. AAV vectors have been approved for human use and several clinical trials using AAV vector delivery to the brain have been performed or are ongoing PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QaWd1ZXQ8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS

ZWNOdW0+NDMyNDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjM5OTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQzMjQ8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0MDkzMTQwNyI+NDMyNDwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+UGlndWV0LCBGLjwvYXV0aG9yPjxhdXRo

b3I+QWx2ZXMsIFMuPC9hdXRob3I+PGF1dGhvcj5DYXJ0aWVyLCBOLjwvYXV0aG9yPjwvYXV0aG9y

cz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPjEgVHJhbnNsYXRpb25hbCBNZWRpY2luZSBh

bmQgTmV1cm9nZW5ldGljcyBEZXBhcnRtZW50LCBJbnN0aXR1dCBkZSBHZW5ldGlxdWUgZXQgZGUg

QmlvbG9naWUgTW9sZWN1bGFpcmUgZXQgQ2VsbHVsYWlyZSAsIFN0cmFzYm91cmcsIEZyYW5jZS4m

I3hEOzIgSW5zZXJtIFU1OTYgLCBJbGxraXJjaCwgRnJhbmNlOyBDTlJTLCBVTVI3MTA0LCBJbGxr

aXJjaCwgRnJhbmNlLiYjeEQ7MyBGYWN1bHRlIGRlcyBTY2llbmNlcyBkZSBsYSBWaWUsIFVuaXZl

cnNpdGUgZGUgU3RyYXNib3VyZyAsIFN0cmFzYm91cmcsIEZyYW5jZS4mI3hEOzQgQnJhaW5WZWN0

aXMgVGhlcmFwZXV0aWNzICwgUGFyaXMsIEZyYW5jZS4mI3hEOzUgSU5TRVJNL0NFQSBVTVIxMTY5

LCBNSVJDZW4gRm9udGVuYXkgYXV4IFJvc2VzLCBGcmFuY2UuJiN4RDs2IFVuaXZlcnNpdGUgUGFy

aXMtU3VkICwgT3JzYXksIEZyYW5jZSAuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Q2xp

bmljYWwgR2VuZSBUaGVyYXB5IGZvciBOZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlczogUGFzdCwg

UHJlc2VudCwgYW5kIEZ1dHVyZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5IdW0gR2VuZSBUaGVy

PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SHVtIEdl

bmUgVGhlcjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjk4OC0xMDAzPC9wYWdlcz48

dm9sdW1lPjI4PC92b2x1bWU+PG51bWJlcj4xMTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5D

ZW50cmFsIE5lcnZvdXMgU3lzdGVtL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5EZXBlbmRv

dmlydXMvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXRpYyBUaGVyYXB5Lyp0cmVuZHM8

L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXRpYyBWZWN0b3JzLyp0aGVyYXBldXRpYyB1c2U8L2tleXdv

cmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvZGVnZW5lcmF0aXZlIERp

c2Vhc2VzL2dlbmV0aWNzL3BhdGhvbG9neS8qdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5QYXJr

aW5zb24gRGlzZWFzZS9nZW5ldGljcy9wYXRob2xvZ3kvKnRoZXJhcHk8L2tleXdvcmQ+PGtleXdv

cmQ+KkFhdjwva2V5d29yZD48a2V5d29yZD4qY2VsbC1iYXNlZCB0aGVyYXBpZXM8L2tleXdvcmQ+

PGtleXdvcmQ+KmNsaW5pY2FsIHRyaWFsczwva2V5d29yZD48a2V5d29yZD4qZGVsaXZlcnkgbWV0

aG9kczwva2V5d29yZD48a2V5d29yZD4qbGVudGl2aXJ1cyBhbmQgb3RoZXIgUk5BIHZpcnVzZXM8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxk

YXRlPk5vdjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTctNzQyMiAoRWxlY3Ry

b25pYykmI3hEOzEwNDMtMDM0MiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjkwMzUx

MTg8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNi

aS5ubG0ubmloLmdvdi9wdWJtZWQvMjkwMzUxMTg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwODkvaHVtLjIwMTcuMTYwPC9lbGVjdHJvbmlj

LXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QaWd1ZXQ8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS

ZWNOdW0+NDMyNDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjM5OTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQzMjQ8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTU0MDkzMTQwNyI+NDMyNDwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+UGlndWV0LCBGLjwvYXV0aG9yPjxhdXRo

b3I+QWx2ZXMsIFMuPC9hdXRob3I+PGF1dGhvcj5DYXJ0aWVyLCBOLjwvYXV0aG9yPjwvYXV0aG9y

cz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPjEgVHJhbnNsYXRpb25hbCBNZWRpY2luZSBh

bmQgTmV1cm9nZW5ldGljcyBEZXBhcnRtZW50LCBJbnN0aXR1dCBkZSBHZW5ldGlxdWUgZXQgZGUg

QmlvbG9naWUgTW9sZWN1bGFpcmUgZXQgQ2VsbHVsYWlyZSAsIFN0cmFzYm91cmcsIEZyYW5jZS4m

I3hEOzIgSW5zZXJtIFU1OTYgLCBJbGxraXJjaCwgRnJhbmNlOyBDTlJTLCBVTVI3MTA0LCBJbGxr

aXJjaCwgRnJhbmNlLiYjeEQ7MyBGYWN1bHRlIGRlcyBTY2llbmNlcyBkZSBsYSBWaWUsIFVuaXZl

cnNpdGUgZGUgU3RyYXNib3VyZyAsIFN0cmFzYm91cmcsIEZyYW5jZS4mI3hEOzQgQnJhaW5WZWN0

aXMgVGhlcmFwZXV0aWNzICwgUGFyaXMsIEZyYW5jZS4mI3hEOzUgSU5TRVJNL0NFQSBVTVIxMTY5

LCBNSVJDZW4gRm9udGVuYXkgYXV4IFJvc2VzLCBGcmFuY2UuJiN4RDs2IFVuaXZlcnNpdGUgUGFy

aXMtU3VkICwgT3JzYXksIEZyYW5jZSAuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Q2xp

bmljYWwgR2VuZSBUaGVyYXB5IGZvciBOZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlczogUGFzdCwg

UHJlc2VudCwgYW5kIEZ1dHVyZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5IdW0gR2VuZSBUaGVy

PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SHVtIEdl

bmUgVGhlcjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjk4OC0xMDAzPC9wYWdlcz48

dm9sdW1lPjI4PC92b2x1bWU+PG51bWJlcj4xMTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5D

ZW50cmFsIE5lcnZvdXMgU3lzdGVtL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5EZXBlbmRv

dmlydXMvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXRpYyBUaGVyYXB5Lyp0cmVuZHM8

L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXRpYyBWZWN0b3JzLyp0aGVyYXBldXRpYyB1c2U8L2tleXdv

cmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvZGVnZW5lcmF0aXZlIERp

c2Vhc2VzL2dlbmV0aWNzL3BhdGhvbG9neS8qdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5QYXJr

aW5zb24gRGlzZWFzZS9nZW5ldGljcy9wYXRob2xvZ3kvKnRoZXJhcHk8L2tleXdvcmQ+PGtleXdv

cmQ+KkFhdjwva2V5d29yZD48a2V5d29yZD4qY2VsbC1iYXNlZCB0aGVyYXBpZXM8L2tleXdvcmQ+

PGtleXdvcmQ+KmNsaW5pY2FsIHRyaWFsczwva2V5d29yZD48a2V5d29yZD4qZGVsaXZlcnkgbWV0

aG9kczwva2V5d29yZD48a2V5d29yZD4qbGVudGl2aXJ1cyBhbmQgb3RoZXIgUk5BIHZpcnVzZXM8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxk

YXRlPk5vdjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTctNzQyMiAoRWxlY3Ry

b25pYykmI3hEOzEwNDMtMDM0MiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjkwMzUx

MTg8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNi

aS5ubG0ubmloLmdvdi9wdWJtZWQvMjkwMzUxMTg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwODkvaHVtLjIwMTcuMTYwPC9lbGVjdHJvbmlj

LXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 399. These vectors allow long-lasting expression with only one injection.A first application in human patients could be in severe familial forms of Alzheimer’s disease. Patients can be diagnosed and treated at very early stages of the disease, when a therapeutic benefit could be expected.Molecular mechanisms behind glucose and cholesterol metabolism for developing ADSeveral genetic and epidemiological studies have found that energy-related genes are important contributors to AD risk. In a previous revision, 700 genes were grouped into five general mechanisms for disease, namely, oxidative stress, transport cholesterol metabolism, glucose metabolism, membrane or vesicle recycling and inflammation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjI3MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yNzI8L3JlYy1udW1i

ZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBo

cGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMTc3NTI3MSI+MjcyPC9rZXk+PC9mb3Jl

aWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxj

b250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XaW5ibGFkLCBCLjwvYXV0aG9yPjxhdXRob3I+

QW1vdXllbCwgUC48L2F1dGhvcj48YXV0aG9yPkFuZHJpZXUsIFMuPC9hdXRob3I+PGF1dGhvcj5C

YWxsYXJkLCBDLjwvYXV0aG9yPjxhdXRob3I+QnJheW5lLCBDLjwvYXV0aG9yPjxhdXRob3I+QnJv

ZGF0eSwgSC48L2F1dGhvcj48YXV0aG9yPkNlZGF6by1NaW5ndWV6LCBBLjwvYXV0aG9yPjxhdXRo

b3I+RHVib2lzLCBCLjwvYXV0aG9yPjxhdXRob3I+RWR2YXJkc3NvbiwgRC48L2F1dGhvcj48YXV0

aG9yPkZlbGRtYW4sIEguPC9hdXRob3I+PGF1dGhvcj5GcmF0aWdsaW9uaSwgTC48L2F1dGhvcj48

YXV0aG9yPkZyaXNvbmksIEcuIEIuPC9hdXRob3I+PGF1dGhvcj5HYXV0aGllciwgUy48L2F1dGhv

cj48YXV0aG9yPkdlb3JnZXMsIEouPC9hdXRob3I+PGF1dGhvcj5HcmFmZiwgQy48L2F1dGhvcj48

YXV0aG9yPklxYmFsLCBLLjwvYXV0aG9yPjxhdXRob3I+SmVzc2VuLCBGLjwvYXV0aG9yPjxhdXRo

b3I+Sm9oYW5zc29uLCBHLjwvYXV0aG9yPjxhdXRob3I+Sm9uc3NvbiwgTC48L2F1dGhvcj48YXV0

aG9yPktpdmlwZWx0bywgTS48L2F1dGhvcj48YXV0aG9yPktuYXBwLCBNLjwvYXV0aG9yPjxhdXRo

b3I+TWFuZ2lhbGFzY2hlLCBGLjwvYXV0aG9yPjxhdXRob3I+TWVsaXMsIFIuPC9hdXRob3I+PGF1

dGhvcj5Ob3JkYmVyZywgQS48L2F1dGhvcj48YXV0aG9yPlJpa2tlcnQsIE0uIE8uPC9hdXRob3I+

PGF1dGhvcj5RaXUsIEMuPC9hdXRob3I+PGF1dGhvcj5TYWttYXIsIFQuIFAuPC9hdXRob3I+PGF1

dGhvcj5TY2hlbHRlbnMsIFAuPC9hdXRob3I+PGF1dGhvcj5TY2huZWlkZXIsIEwuIFMuPC9hdXRo

b3I+PGF1dGhvcj5TcGVybGluZywgUi48L2F1dGhvcj48YXV0aG9yPlRqZXJuYmVyZywgTC4gTy48

L2F1dGhvcj48YXV0aG9yPldhbGRlbWFyLCBHLjwvYXV0aG9yPjxhdXRob3I+V2ltbywgQS48L2F1

dGhvcj48YXV0aG9yPlpldHRlcmJlcmcsIEguPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5j

ZXMgYW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEaXZpc2lvbiBv

ZiBOZXVyb2dlcmlhdHJpY3MsIEthcm9saW5za2EgSW5zdGl0dXRldCwgSHVkZGluZ2UsIFN3ZWRl

bjsgRGVwYXJ0bWVudCBvZiBHZXJpYXRyaWMgTWVkaWNpbmUsIEthcm9saW5za2EgVW5pdmVyc2l0

eSBIb3NwaXRhbCwgSHVkZGluZ2UsIFN3ZWRlbi4gRWxlY3Ryb25pYyBhZGRyZXNzOiBiZW5ndC13

aW5ibGFkLXN3ZWRpc2hicmFpbnBvd2VyQGtpLnNlLiYjeEQ7Q2VudHJlIEhvc3BpdGFsaWVyIFJl

Z2lvbmFsIFVuaXZlcnNpdGFpcmUgZGUgTGlsbGUsIEluc3RpdHV0IFBhc3RldXIgZGUgTGlsbGUs

IElOU0VSTSBVMTE2NyBSSUQtQUdFLCBVbml0ZSBkJmFwb3M7RXBpZGVtaW9sb2dpZSBldCBkZSBT

YW50ZSBQdWJsaXF1ZSwgTGFiZXggRElTVEFMWiwgTGlsbGUsIEZyYW5jZS4mI3hEO0RlcGFydG1l

bnQgb2YgRXBpZGVtaW9sb2d5IGFuZCBQdWJsaWMgSGVhbHRoLCBGYWN1bHR5IG9mIE1lZGljaW5l

LCBUb3Vsb3VzZSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBUb3Vsb3VzZSwgRnJhbmNlLiYjeEQ7V29s

ZnNvbiBDZW50cmUgZm9yIEFnZS1SZWxhdGVkIERpc2Vhc2VzLCBLaW5nJmFwb3M7cyBDb2xsZWdl

IExvbmRvbiwgTG9uZG9uLCBVSy4mI3hEO0NhbWJyaWRnZSBJbnN0aXR1dGUgb2YgUHVibGljIEhl

YWx0aCwgVW5pdmVyc2l0eSBvZiBDYW1icmlkZ2UsIENhbWJyaWRnZSwgVUsuJiN4RDtDZW50cmUg

Zm9yIEhlYWx0aHkgQnJhaW4gQWdlaW5nIGFuZCBEZW1lbnRpYSBDb2xsYWJvcmF0aXZlIFJlc2Vh

cmNoIENlbnRyZSwgVW5pdmVyc2l0eSBvZiBOZXcgU291dGggV2FsZXMsIFN5ZG5leSwgTlNXLCBB

dXN0cmFsaWEuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBh

bmQgU29jaWV0eSwgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIE5l

dXJvZ2VyaWF0cmljcywgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBIdWRkaW5nZSwgU3dlZGVuLiYj

eEQ7SW5zdGl0dXQgZGUgbGEgTWVtb2lyZSBldCBkZSBsYSBNYWxhZGllIGQmYXBvcztBbHpoZWlt

ZXIsIElNMkEsIElOU0VSTSwgSW5zdGl0dXQgZHUgQ2VydmVhdSBldCBkZSBsYSBNb2VsbGUgRXBp

bmllcmUsIFVNUi1TOTc1LCBHcm91cGUgSG9zcGl0YWxpZXIgUGl0aWUtU2FscGV0cmllcmUsIFVu

aXZlcnNpdGUgUGllcnJlIGV0IE1hcmllIEN1cmllLVBhcmlzIDYsIFBhcmlzLCBGcmFuY2UuJiN4

RDtTY2hvb2wgb2YgTnVyc2luZyBhbmQgTWlkd2lmZXJ5LCBMYSBUcm9iZSBVbml2ZXJzaXR5LCBN

ZWxib3VybmUsIFZJQywgQXVzdHJhbGlhOyBEZXBhcnRtZW50IG9mIE51cnNpbmcsIFVtZWEgVW5p

dmVyc2l0eSwgVW1lYSwgU3dlZGVuLiYjeEQ7RGl2aXNpb24gb2YgTmV1cm9sb2d5LCBGYWN1bHR5

IG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIEJyaXRpc2ggQ29sdW1iaWEsIFZhbmNvdXZlciwg

QkMsIENhbmFkYS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2Vz

IGFuZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgQWdpbmcgUmVzZWFy

Y2ggQ2VudGVyLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7

R2VuZXZhIFVuaXZlcnNpdHkgSG9zcGl0YWxzIGFuZCBVbml2ZXJzaXR5IG9mIEdlbmV2YSwgR2Vu

ZXZhLCBTd2l0emVybGFuZDsgSVJDQ1MgQ2VudHJvIFNhbiBHaW92YW5uaSBkaSBEaW8gRmF0ZWJl

bmVmcmF0ZWxsaSwgQnJlc2NpYSwgSXRhbHkuJiN4RDtNY0dpbGwgQ2VudGVyIGZvciBTdHVkaWVz

IGluIEFnaW5nLCBBbHpoZWltZXImYXBvcztzIERpc2Vhc2UgUmVzZWFyY2ggVW5pdCwgYW5kIERv

dWdsYXMgTWVudGFsIEhlYWx0aCBVbml2ZXJzaXR5IEluc3RpdHV0ZSwgTW9udHJlYWwsIFFDLCBD

YW5hZGEuJiN4RDtBbHpoZWltZXIgRXVyb3BlLCBMdXhlbWJvdXJnIENpdHksIEx1eGVtYm91cmcu

JiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29jaWV0

eSwgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0

cmljcywgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBIdWRkaW5nZSwgU3dlZGVuOyBEZXBhcnRtZW50

IG9mIEdlcmlhdHJpYyBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBI

dWRkaW5nZSwgU3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2NoZW1pc3RyeSwgSW5nZSBH

cnVuZGtlLUlxYmFsIFJlc2VhcmNoIEZsb29yLCBOZXcgWW9yayBTdGF0ZSBJbnN0aXR1dGUgZm9y

IEJhc2ljIFJlc2VhcmNoLCBTdGF0ZW4gSXNsYW5kLCBOWSwgVVNBLiYjeEQ7RGVwYXJ0bWVudCBv

ZiBQc3ljaGlhdHJ5LCBVbml2ZXJzaXR5IG9mIENvbG9nbmUsIENvbG9nbmUsIEdlcm1hbnk7IEdl

cm1hbiBDZW50ZXIgZm9yIE5ldXJvZGVnZW5lcmF0aXZlIERpc2Vhc2VzIChEWk5FKSwgQm9ubiwg

R2VybWFueS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFu

ZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2YgTmV1

cm9nZXJpYXRyaWNzLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIEh1ZGRpbmdlLCBTd2VkZW47IERl

cGFydG1lbnQgb2YgR2VyaWF0cmljIE1lZGljaW5lLCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9z

cGl0YWwsIEh1ZGRpbmdlLCBTd2VkZW47IERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJl

IFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgQWdp

bmcgUmVzZWFyY2ggQ2VudGVyLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dl

ZGVuLiYjeEQ7UGVyc29uYWwgU29jaWFsIFNlcnZpY2VzIFJlc2VhcmNoIFVuaXQsIExvbmRvbiBT

Y2hvb2wgb2YgRWNvbm9taWNzIGFuZCBQb2xpdGljYWwgU2NpZW5jZSwgTG9uZG9uLCBVSy4mI3hE

O1JhZGJvdWR1bWMgQWx6aGVpbWVyIENlbnRyZSBhbmQgRGVwYXJ0bWVudCBvZiBHZXJpYXRyaWMg

TWVkaWNpbmUsIFJhZGJvdWQgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRlciwgTmlqbWVnZW4sIE5l

dGhlcmxhbmRzLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMg

YW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEaXZpc2lvbiBvZiBU

cmFuc2xhdGlvbmFsIEFsemhlaW1lciBCaW9sb2d5LCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIEh1

ZGRpbmdlLCBTd2VkZW47IERlcGFydG1lbnQgb2YgR2VyaWF0cmljIE1lZGljaW5lLCBLYXJvbGlu

c2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50

IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgQ2VudGVyIGZvciBB

bHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0cmljcywgS2Fyb2xpbnNr

YSBJbnN0aXR1dGV0LCBIdWRkaW5nZSwgU3dlZGVuOyBMYWJvcmF0b3J5IG9mIENoZW1pY2FsIEJp

b2xvZ3kgJmFtcDsgU2lnbmFsIFRyYW5zZHVjdGlvbiwgVGhlIFJvY2tlZmVsbGVyIFVuaXZlcnNp

dHksIE5ldyBZb3JrLCBOWSwgVVNBLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3kgYW5kIEFs

emhlaW1lciBDZW50ZXIsIFZVIFVuaXZlcnNpdHkgTWVkaWNhbCBDZW50ZXIsIE5ldXJvc2NpZW5j

ZSBDYW1wdXMsIEFtc3RlcmRhbSwgTmV0aGVybGFuZHMuJiN4RDtEZXBhcnRtZW50IG9mIFBzeWNo

aWF0cnkgYW5kIHRoZSBCZWhhdmlvcmFsIFNjaWVuY2VzIGFuZCBEZXBhcnRtZW50IG9mIE5ldXJv

bG9neSwgS2VjayBTY2hvb2wgb2YgTWVkaWNpbmUsIExlb25hcmQgRGF2aXMgU2Nob29sIG9mIEdl

cm9udG9sb2d5IG9mIHRoZSBVbml2ZXJzaXR5IG9mIFNvdXRoZXJuIENhbGlmb3JuaWEsIExvcyBB

bmdlbGVzLCBDQSwgVVNBLiYjeEQ7Q2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2ggYW5kIFRy

ZWF0bWVudCwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIEJyaWdoYW0gYW5kIFdvbWVuJmFwb3M7

cyBIb3NwaXRhbCBhbmQgTWFzc2FjaHVzZXR0cyBHZW5lcmFsIEhvc3BpdGFsLCBIYXJ2YXJkIE1l

ZGljYWwgU2Nob29sLCBCb3N0b24sIE1BLCBVU0EuJiN4RDtEYW5pc2ggRGVtZW50aWEgUmVzZWFy

Y2ggQ2VudHJlLCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgUmlnc2hvc3BpdGFsZXQsIFVuaXZl

cnNpdHkgb2YgQ29wZW5oYWdlbiwgQ29wZW5oYWdlbiwgRGVubWFyay4mI3hEO0NsaW5pY2FsIE5l

dXJvY2hlbWlzdHJ5IExhYm9yYXRvcnksIERlcGFydG1lbnQgb2YgTmV1cm9zY2llbmNlIGFuZCBQ

aHlzaW9sb2d5LCBUaGUgU2FobGdyZW5za2EgQWNhZGVteSBhdCB0aGUgVW5pdmVyc2l0eSBvZiBH

b3RoZW5idXJnLCBNb2xuZGFsLCBTd2VkZW47IFVDTCBJbnN0aXR1dGUgb2YgTmV1cm9sb2d5LCBR

dWVlbiBTcXVhcmUsIExvbmRvbiwgVUsuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+RGVm

ZWF0aW5nIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZSBhbmQgb3RoZXIgZGVtZW50aWFzOiBhIHBy

aW9yaXR5IGZvciBFdXJvcGVhbiBzY2llbmNlIGFuZCBzb2NpZXR5PC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPkxhbmNldCBOZXVyb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NDU1

LTUzMjwvcGFnZXM+PHZvbHVtZT4xNTwvdm9sdW1lPjxudW1iZXI+NTwvbnVtYmVyPjxrZXl3b3Jk

cz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5C

aW9tZWRpY2FsIFJlc2VhcmNoL2Vjb25vbWljcy8qb3JnYW5pemF0aW9uICZhbXA7IGFkbWluaXN0

cmF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkRlbWVudGlhLyp0aGVyYXB5PC9rZXl3b3JkPjxrZXl3

b3JkPkV1cm9wZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48

ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkFwcjwvZGF0ZT48L3B1Yi1k

YXRlcz48L2RhdGVzPjxpc2JuPjE0NzQtNDQ2NSAoRWxlY3Ryb25pYykmI3hEOzE0NzQtNDQyMiAo

TGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjY5ODc3MDE8L2FjY2Vzc2lvbi1udW0+PHVy

bHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQv

MjY5ODc3MDE8L3VybD48dXJsPmh0dHBzOi8vYWMuZWxzLWNkbi5jb20vUzE0NzQ0NDIyMTYwMDA2

MjQvMS1zMi4wLVMxNDc0NDQyMjE2MDAwNjI0LW1haW4ucGRmP190aWQ9MDc3ZjA4MTUtY2I1Ni00

MGM1LWFkYmYtZjhiZmFhNWJjOWE3JmFtcDthY2RuYXQ9MTUzNDQ5NTI2MF84MWYwMmEzZGZiOGRi

Y2IwMWNjY2VjMTJlMjlmNmNlZTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMTQ3NC00NDIyKDE2KTAwMDYyLTQ8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjI3MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjQ8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yNzI8L3JlYy1udW1i

ZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBo

cGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMTc3NTI3MSI+MjcyPC9rZXk+PC9mb3Jl

aWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxj

b250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XaW5ibGFkLCBCLjwvYXV0aG9yPjxhdXRob3I+

QW1vdXllbCwgUC48L2F1dGhvcj48YXV0aG9yPkFuZHJpZXUsIFMuPC9hdXRob3I+PGF1dGhvcj5C

YWxsYXJkLCBDLjwvYXV0aG9yPjxhdXRob3I+QnJheW5lLCBDLjwvYXV0aG9yPjxhdXRob3I+QnJv

ZGF0eSwgSC48L2F1dGhvcj48YXV0aG9yPkNlZGF6by1NaW5ndWV6LCBBLjwvYXV0aG9yPjxhdXRo

b3I+RHVib2lzLCBCLjwvYXV0aG9yPjxhdXRob3I+RWR2YXJkc3NvbiwgRC48L2F1dGhvcj48YXV0

aG9yPkZlbGRtYW4sIEguPC9hdXRob3I+PGF1dGhvcj5GcmF0aWdsaW9uaSwgTC48L2F1dGhvcj48

YXV0aG9yPkZyaXNvbmksIEcuIEIuPC9hdXRob3I+PGF1dGhvcj5HYXV0aGllciwgUy48L2F1dGhv

cj48YXV0aG9yPkdlb3JnZXMsIEouPC9hdXRob3I+PGF1dGhvcj5HcmFmZiwgQy48L2F1dGhvcj48

YXV0aG9yPklxYmFsLCBLLjwvYXV0aG9yPjxhdXRob3I+SmVzc2VuLCBGLjwvYXV0aG9yPjxhdXRo

b3I+Sm9oYW5zc29uLCBHLjwvYXV0aG9yPjxhdXRob3I+Sm9uc3NvbiwgTC48L2F1dGhvcj48YXV0

aG9yPktpdmlwZWx0bywgTS48L2F1dGhvcj48YXV0aG9yPktuYXBwLCBNLjwvYXV0aG9yPjxhdXRo

b3I+TWFuZ2lhbGFzY2hlLCBGLjwvYXV0aG9yPjxhdXRob3I+TWVsaXMsIFIuPC9hdXRob3I+PGF1

dGhvcj5Ob3JkYmVyZywgQS48L2F1dGhvcj48YXV0aG9yPlJpa2tlcnQsIE0uIE8uPC9hdXRob3I+

PGF1dGhvcj5RaXUsIEMuPC9hdXRob3I+PGF1dGhvcj5TYWttYXIsIFQuIFAuPC9hdXRob3I+PGF1

dGhvcj5TY2hlbHRlbnMsIFAuPC9hdXRob3I+PGF1dGhvcj5TY2huZWlkZXIsIEwuIFMuPC9hdXRo

b3I+PGF1dGhvcj5TcGVybGluZywgUi48L2F1dGhvcj48YXV0aG9yPlRqZXJuYmVyZywgTC4gTy48

L2F1dGhvcj48YXV0aG9yPldhbGRlbWFyLCBHLjwvYXV0aG9yPjxhdXRob3I+V2ltbywgQS48L2F1

dGhvcj48YXV0aG9yPlpldHRlcmJlcmcsIEguPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5j

ZXMgYW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEaXZpc2lvbiBv

ZiBOZXVyb2dlcmlhdHJpY3MsIEthcm9saW5za2EgSW5zdGl0dXRldCwgSHVkZGluZ2UsIFN3ZWRl

bjsgRGVwYXJ0bWVudCBvZiBHZXJpYXRyaWMgTWVkaWNpbmUsIEthcm9saW5za2EgVW5pdmVyc2l0

eSBIb3NwaXRhbCwgSHVkZGluZ2UsIFN3ZWRlbi4gRWxlY3Ryb25pYyBhZGRyZXNzOiBiZW5ndC13

aW5ibGFkLXN3ZWRpc2hicmFpbnBvd2VyQGtpLnNlLiYjeEQ7Q2VudHJlIEhvc3BpdGFsaWVyIFJl

Z2lvbmFsIFVuaXZlcnNpdGFpcmUgZGUgTGlsbGUsIEluc3RpdHV0IFBhc3RldXIgZGUgTGlsbGUs

IElOU0VSTSBVMTE2NyBSSUQtQUdFLCBVbml0ZSBkJmFwb3M7RXBpZGVtaW9sb2dpZSBldCBkZSBT

YW50ZSBQdWJsaXF1ZSwgTGFiZXggRElTVEFMWiwgTGlsbGUsIEZyYW5jZS4mI3hEO0RlcGFydG1l

bnQgb2YgRXBpZGVtaW9sb2d5IGFuZCBQdWJsaWMgSGVhbHRoLCBGYWN1bHR5IG9mIE1lZGljaW5l

LCBUb3Vsb3VzZSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBUb3Vsb3VzZSwgRnJhbmNlLiYjeEQ7V29s

ZnNvbiBDZW50cmUgZm9yIEFnZS1SZWxhdGVkIERpc2Vhc2VzLCBLaW5nJmFwb3M7cyBDb2xsZWdl

IExvbmRvbiwgTG9uZG9uLCBVSy4mI3hEO0NhbWJyaWRnZSBJbnN0aXR1dGUgb2YgUHVibGljIEhl

YWx0aCwgVW5pdmVyc2l0eSBvZiBDYW1icmlkZ2UsIENhbWJyaWRnZSwgVUsuJiN4RDtDZW50cmUg

Zm9yIEhlYWx0aHkgQnJhaW4gQWdlaW5nIGFuZCBEZW1lbnRpYSBDb2xsYWJvcmF0aXZlIFJlc2Vh

cmNoIENlbnRyZSwgVW5pdmVyc2l0eSBvZiBOZXcgU291dGggV2FsZXMsIFN5ZG5leSwgTlNXLCBB

dXN0cmFsaWEuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBh

bmQgU29jaWV0eSwgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIE5l

dXJvZ2VyaWF0cmljcywgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBIdWRkaW5nZSwgU3dlZGVuLiYj

eEQ7SW5zdGl0dXQgZGUgbGEgTWVtb2lyZSBldCBkZSBsYSBNYWxhZGllIGQmYXBvcztBbHpoZWlt

ZXIsIElNMkEsIElOU0VSTSwgSW5zdGl0dXQgZHUgQ2VydmVhdSBldCBkZSBsYSBNb2VsbGUgRXBp

bmllcmUsIFVNUi1TOTc1LCBHcm91cGUgSG9zcGl0YWxpZXIgUGl0aWUtU2FscGV0cmllcmUsIFVu

aXZlcnNpdGUgUGllcnJlIGV0IE1hcmllIEN1cmllLVBhcmlzIDYsIFBhcmlzLCBGcmFuY2UuJiN4

RDtTY2hvb2wgb2YgTnVyc2luZyBhbmQgTWlkd2lmZXJ5LCBMYSBUcm9iZSBVbml2ZXJzaXR5LCBN

ZWxib3VybmUsIFZJQywgQXVzdHJhbGlhOyBEZXBhcnRtZW50IG9mIE51cnNpbmcsIFVtZWEgVW5p

dmVyc2l0eSwgVW1lYSwgU3dlZGVuLiYjeEQ7RGl2aXNpb24gb2YgTmV1cm9sb2d5LCBGYWN1bHR5

IG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIEJyaXRpc2ggQ29sdW1iaWEsIFZhbmNvdXZlciwg

QkMsIENhbmFkYS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2Vz

IGFuZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgQWdpbmcgUmVzZWFy

Y2ggQ2VudGVyLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7

R2VuZXZhIFVuaXZlcnNpdHkgSG9zcGl0YWxzIGFuZCBVbml2ZXJzaXR5IG9mIEdlbmV2YSwgR2Vu

ZXZhLCBTd2l0emVybGFuZDsgSVJDQ1MgQ2VudHJvIFNhbiBHaW92YW5uaSBkaSBEaW8gRmF0ZWJl

bmVmcmF0ZWxsaSwgQnJlc2NpYSwgSXRhbHkuJiN4RDtNY0dpbGwgQ2VudGVyIGZvciBTdHVkaWVz

IGluIEFnaW5nLCBBbHpoZWltZXImYXBvcztzIERpc2Vhc2UgUmVzZWFyY2ggVW5pdCwgYW5kIERv

dWdsYXMgTWVudGFsIEhlYWx0aCBVbml2ZXJzaXR5IEluc3RpdHV0ZSwgTW9udHJlYWwsIFFDLCBD

YW5hZGEuJiN4RDtBbHpoZWltZXIgRXVyb3BlLCBMdXhlbWJvdXJnIENpdHksIEx1eGVtYm91cmcu

JiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29jaWV0

eSwgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0

cmljcywgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBIdWRkaW5nZSwgU3dlZGVuOyBEZXBhcnRtZW50

IG9mIEdlcmlhdHJpYyBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBI

dWRkaW5nZSwgU3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2NoZW1pc3RyeSwgSW5nZSBH

cnVuZGtlLUlxYmFsIFJlc2VhcmNoIEZsb29yLCBOZXcgWW9yayBTdGF0ZSBJbnN0aXR1dGUgZm9y

IEJhc2ljIFJlc2VhcmNoLCBTdGF0ZW4gSXNsYW5kLCBOWSwgVVNBLiYjeEQ7RGVwYXJ0bWVudCBv

ZiBQc3ljaGlhdHJ5LCBVbml2ZXJzaXR5IG9mIENvbG9nbmUsIENvbG9nbmUsIEdlcm1hbnk7IEdl

cm1hbiBDZW50ZXIgZm9yIE5ldXJvZGVnZW5lcmF0aXZlIERpc2Vhc2VzIChEWk5FKSwgQm9ubiwg

R2VybWFueS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFu

ZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2YgTmV1

cm9nZXJpYXRyaWNzLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIEh1ZGRpbmdlLCBTd2VkZW47IERl

cGFydG1lbnQgb2YgR2VyaWF0cmljIE1lZGljaW5lLCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9z

cGl0YWwsIEh1ZGRpbmdlLCBTd2VkZW47IERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJl

IFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgQWdp

bmcgUmVzZWFyY2ggQ2VudGVyLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dl

ZGVuLiYjeEQ7UGVyc29uYWwgU29jaWFsIFNlcnZpY2VzIFJlc2VhcmNoIFVuaXQsIExvbmRvbiBT

Y2hvb2wgb2YgRWNvbm9taWNzIGFuZCBQb2xpdGljYWwgU2NpZW5jZSwgTG9uZG9uLCBVSy4mI3hE

O1JhZGJvdWR1bWMgQWx6aGVpbWVyIENlbnRyZSBhbmQgRGVwYXJ0bWVudCBvZiBHZXJpYXRyaWMg

TWVkaWNpbmUsIFJhZGJvdWQgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRlciwgTmlqbWVnZW4sIE5l

dGhlcmxhbmRzLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMg

YW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEaXZpc2lvbiBvZiBU

cmFuc2xhdGlvbmFsIEFsemhlaW1lciBCaW9sb2d5LCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIEh1

ZGRpbmdlLCBTd2VkZW47IERlcGFydG1lbnQgb2YgR2VyaWF0cmljIE1lZGljaW5lLCBLYXJvbGlu

c2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50

IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgQ2VudGVyIGZvciBB

bHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0cmljcywgS2Fyb2xpbnNr

YSBJbnN0aXR1dGV0LCBIdWRkaW5nZSwgU3dlZGVuOyBMYWJvcmF0b3J5IG9mIENoZW1pY2FsIEJp

b2xvZ3kgJmFtcDsgU2lnbmFsIFRyYW5zZHVjdGlvbiwgVGhlIFJvY2tlZmVsbGVyIFVuaXZlcnNp

dHksIE5ldyBZb3JrLCBOWSwgVVNBLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3kgYW5kIEFs

emhlaW1lciBDZW50ZXIsIFZVIFVuaXZlcnNpdHkgTWVkaWNhbCBDZW50ZXIsIE5ldXJvc2NpZW5j

ZSBDYW1wdXMsIEFtc3RlcmRhbSwgTmV0aGVybGFuZHMuJiN4RDtEZXBhcnRtZW50IG9mIFBzeWNo

aWF0cnkgYW5kIHRoZSBCZWhhdmlvcmFsIFNjaWVuY2VzIGFuZCBEZXBhcnRtZW50IG9mIE5ldXJv

bG9neSwgS2VjayBTY2hvb2wgb2YgTWVkaWNpbmUsIExlb25hcmQgRGF2aXMgU2Nob29sIG9mIEdl

cm9udG9sb2d5IG9mIHRoZSBVbml2ZXJzaXR5IG9mIFNvdXRoZXJuIENhbGlmb3JuaWEsIExvcyBB

bmdlbGVzLCBDQSwgVVNBLiYjeEQ7Q2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2ggYW5kIFRy

ZWF0bWVudCwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIEJyaWdoYW0gYW5kIFdvbWVuJmFwb3M7

cyBIb3NwaXRhbCBhbmQgTWFzc2FjaHVzZXR0cyBHZW5lcmFsIEhvc3BpdGFsLCBIYXJ2YXJkIE1l

ZGljYWwgU2Nob29sLCBCb3N0b24sIE1BLCBVU0EuJiN4RDtEYW5pc2ggRGVtZW50aWEgUmVzZWFy

Y2ggQ2VudHJlLCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgUmlnc2hvc3BpdGFsZXQsIFVuaXZl

cnNpdHkgb2YgQ29wZW5oYWdlbiwgQ29wZW5oYWdlbiwgRGVubWFyay4mI3hEO0NsaW5pY2FsIE5l

dXJvY2hlbWlzdHJ5IExhYm9yYXRvcnksIERlcGFydG1lbnQgb2YgTmV1cm9zY2llbmNlIGFuZCBQ

aHlzaW9sb2d5LCBUaGUgU2FobGdyZW5za2EgQWNhZGVteSBhdCB0aGUgVW5pdmVyc2l0eSBvZiBH

b3RoZW5idXJnLCBNb2xuZGFsLCBTd2VkZW47IFVDTCBJbnN0aXR1dGUgb2YgTmV1cm9sb2d5LCBR

dWVlbiBTcXVhcmUsIExvbmRvbiwgVUsuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+RGVm

ZWF0aW5nIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZSBhbmQgb3RoZXIgZGVtZW50aWFzOiBhIHBy

aW9yaXR5IGZvciBFdXJvcGVhbiBzY2llbmNlIGFuZCBzb2NpZXR5PC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPkxhbmNldCBOZXVyb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NDU1

LTUzMjwvcGFnZXM+PHZvbHVtZT4xNTwvdm9sdW1lPjxudW1iZXI+NTwvbnVtYmVyPjxrZXl3b3Jk

cz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5C

aW9tZWRpY2FsIFJlc2VhcmNoL2Vjb25vbWljcy8qb3JnYW5pemF0aW9uICZhbXA7IGFkbWluaXN0

cmF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkRlbWVudGlhLyp0aGVyYXB5PC9rZXl3b3JkPjxrZXl3

b3JkPkV1cm9wZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48

ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkFwcjwvZGF0ZT48L3B1Yi1k

YXRlcz48L2RhdGVzPjxpc2JuPjE0NzQtNDQ2NSAoRWxlY3Ryb25pYykmI3hEOzE0NzQtNDQyMiAo

TGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjY5ODc3MDE8L2FjY2Vzc2lvbi1udW0+PHVy

bHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQv

MjY5ODc3MDE8L3VybD48dXJsPmh0dHBzOi8vYWMuZWxzLWNkbi5jb20vUzE0NzQ0NDIyMTYwMDA2

MjQvMS1zMi4wLVMxNDc0NDQyMjE2MDAwNjI0LW1haW4ucGRmP190aWQ9MDc3ZjA4MTUtY2I1Ni00

MGM1LWFkYmYtZjhiZmFhNWJjOWE3JmFtcDthY2RuYXQ9MTUzNDQ5NTI2MF84MWYwMmEzZGZiOGRi

Y2IwMWNjY2VjMTJlMjlmNmNlZTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMTQ3NC00NDIyKDE2KTAwMDYyLTQ8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 4. Moreover, some of these genes also contribute to other pathologies such as cardiovascular disease, insulin resistance and obesity ADDIN EN.CITE <EndNote><Cite><Author>Hardy</Author><Year>2014</Year><RecNum>283</RecNum><DisplayText><style face="superscript">46</style></DisplayText><record><rec-number>283</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1531775273">283</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hardy, J.</author><author>Bogdanovic, N.</author><author>Winblad, B.</author><author>Portelius, E.</author><author>Andreasen, N.</author><author>Cedazo-Minguez, A.</author><author>Zetterberg, H.</author></authors></contributors><titles><title>Pathways to Alzheimer&apos;s disease</title><secondary-title>J Intern Med</secondary-title></titles><periodical><full-title>J Intern Med</full-title></periodical><pages>296-303</pages><volume>275</volume><number>3</number><keywords><keyword>*Alzheimer Disease/genetics/metabolism</keyword><keyword>*Amyloid/genetics/metabolism</keyword><keyword>Amyloid beta-Peptides/*antagonists &amp; inhibitors</keyword><keyword>Brain/metabolism</keyword><keyword>Early Medical Intervention</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Humans</keyword><keyword>Immunotherapy/methods</keyword></keywords><dates><year>2014</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1365-2796 (Electronic)&#xD;0954-6820 (Linking)</isbn><accession-num>24749173</accession-num><urls><related-urls><url>. Together with studies on the effect of environmental factors such as diet, lifestyle and exercise PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaXZpcGVsdG88L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFy

PjxSZWNOdW0+MzIwPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjM2LDQwMC00MDI8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4z

MjA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1

MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMTc3NTI3OCI+MzIw

PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8

L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LaXZpcGVsdG8sIE0uPC9h

dXRob3I+PGF1dGhvcj5Sb3ZpbywgUy48L2F1dGhvcj48YXV0aG9yPk5nYW5kdSwgVC48L2F1dGhv

cj48YXV0aG9yPkthcmVob2x0LCBJLjwvYXV0aG9yPjxhdXRob3I+RXNrZWxpbmVuLCBNLjwvYXV0

aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48YXV0aG9yPkhhY2hpbnNraSwgVi48L2F1

dGhvcj48YXV0aG9yPkNlZGF6by1NaW5ndWV6LCBBLjwvYXV0aG9yPjxhdXRob3I+U29pbmluZW4s

IEguPC9hdXRob3I+PGF1dGhvcj5UdW9taWxlaHRvLCBKLjwvYXV0aG9yPjxhdXRob3I+Tmlzc2lu

ZW4sIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+QWdp

bmcgUmVzZWFyY2ggQ2VudGVyLCBOVlMsIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xt

LCBTd2VkZW4uIE1paWEuS2l2aXBlbHRvQGtpLnNlPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+QXBvbGlwb3Byb3RlaW4gRSBlcHNpbG9uNCBtYWduaWZpZXMgbGlmZXN0eWxlIHJpc2tzIGZv

ciBkZW1lbnRpYTogYSBwb3B1bGF0aW9uLWJhc2VkIHN0dWR5PC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPkogQ2VsbCBNb2wgTWVkPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjI3NjIt

NzE8L3BhZ2VzPjx2b2x1bWU+MTI8L3ZvbHVtZT48bnVtYmVyPjZCPC9udW1iZXI+PGtleXdvcmRz

PjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvZ2VuZXRp

Y3M8L2tleXdvcmQ+PGtleXdvcmQ+QXBvbGlwb3Byb3RlaW4gRTQvKmdlbmV0aWNzPC9rZXl3b3Jk

PjxrZXl3b3JkPkRlbWVudGlhLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5EZW1vZ3JhcGh5

PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IZXRlcm96eWdvdGU8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPipMaWZlIFN0eWxlPC9r

ZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdv

cmQ+PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlNvY2lvZWNvbm9taWMg

RmFjdG9yczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA4PC95ZWFyPjxwdWIt

ZGF0ZXM+PGRhdGU+RGVjPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU4Mi0xODM4

IChQcmludCkmI3hEOzE1ODItMTgzOCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTgz

MTg2OTM8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTgzMTg2OTM8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGN1c3RvbTI+UE1DMzgyODg4OTwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

MTAuMTExMS9qLjE1ODItNDkzNC4yMDA4LjAwMjk2Lng8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk1hcmVuZ29uaTwvQXV0aG9yPjxZZWFyPjIw

MTg8L1llYXI+PFJlY051bT4zNTk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM1OTwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTQ4NjM0Ij4zNTk8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1hcmVuZ29uaSwgQS48L2F1dGhvcj48

YXV0aG9yPlJpenp1dG8sIEQuPC9hdXRob3I+PGF1dGhvcj5GcmF0aWdsaW9uaSwgTC48L2F1dGhv

cj48YXV0aG9yPkFudGlrYWluZW4sIFIuPC9hdXRob3I+PGF1dGhvcj5MYWF0aWthaW5lbiwgVC48

L2F1dGhvcj48YXV0aG9yPkxlaHRpc2FsbywgSi48L2F1dGhvcj48YXV0aG9yPlBlbHRvbmVuLCBN

LjwvYXV0aG9yPjxhdXRob3I+U29pbmluZW4sIEguPC9hdXRob3I+PGF1dGhvcj5TdHJhbmRiZXJn

LCBULjwvYXV0aG9yPjxhdXRob3I+VHVvbWlsZWh0bywgSi48L2F1dGhvcj48YXV0aG9yPktpdmlw

ZWx0bywgTS48L2F1dGhvcj48YXV0aG9yPk5nYW5kdSwgVC48L2F1dGhvcj48L2F1dGhvcnM+PC9j

b250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIENsaW5pY2FsIGFuZCBFeHBl

cmltZW50YWwgU2NpZW5jZXMsIFVuaXZlcnNpdHkgb2YgQnJlc2NpYSwgQnJlc2NpYSwgSXRhbHk7

IEFnaW5nIFJlc2VhcmNoIENlbnRlciwgRGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUg

U2NpZW5jZXMgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0dXRldCwgYW5kIFN0b2NraG9s

bSBVbml2ZXJzaXR5LCBTdG9ja2hvbG0sIFN3ZWRlbi4gRWxlY3Ryb25pYyBhZGRyZXNzOiBhbGVz

c2FuZHJhLm1hcmVuZ29uaUBraS5zZS4mI3hEO0FnaW5nIFJlc2VhcmNoIENlbnRlciwgRGVwYXJ0

bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIEthcm9saW5z

a2EgSW5zdGl0dXRldCwgYW5kIFN0b2NraG9sbSBVbml2ZXJzaXR5LCBTdG9ja2hvbG0sIFN3ZWRl

bi4mI3hEO0FnaW5nIFJlc2VhcmNoIENlbnRlciwgRGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ks

IENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0dXRldCwgYW5kIFN0

b2NraG9sbSBVbml2ZXJzaXR5LCBTdG9ja2hvbG0sIFN3ZWRlbjsgU3RvY2tob2xtIEdlcm9udG9s

b2d5IFJlc2VhcmNoIENlbnRlciwgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtDZW50ZXIgZm9yIExp

ZmUgQ291cnNlIEhlYWx0aCBSZXNlYXJjaC9HZXJpYXRyaWNzLCBVbml2ZXJzaXR5IG9mIE91bHUs

IE91bHUsIEZpbmxhbmQ7IE1lZGljYWwgUmVzZWFyY2ggQ2VudGVyIE91bHUsIE91bHUgVW5pdmVy

c2l0eSBIb3NwaXRhbCwgT3VsdSwgRmlubGFuZDsgT3VsdSBDaXR5IEhvc3BpdGFsLCBPdWx1LCBG

aW5sYW5kLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoIFNvbHV0aW9ucywgQ2hyb25p

YyBEaXNlYXNlIFByZXZlbnRpb24gVW5pdCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGgg

YW5kIFdlbGZhcmUsIEhlbHNpbmtpLCBGaW5sYW5kOyBJbnN0aXR1dGUgb2YgUHVibGljIEhlYWx0

aCBhbmQgQ2xpbmljYWwgTnV0cml0aW9uLCBVbml2ZXJzaXR5IG9mIEVhc3Rlcm4gRmlubGFuZCwg

S3VvcGlvLCBGaW5sYW5kOyBKb2ludCBtdW5pY2lwYWwgYXV0aG9yaXR5IGZvciBOb3J0aCBLYXJl

bGlhIHNvY2lhbCBhbmQgaGVhbHRoIHNlcnZpY2VzLCBKb2Vuc3V1LCBGaW5sYW5kLiYjeEQ7RGVw

YXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoIFNvbHV0aW9ucywgQ2hyb25pYyBEaXNlYXNlIFByZXZl

bnRpb24gVW5pdCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5kIFdlbGZhcmUsIEhl

bHNpbmtpLCBGaW5sYW5kOyBEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFsdGgsIFVuaXZlcnNpdHkg

b2YgSGVsc2lua2ksIEhlbHNpbmtpLCBGaW5sYW5kLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMg

SGVhbHRoIFNvbHV0aW9ucywgQ2hyb25pYyBEaXNlYXNlIFByZXZlbnRpb24gVW5pdCwgTmF0aW9u

YWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5kIFdlbGZhcmUsIEhlbHNpbmtpLCBGaW5sYW5kLiYj

eEQ7SW5zdGl0dXRlIG9mIENsaW5pY2FsIE1lZGljaW5lL05ldXJvbG9neSwgVW5pdmVyc2l0eSBv

ZiBFYXN0ZXJuIEZpbmxhbmQsIEt1b3BpbywgRmlubGFuZC4mI3hEO0NlbnRlciBmb3IgTGlmZSBD

b3Vyc2UgSGVhbHRoIFJlc2VhcmNoL0dlcmlhdHJpY3MsIFVuaXZlcnNpdHkgb2YgT3VsdSwgT3Vs

dSwgRmlubGFuZDsgTWVkaWNhbCBSZXNlYXJjaCBDZW50ZXIgT3VsdSwgT3VsdSBVbml2ZXJzaXR5

IEhvc3BpdGFsLCBPdWx1LCBGaW5sYW5kOyBVbml2ZXJzaXR5IG9mIEhlbHNpbmtpLCBIZWxzaW5r

aSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIZWxzaW5raSwgRmlubGFuZC4mI3hEO0RlcGFydG1lbnQg

b2YgUHVibGljIEhlYWx0aCBTb2x1dGlvbnMsIENocm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVu

aXQsIE5hdGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwg

RmlubGFuZDsgRGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoLCBVbml2ZXJzaXR5IG9mIEhlbHNp

bmtpLCBIZWxzaW5raSwgRmlubGFuZDsgU291dGggT3N0cm9ib3RobmlhIENlbnRyYWwgSG9zcGl0

YWwsIFNlaW5ham9raSwgRmlubGFuZDsgRGFzbWFuIERpYWJldGVzIEluc3RpdHV0ZSwgRGFzbWFu

LCBLdXdhaXQ7IERpYWJldGVzIFJlc2VhcmNoIEdyb3VwLCBLaW5nIEFiZHVsYXppeiBVbml2ZXJz

aXR5LCBKZWRkYWgsIFNhdWRpIEFyYWJpYS4mI3hEO0FnaW5nIFJlc2VhcmNoIENlbnRlciwgRGVw

YXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIEthcm9s

aW5za2EgSW5zdGl0dXRldCwgYW5kIFN0b2NraG9sbSBVbml2ZXJzaXR5LCBTdG9ja2hvbG0sIFN3

ZWRlbjsgRGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoIFNvbHV0aW9ucywgQ2hyb25pYyBEaXNl

YXNlIFByZXZlbnRpb24gVW5pdCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5kIFdl

bGZhcmUsIEhlbHNpbmtpLCBGaW5sYW5kOyBJbnN0aXR1dGUgb2YgQ2xpbmljYWwgTWVkaWNpbmUv

TmV1cm9sb2d5LCBVbml2ZXJzaXR5IG9mIEVhc3Rlcm4gRmlubGFuZCwgS3VvcGlvLCBGaW5sYW5k

OyBEaXZpc2lvbiBvZiBDbGluaWNhbCBHZXJpYXRyaWNzLCBDZW50ZXIgZm9yIEFsemhlaW1lciBS

ZXNlYXJjaCwgRGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNv

Y2lldHksIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW47IFN0b2NraG9s

bXMgU2p1a2hlbSwgUmVzZWFyY2ggJmFtcDsgRGV2ZWxvcG1lbnQgdW5pdCwgU3RvY2tob2xtLCBT

d2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFsdGggU29sdXRpb25zLCBDaHJvbmlj

IERpc2Vhc2UgUHJldmVudGlvbiBVbml0LCBOYXRpb25hbCBJbnN0aXR1dGUgZm9yIEhlYWx0aCBh

bmQgV2VsZmFyZSwgSGVsc2lua2ksIEZpbmxhbmQ7IERpdmlzaW9uIG9mIENsaW5pY2FsIEdlcmlh

dHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5ldXJv

YmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0

LCBTdG9ja2hvbG0sIFN3ZWRlbi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5UaGUgRWZm

ZWN0IG9mIGEgMi1ZZWFyIEludGVydmVudGlvbiBDb25zaXN0aW5nIG9mIERpZXQsIFBoeXNpY2Fs

IEV4ZXJjaXNlLCBDb2duaXRpdmUgVHJhaW5pbmcsIGFuZCBNb25pdG9yaW5nIG9mIFZhc2N1bGFy

IFJpc2sgb24gQ2hyb25pYyBNb3JiaWRpdHktdGhlIEZJTkdFUiBSYW5kb21pemVkIENvbnRyb2xs

ZWQgVHJpYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBBbSBNZWQgRGlyIEFzc29jPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjM1NS0zNjAgZTE8L3BhZ2VzPjx2b2x1bWU+MTk8

L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+RGlldDwva2V5d29y

ZD48a2V5d29yZD5jaHJvbmljIG1vcmJpZGl0eTwva2V5d29yZD48a2V5d29yZD5jb2duaXRpdmUg

dHJhaW5pbmc8L2tleXdvcmQ+PGtleXdvcmQ+cGh5c2ljYWwgZXhlcmNpc2U8L2tleXdvcmQ+PGtl

eXdvcmQ+cmFuZG9taXplZCBjbGluaWNhbCB0cmlhbDwva2V5d29yZD48a2V5d29yZD52YXNjdWxh

ciByaXNrPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1k

YXRlcz48ZGF0ZT5BcHI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTM4LTkzNzUg

KEVsZWN0cm9uaWMpJiN4RDsxNTI1LTg2MTAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVt

PjI5MTA4ODg4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8v

d3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI5MTA4ODg4PC91cmw+PC9yZWxhdGVkLXVybHM+

PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ouamFtZGEuMjAxNy4wOS4w

MjA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9y

PlJvc2VuYmVyZzwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJlY051bT4zNjA8L1JlY051bT48

cmVjb3JkPjxyZWMtbnVtYmVyPjM2MDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0

YW1wPSIxNTMyNTQ4NjM0Ij4zNjA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPlJvc2VuYmVyZywgQS48L2F1dGhvcj48YXV0aG9yPk5nYW5kdSwgVC48L2F1dGhvcj48YXV0

aG9yPlJ1c2FuZW4sIE0uPC9hdXRob3I+PGF1dGhvcj5BbnRpa2FpbmVuLCBSLjwvYXV0aG9yPjxh

dXRob3I+QmFja21hbiwgTC48L2F1dGhvcj48YXV0aG9yPkhhdnVsaW5uYSwgUy48L2F1dGhvcj48

YXV0aG9yPkhhbm5pbmVuLCBULjwvYXV0aG9yPjxhdXRob3I+TGFhdGlrYWluZW4sIFQuPC9hdXRo

b3I+PGF1dGhvcj5MZWh0aXNhbG8sIEouPC9hdXRob3I+PGF1dGhvcj5MZXZhbGFodGksIEUuPC9h

dXRob3I+PGF1dGhvcj5MaW5kc3Ryb20sIEouPC9hdXRob3I+PGF1dGhvcj5QYWFqYW5lbiwgVC48

L2F1dGhvcj48YXV0aG9yPlBlbHRvbmVuLCBNLjwvYXV0aG9yPjxhdXRob3I+U29pbmluZW4sIEgu

PC9hdXRob3I+PGF1dGhvcj5TdGlnc2RvdHRlci1OZWVseSwgQS48L2F1dGhvcj48YXV0aG9yPlN0

cmFuZGJlcmcsIFQuPC9hdXRob3I+PGF1dGhvcj5UdW9taWxlaHRvLCBKLjwvYXV0aG9yPjxhdXRo

b3I+U29sb21vbiwgQS48L2F1dGhvcj48YXV0aG9yPktpdmlwZWx0bywgTS48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5JbnN0aXR1dGUgb2YgQ2xpbmljYWwg

TWVkaWNpbmUsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IG9mIEVhc3Rlcm4g

RmlubGFuZCwgS3VvcGlvLCBGaW5sYW5kLiBFbGVjdHJvbmljIGFkZHJlc3M6IGFubmEucm9zZW5i

ZXJnQHVlZi5maS4mI3hEO0RlcGFydG1lbnQgb2YgUHVibGljIEhlYWx0aCBTb2x1dGlvbnMsIENo

cm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVh

bHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlubGFuZDsgRGl2aXNpb24gb2YgQ2xpbmljYWwg

R2VyaWF0cmljcywgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIE5WUywgS2Fyb2xpbnNr

YSBJbnN0aXR1dGV0LCBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0RlcGFydG1lbnQgb2YgUHVibGlj

IEhlYWx0aCBTb2x1dGlvbnMsIENocm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQsIE5hdGlv

bmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlubGFuZDsg

RGl2aXNpb24gb2YgQ2xpbmljYWwgR2VyaWF0cmljcywgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVz

ZWFyY2gsIE5WUywgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBTdG9ja2hvbG0sIFN3ZWRlbjsgRGVw

YXJ0bWVudCBvZiBOZXVyb2xvZ3ksIE5vcnRoIEthcmVsaWEgQ2VudHJhbCBIb3NwaXRhbCwgSm9l

bnN1dSwgRmlubGFuZC4mI3hEO0NlbnRlciBmb3IgTGlmZSBDb3Vyc2UgSGVhbHRoIFJlc2VhcmNo

L0dlcmlhdHJpY3MsIFVuaXZlcnNpdHkgb2YgT3VsdSwgT3VsdSwgRmlubGFuZDsgTWVkaWNhbCBS

ZXNlYXJjaCBDZW50ZXIgT3VsdSwgT3VsdSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBPdWx1LCBGaW5s

YW5kOyBPdWx1IENpdHkgSG9zcGl0YWwsIE91bHUsIEZpbmxhbmQuJiN4RDtBZ2luZyBSZXNlYXJj

aCBDZW50ZXIsIEthcm9saW5za2EgSW5zdGl0dXRldC1TdG9ja2hvbG0gVW5pdmVyc2l0eSwgU3Rv

Y2tob2xtLCBTd2VkZW4uJiN4RDtBZ2luZywgRGlzYWJpbGl0eSBhbmQgRnVuY3Rpb25pbmcgVW5p

dCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5kIFdlbGZhcmUsIEhlbHNpbmtpLCBG

aW5sYW5kLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIEt1b3BpbyBVbml2ZXJzaXR5IEhv

c3BpdGFsLCBLdW9waW8sIEZpbmxhbmQuJiN4RDtEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFsdGgg

U29sdXRpb25zLCBDaHJvbmljIERpc2Vhc2UgUHJldmVudGlvbiBVbml0LCBOYXRpb25hbCBJbnN0

aXR1dGUgZm9yIEhlYWx0aCBhbmQgV2VsZmFyZSwgSGVsc2lua2ksIEZpbmxhbmQ7IEluc3RpdHV0

ZSBvZiBQdWJsaWMgSGVhbHRoIGFuZCBDbGluaWNhbCBOdXRyaXRpb24sIFVuaXZlcnNpdHkgb2Yg

RWFzdGVybiBGaW5sYW5kLCBLdW9waW8sIEZpbmxhbmQ7IEpvaW50IG11bmljaXBhbCBhdXRob3Jp

dHkgZm9yIE5vcnRoIEthcmVsaWEgU29jaWFsIGFuZCBIZWFsdGggc2VydmljZXMsIEpvZW5zdXUs

IEZpbmxhbmQuJiN4RDtEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFsdGggU29sdXRpb25zLCBDaHJv

bmljIERpc2Vhc2UgUHJldmVudGlvbiBVbml0LCBOYXRpb25hbCBJbnN0aXR1dGUgZm9yIEhlYWx0

aCBhbmQgV2VsZmFyZSwgSGVsc2lua2ksIEZpbmxhbmQ7IERlcGFydG1lbnQgb2YgUHVibGljIEhl

YWx0aCwgVW5pdmVyc2l0eSBvZiBIZWxzaW5raSwgSGVsc2lua2ksIEZpbmxhbmQuJiN4RDtEZXBh

cnRtZW50IG9mIFB1YmxpYyBIZWFsdGggU29sdXRpb25zLCBDaHJvbmljIERpc2Vhc2UgUHJldmVu

dGlvbiBVbml0LCBOYXRpb25hbCBJbnN0aXR1dGUgZm9yIEhlYWx0aCBhbmQgV2VsZmFyZSwgSGVs

c2lua2ksIEZpbmxhbmQuJiN4RDtGaW5uaXNoIEluc3RpdHV0ZSBvZiBPY2N1cGF0aW9uYWwgSGVh

bHRoLCBIZWxzaW5raSwgRmlubGFuZC4mI3hEO0luc3RpdHV0ZSBvZiBDbGluaWNhbCBNZWRpY2lu

ZSwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIFVuaXZlcnNpdHkgb2YgRWFzdGVybiBGaW5sYW5k

LCBLdW9waW8sIEZpbmxhbmQ7IE5ldXJvY2VudGVyLCBOZXVyb2xvZ3ksIEt1b3BpbyBVbml2ZXJz

aXR5IEhvc3BpdGFsLCBLdW9waW8sIEZpbmxhbmQuJiN4RDtEZXBhcnRtZW50IG9mIFBzeWNob2xv

Z3ksIFVtZWEgVW5pdmVyc2l0eSwgVW1lYSwgU3dlZGVuOyBEZXBhcnRtZW50IG9mIFNvY2lhbCBh

bmQgUHN5Y2hvbG9naWNhbCBTY2llbmNlcywgS2FybHN0YWQgVW5pdmVyc2l0eSwgS2FybHN0YWQs

IFN3ZWRlbi4mI3hEO0NlbnRlciBmb3IgTGlmZSBDb3Vyc2UgSGVhbHRoIFJlc2VhcmNoL0dlcmlh

dHJpY3MsIFVuaXZlcnNpdHkgb2YgT3VsdSwgT3VsdSwgRmlubGFuZDsgTWVkaWNhbCBSZXNlYXJj

aCBDZW50ZXIgT3VsdSwgT3VsdSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBPdWx1LCBGaW5sYW5kOyBV

bml2ZXJzaXR5IG9mIEhlbHNpbmtpLCBIZWxzaW5raSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIZWxz

aW5raSwgRmlubGFuZC4mI3hEO0RlcGFydG1lbnQgb2YgUHVibGljIEhlYWx0aCBTb2x1dGlvbnMs

IENocm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0ZSBmb3Ig

SGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlubGFuZDsgRGVwYXJ0bWVudCBvZiBQdWJs

aWMgSGVhbHRoLCBVbml2ZXJzaXR5IG9mIEhlbHNpbmtpLCBIZWxzaW5raSwgRmlubGFuZDsgU291

dGggT3N0cm9ib3RobmlhIENlbnRyYWwgSG9zcGl0YWwsIFNlaW5ham9raSwgRmlubGFuZC4mI3hE

O0luc3RpdHV0ZSBvZiBDbGluaWNhbCBNZWRpY2luZSwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ks

IFVuaXZlcnNpdHkgb2YgRWFzdGVybiBGaW5sYW5kLCBLdW9waW8sIEZpbmxhbmQ7IERpdmlzaW9u

IG9mIENsaW5pY2FsIEdlcmlhdHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBO

VlMsIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW47IEFnaW5nIFJlc2Vh

cmNoIENlbnRlciwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LVN0b2NraG9sbSBVbml2ZXJzaXR5LCBT

dG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0luc3RpdHV0ZSBvZiBDbGluaWNhbCBNZWRpY2luZSwgRGVw

YXJ0bWVudCBvZiBOZXVyb2xvZ3ksIFVuaXZlcnNpdHkgb2YgRWFzdGVybiBGaW5sYW5kLCBLdW9w

aW8sIEZpbmxhbmQ7IERlcGFydG1lbnQgb2YgUHVibGljIEhlYWx0aCBTb2x1dGlvbnMsIENocm9u

aWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRo

IGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlubGFuZDsgRGl2aXNpb24gb2YgQ2xpbmljYWwgR2Vy

aWF0cmljcywgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIE5WUywgS2Fyb2xpbnNrYSBJ

bnN0aXR1dGV0LCBTdG9ja2hvbG0sIFN3ZWRlbjsgQWdpbmcgUmVzZWFyY2ggQ2VudGVyLCBLYXJv

bGluc2thIEluc3RpdHV0ZXQtU3RvY2tob2xtIFVuaXZlcnNpdHksIFN0b2NraG9sbSwgU3dlZGVu

OyBTdG9ja2hvbG1zIFNqdWtoZW0sIFJlc2VhcmNoICZhbXA7IERldmVsb3BtZW50IFVuaXQsIFN0

b2NraG9sbSwgU3dlZGVuLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPk11bHRpZG9tYWlu

IGxpZmVzdHlsZSBpbnRlcnZlbnRpb24gYmVuZWZpdHMgYSBsYXJnZSBlbGRlcmx5IHBvcHVsYXRp

b24gYXQgcmlzayBmb3IgY29nbml0aXZlIGRlY2xpbmUgYW5kIGRlbWVudGlhIHJlZ2FyZGxlc3Mg

b2YgYmFzZWxpbmUgY2hhcmFjdGVyaXN0aWNzOiBUaGUgRklOR0VSIHRyaWFsPC90aXRsZT48c2Vj

b25kYXJ5LXRpdGxlPkFsemhlaW1lcnMgRGVtZW50PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBhZ2VzPjI2My0yNzA8L3BhZ2VzPjx2b2x1bWU+MTQ8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJl

cj48a2V5d29yZHM+PGtleXdvcmQ+KkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48

a2V5d29yZD4qQ29nbml0aXZlIGltcGFpcm1lbnQ8L2tleXdvcmQ+PGtleXdvcmQ+KkRlbWVudGlh

PC9rZXl3b3JkPjxrZXl3b3JkPipJbnRlcnZlbnRpb248L2tleXdvcmQ+PGtleXdvcmQ+KkxpZmVz

dHlsZTwva2V5d29yZD48a2V5d29yZD4qTXVsdGlkb21haW48L2tleXdvcmQ+PGtleXdvcmQ+KlBy

ZXZlbnRpb248L2tleXdvcmQ+PGtleXdvcmQ+KlJhbmRvbWl6ZWQgY29udHJvbGxlZCB0cmlhbDwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+TWFyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU1Mi01Mjc5IChFbGVjdHJv

bmljKSYjeEQ7MTU1Mi01MjYwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yOTA1NTgx

NDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3B1Ym1lZC8yOTA1NTgxNDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmphbHouMjAxNy4wOS4wMDY8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk5nYW5kdTwv

QXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJlY051bT4zNjU8L1JlY051bT48cmVjb3JkPjxyZWMt

bnVtYmVyPjM2NTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9

ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTQ4

NjM0Ij4zNjU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRp

Y2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk5nYW5kdSwg

VC48L2F1dGhvcj48YXV0aG9yPkxlaHRpc2FsbywgSi48L2F1dGhvcj48YXV0aG9yPlNvbG9tb24s

IEEuPC9hdXRob3I+PGF1dGhvcj5MZXZhbGFodGksIEUuPC9hdXRob3I+PGF1dGhvcj5BaHRpbHVv

dG8sIFMuPC9hdXRob3I+PGF1dGhvcj5BbnRpa2FpbmVuLCBSLjwvYXV0aG9yPjxhdXRob3I+QmFj

a21hbiwgTC48L2F1dGhvcj48YXV0aG9yPkhhbm5pbmVuLCBULjwvYXV0aG9yPjxhdXRob3I+SnVs

YSwgQS48L2F1dGhvcj48YXV0aG9yPkxhYXRpa2FpbmVuLCBULjwvYXV0aG9yPjxhdXRob3I+TGlu

ZHN0cm9tLCBKLjwvYXV0aG9yPjxhdXRob3I+TWFuZ2lhbGFzY2hlLCBGLjwvYXV0aG9yPjxhdXRo

b3I+UGFhamFuZW4sIFQuPC9hdXRob3I+PGF1dGhvcj5QYWphbGEsIFMuPC9hdXRob3I+PGF1dGhv

cj5QZWx0b25lbiwgTS48L2F1dGhvcj48YXV0aG9yPlJhdXJhbWFhLCBSLjwvYXV0aG9yPjxhdXRo

b3I+U3RpZ3Nkb3R0ZXItTmVlbHksIEEuPC9hdXRob3I+PGF1dGhvcj5TdHJhbmRiZXJnLCBULjwv

YXV0aG9yPjxhdXRob3I+VHVvbWlsZWh0bywgSi48L2F1dGhvcj48YXV0aG9yPlNvaW5pbmVuLCBI

LjwvYXV0aG9yPjxhdXRob3I+S2l2aXBlbHRvLCBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy

aWJ1dG9ycz48YXV0aC1hZGRyZXNzPkNocm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQsIE5h

dGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlubGFu

ZDsgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0IENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBT

dG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0Nocm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQsIE5h

dGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlubGFu

ZC4mI3hEO0thcm9saW5za2EgSW5zdGl0dXRldCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJj

aCwgU3RvY2tob2xtLCBTd2VkZW47IEluc3RpdHV0ZSBvZiBDbGluaWNhbCBNZWRpY2luZS9OZXVy

b2xvZ3ksIFVuaXZlcnNpdHkgb2YgRWFzdGVybiBGaW5sYW5kLCBLdW9waW8sIEZpbmxhbmQ7IEFn

aW5nIFJlc2VhcmNoIENlbnRlciwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LVN0b2NraG9sbSBVbml2

ZXJzaXR5LCBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0luc3RpdHV0ZSBvZiBIZWFsdGggU2NpZW5j

ZXMvR2VyaWF0cmljcywgVW5pdmVyc2l0eSBvZiBPdWx1IGFuZCBPdWx1IFVuaXZlcnNpdHkgSG9z

cGl0YWwsIE91bHUsIEZpbmxhbmQ7IE1lZGljYWwgUmVzZWFyY2ggQ2VudGVyIE91bHUsIE91bHUg

VW5pdmVyc2l0eSBIb3NwaXRhbCwgT3VsdSwgRmlubGFuZDsgT3VsdSBDaXR5IEhvc3BpdGFsLCBP

dWx1LCBGaW5sYW5kLiYjeEQ7QWdpbmcgUmVzZWFyY2ggQ2VudGVyLCBLYXJvbGluc2thIEluc3Rp

dHV0ZXQtU3RvY2tob2xtIFVuaXZlcnNpdHksIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7RGVwYXJ0

bWVudCBvZiBOZXVyb2xvZ3ksIEt1b3BpbyBVbml2ZXJzaXR5IEhvc3BpdGFsLCBLdW9waW8sIEZp

bmxhbmQuJiN4RDtDaHJvbmljIERpc2Vhc2UgUHJldmVudGlvbiBVbml0LCBOYXRpb25hbCBJbnN0

aXR1dGUgZm9yIEhlYWx0aCBhbmQgV2VsZmFyZSwgSGVsc2lua2ksIEZpbmxhbmQ7IEluc3RpdHV0

ZSBvZiBQdWJsaWMgSGVhbHRoIGFuZCBDbGluaWNhbCBOdXRyaXRpb24sIFVuaXZlcnNpdHkgb2Yg

RWFzdGVybiBGaW5sYW5kLCBLdW9waW8sIEZpbmxhbmQuJiN4RDtGaW5uaXNoIEluc3RpdHV0ZSBv

ZiBPY2N1cGF0aW9uYWwgSGVhbHRoLCBIZWxzaW5raSwgRmlubGFuZC4mI3hEO1dlbGZhcmUgYW5k

IEhlYWx0aCBQcm9tb3Rpb24gVW5pdCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5k

IFdlbGZhcmUsIEhlbHNpbmtpLCBGaW5sYW5kLiYjeEQ7RGVwYXJ0bWVudCBvZiBDbGluaWNhbCBQ

aHlzaW9sb2d5IGFuZCBOdWNsZWFyIE1lZGljaW5lLCBLdW9waW8gVW5pdmVyc2l0eSBIb3NwaXRh

bCwgS3VvcGlvLCBGaW5sYW5kOyBLdW9waW8gUmVzZWFyY2ggSW5zdGl0dXRlIG9mIEV4ZXJjaXNl

IE1lZGljaW5lLCBLdW9waW8sIEZpbmxhbmQuJiN4RDtEZXBhcnRtZW50IG9mIFBzeWNob2xvZ3ks

IFVtZWEgVW5pdmVyc2l0eSwgVW1lYSwgU3dlZGVuLiYjeEQ7SW5zdGl0dXRlIG9mIEhlYWx0aCBT

Y2llbmNlcy9HZXJpYXRyaWNzLCBVbml2ZXJzaXR5IG9mIE91bHUgYW5kIE91bHUgVW5pdmVyc2l0

eSBIb3NwaXRhbCwgT3VsdSwgRmlubGFuZDsgRGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgR2VyaWF0

cmljIENsaW5pYywgVW5pdmVyc2l0eSBvZiBIZWxzaW5raSwgSGVsc2lua2kgVW5pdmVyc2l0eSBD

ZW50cmFsIEhvc3BpdGFsLCBIZWxzaW5raSwgRmlubGFuZC4mI3hEO0Nocm9uaWMgRGlzZWFzZSBQ

cmV2ZW50aW9uIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJl

LCBIZWxzaW5raSwgRmlubGFuZDsgRGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoLCBISkVMVCBJ

bnN0aXR1dGUsIFVuaXZlcnNpdHkgb2YgSGVsc2lua2ksIEhlbHNpbmtpIFVuaXZlcnNpdHkgQ2Vu

dHJhbCBIb3NwaXRhbCwgSGVsc2lua2ksIEZpbmxhbmQ7IFNvdXRoIE9zdHJvYm90aG5pYSBDZW50

cmFsIEhvc3BpdGFsLCBTZWluYWpva2ksIEZpbmxhbmQ7IENlbnRlciBmb3IgVmFzY3VsYXIgUHJl

dmVudGlvbiwgRGFudWJlLVVuaXZlcnNpdHkgS3JlbXMsIEtyZW1zLCBBdXN0cmlhOyBEaWFiZXRl

cyBSZXNlYXJjaCBHcm91cCwgS2luZyBBYmR1bGF6aXogVW5pdmVyc2l0eSwgSmVkZGFoLCBTYXVk

aSBBcmFiaWEuJiN4RDtJbnN0aXR1dGUgb2YgQ2xpbmljYWwgTWVkaWNpbmUvTmV1cm9sb2d5LCBV

bml2ZXJzaXR5IG9mIEVhc3Rlcm4gRmlubGFuZCwgS3VvcGlvLCBGaW5sYW5kOyBEZXBhcnRtZW50

IG9mIE5ldXJvbG9neSwgS3VvcGlvIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEt1b3BpbywgRmlubGFu

ZC4mI3hEO0Nocm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0

ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlubGFuZDsgS2Fyb2xpbnNrYSBJ

bnN0aXR1dGV0IENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBTdG9ja2hvbG0sIFN3ZWRl

bjsgSW5zdGl0dXRlIG9mIENsaW5pY2FsIE1lZGljaW5lL05ldXJvbG9neSwgVW5pdmVyc2l0eSBv

ZiBFYXN0ZXJuIEZpbmxhbmQsIEt1b3BpbywgRmlubGFuZDsgQWdpbmcgUmVzZWFyY2ggQ2VudGVy

LCBLYXJvbGluc2thIEluc3RpdHV0ZXQtU3RvY2tob2xtIFVuaXZlcnNpdHksIFN0b2NraG9sbSwg

U3dlZGVuLiBFbGVjdHJvbmljIGFkZHJlc3M6IG1paWEua2l2aXBlbHRvQGtpLnNlLjwvYXV0aC1h

ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkEgMiB5ZWFyIG11bHRpZG9tYWluIGludGVydmVudGlvbiBv

ZiBkaWV0LCBleGVyY2lzZSwgY29nbml0aXZlIHRyYWluaW5nLCBhbmQgdmFzY3VsYXIgcmlzayBt

b25pdG9yaW5nIHZlcnN1cyBjb250cm9sIHRvIHByZXZlbnQgY29nbml0aXZlIGRlY2xpbmUgaW4g

YXQtcmlzayBlbGRlcmx5IHBlb3BsZSAoRklOR0VSKTogYSByYW5kb21pc2VkIGNvbnRyb2xsZWQg

dHJpYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TGFuY2V0PC9zZWNvbmRhcnktdGl0bGU+PC90

aXRsZXM+PHBhZ2VzPjIyNTUtNjM8L3BhZ2VzPjx2b2x1bWU+Mzg1PC92b2x1bWU+PG51bWJlcj45

OTg0PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+Q29n

bml0aW9uIERpc29yZGVycy9lcGlkZW1pb2xvZ3kvKnByZXZlbnRpb24gJmFtcDsgY29udHJvbDwv

a2V5d29yZD48a2V5d29yZD4qRGlldDwva2V5d29yZD48a2V5d29yZD5Eb3VibGUtQmxpbmQgTWV0

aG9kPC9rZXl3b3JkPjxrZXl3b3JkPipFeGVyY2lzZTwva2V5d29yZD48a2V5d29yZD4qRXhlcmNp

c2UgVGhlcmFweTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFs

ZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5OZXVyb3Bz

eWNob2xvZ2ljYWwgVGVzdHM8L2tleXdvcmQ+PGtleXdvcmQ+UmlzayBBc3Nlc3NtZW50PC9rZXl3

b3JkPjxrZXl3b3JkPlZhc2N1bGFyIERpc2Vhc2VzLyplcGlkZW1pb2xvZ3kvcHJldmVudGlvbiAm

YW1wOyBjb250cm9sPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5KdW4gNjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0

NzQtNTQ3WCAoRWxlY3Ryb25pYykmI3hEOzAxNDAtNjczNiAoTGlua2luZyk8L2lzYm4+PGFjY2Vz

c2lvbi1udW0+MjU3NzEyNDk8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJs

Pmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjU3NzEyNDk8L3VybD48L3JlbGF0

ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvUzAxNDAtNjcz

NigxNSk2MDQ2MS01PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaXZpcGVsdG88L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFy

PjxSZWNOdW0+MzIwPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjM2LDQwMC00MDI8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4z

MjA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1

MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMTc3NTI3OCI+MzIw

PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8

L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LaXZpcGVsdG8sIE0uPC9h

dXRob3I+PGF1dGhvcj5Sb3ZpbywgUy48L2F1dGhvcj48YXV0aG9yPk5nYW5kdSwgVC48L2F1dGhv

cj48YXV0aG9yPkthcmVob2x0LCBJLjwvYXV0aG9yPjxhdXRob3I+RXNrZWxpbmVuLCBNLjwvYXV0

aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48YXV0aG9yPkhhY2hpbnNraSwgVi48L2F1

dGhvcj48YXV0aG9yPkNlZGF6by1NaW5ndWV6LCBBLjwvYXV0aG9yPjxhdXRob3I+U29pbmluZW4s

IEguPC9hdXRob3I+PGF1dGhvcj5UdW9taWxlaHRvLCBKLjwvYXV0aG9yPjxhdXRob3I+Tmlzc2lu

ZW4sIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+QWdp

bmcgUmVzZWFyY2ggQ2VudGVyLCBOVlMsIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xt

LCBTd2VkZW4uIE1paWEuS2l2aXBlbHRvQGtpLnNlPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+QXBvbGlwb3Byb3RlaW4gRSBlcHNpbG9uNCBtYWduaWZpZXMgbGlmZXN0eWxlIHJpc2tzIGZv

ciBkZW1lbnRpYTogYSBwb3B1bGF0aW9uLWJhc2VkIHN0dWR5PC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPkogQ2VsbCBNb2wgTWVkPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjI3NjIt

NzE8L3BhZ2VzPjx2b2x1bWU+MTI8L3ZvbHVtZT48bnVtYmVyPjZCPC9udW1iZXI+PGtleXdvcmRz

PjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvZ2VuZXRp

Y3M8L2tleXdvcmQ+PGtleXdvcmQ+QXBvbGlwb3Byb3RlaW4gRTQvKmdlbmV0aWNzPC9rZXl3b3Jk

PjxrZXl3b3JkPkRlbWVudGlhLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5EZW1vZ3JhcGh5

PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IZXRlcm96eWdvdGU8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPipMaWZlIFN0eWxlPC9r

ZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdv

cmQ+PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlNvY2lvZWNvbm9taWMg

RmFjdG9yczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA4PC95ZWFyPjxwdWIt

ZGF0ZXM+PGRhdGU+RGVjPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU4Mi0xODM4

IChQcmludCkmI3hEOzE1ODItMTgzOCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTgz

MTg2OTM8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTgzMTg2OTM8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGN1c3RvbTI+UE1DMzgyODg4OTwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

MTAuMTExMS9qLjE1ODItNDkzNC4yMDA4LjAwMjk2Lng8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk1hcmVuZ29uaTwvQXV0aG9yPjxZZWFyPjIw

MTg8L1llYXI+PFJlY051bT4zNTk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM1OTwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTQ4NjM0Ij4zNTk8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1hcmVuZ29uaSwgQS48L2F1dGhvcj48

YXV0aG9yPlJpenp1dG8sIEQuPC9hdXRob3I+PGF1dGhvcj5GcmF0aWdsaW9uaSwgTC48L2F1dGhv

cj48YXV0aG9yPkFudGlrYWluZW4sIFIuPC9hdXRob3I+PGF1dGhvcj5MYWF0aWthaW5lbiwgVC48

L2F1dGhvcj48YXV0aG9yPkxlaHRpc2FsbywgSi48L2F1dGhvcj48YXV0aG9yPlBlbHRvbmVuLCBN

LjwvYXV0aG9yPjxhdXRob3I+U29pbmluZW4sIEguPC9hdXRob3I+PGF1dGhvcj5TdHJhbmRiZXJn

LCBULjwvYXV0aG9yPjxhdXRob3I+VHVvbWlsZWh0bywgSi48L2F1dGhvcj48YXV0aG9yPktpdmlw

ZWx0bywgTS48L2F1dGhvcj48YXV0aG9yPk5nYW5kdSwgVC48L2F1dGhvcj48L2F1dGhvcnM+PC9j

b250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIENsaW5pY2FsIGFuZCBFeHBl

cmltZW50YWwgU2NpZW5jZXMsIFVuaXZlcnNpdHkgb2YgQnJlc2NpYSwgQnJlc2NpYSwgSXRhbHk7

IEFnaW5nIFJlc2VhcmNoIENlbnRlciwgRGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUg

U2NpZW5jZXMgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0dXRldCwgYW5kIFN0b2NraG9s

bSBVbml2ZXJzaXR5LCBTdG9ja2hvbG0sIFN3ZWRlbi4gRWxlY3Ryb25pYyBhZGRyZXNzOiBhbGVz

c2FuZHJhLm1hcmVuZ29uaUBraS5zZS4mI3hEO0FnaW5nIFJlc2VhcmNoIENlbnRlciwgRGVwYXJ0

bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIEthcm9saW5z

a2EgSW5zdGl0dXRldCwgYW5kIFN0b2NraG9sbSBVbml2ZXJzaXR5LCBTdG9ja2hvbG0sIFN3ZWRl

bi4mI3hEO0FnaW5nIFJlc2VhcmNoIENlbnRlciwgRGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ks

IENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0dXRldCwgYW5kIFN0

b2NraG9sbSBVbml2ZXJzaXR5LCBTdG9ja2hvbG0sIFN3ZWRlbjsgU3RvY2tob2xtIEdlcm9udG9s

b2d5IFJlc2VhcmNoIENlbnRlciwgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtDZW50ZXIgZm9yIExp

ZmUgQ291cnNlIEhlYWx0aCBSZXNlYXJjaC9HZXJpYXRyaWNzLCBVbml2ZXJzaXR5IG9mIE91bHUs

IE91bHUsIEZpbmxhbmQ7IE1lZGljYWwgUmVzZWFyY2ggQ2VudGVyIE91bHUsIE91bHUgVW5pdmVy

c2l0eSBIb3NwaXRhbCwgT3VsdSwgRmlubGFuZDsgT3VsdSBDaXR5IEhvc3BpdGFsLCBPdWx1LCBG

aW5sYW5kLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoIFNvbHV0aW9ucywgQ2hyb25p

YyBEaXNlYXNlIFByZXZlbnRpb24gVW5pdCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGgg

YW5kIFdlbGZhcmUsIEhlbHNpbmtpLCBGaW5sYW5kOyBJbnN0aXR1dGUgb2YgUHVibGljIEhlYWx0

aCBhbmQgQ2xpbmljYWwgTnV0cml0aW9uLCBVbml2ZXJzaXR5IG9mIEVhc3Rlcm4gRmlubGFuZCwg

S3VvcGlvLCBGaW5sYW5kOyBKb2ludCBtdW5pY2lwYWwgYXV0aG9yaXR5IGZvciBOb3J0aCBLYXJl

bGlhIHNvY2lhbCBhbmQgaGVhbHRoIHNlcnZpY2VzLCBKb2Vuc3V1LCBGaW5sYW5kLiYjeEQ7RGVw

YXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoIFNvbHV0aW9ucywgQ2hyb25pYyBEaXNlYXNlIFByZXZl

bnRpb24gVW5pdCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5kIFdlbGZhcmUsIEhl

bHNpbmtpLCBGaW5sYW5kOyBEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFsdGgsIFVuaXZlcnNpdHkg

b2YgSGVsc2lua2ksIEhlbHNpbmtpLCBGaW5sYW5kLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMg

SGVhbHRoIFNvbHV0aW9ucywgQ2hyb25pYyBEaXNlYXNlIFByZXZlbnRpb24gVW5pdCwgTmF0aW9u

YWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5kIFdlbGZhcmUsIEhlbHNpbmtpLCBGaW5sYW5kLiYj

eEQ7SW5zdGl0dXRlIG9mIENsaW5pY2FsIE1lZGljaW5lL05ldXJvbG9neSwgVW5pdmVyc2l0eSBv

ZiBFYXN0ZXJuIEZpbmxhbmQsIEt1b3BpbywgRmlubGFuZC4mI3hEO0NlbnRlciBmb3IgTGlmZSBD

b3Vyc2UgSGVhbHRoIFJlc2VhcmNoL0dlcmlhdHJpY3MsIFVuaXZlcnNpdHkgb2YgT3VsdSwgT3Vs

dSwgRmlubGFuZDsgTWVkaWNhbCBSZXNlYXJjaCBDZW50ZXIgT3VsdSwgT3VsdSBVbml2ZXJzaXR5

IEhvc3BpdGFsLCBPdWx1LCBGaW5sYW5kOyBVbml2ZXJzaXR5IG9mIEhlbHNpbmtpLCBIZWxzaW5r

aSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIZWxzaW5raSwgRmlubGFuZC4mI3hEO0RlcGFydG1lbnQg

b2YgUHVibGljIEhlYWx0aCBTb2x1dGlvbnMsIENocm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVu

aXQsIE5hdGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwg

RmlubGFuZDsgRGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoLCBVbml2ZXJzaXR5IG9mIEhlbHNp

bmtpLCBIZWxzaW5raSwgRmlubGFuZDsgU291dGggT3N0cm9ib3RobmlhIENlbnRyYWwgSG9zcGl0

YWwsIFNlaW5ham9raSwgRmlubGFuZDsgRGFzbWFuIERpYWJldGVzIEluc3RpdHV0ZSwgRGFzbWFu

LCBLdXdhaXQ7IERpYWJldGVzIFJlc2VhcmNoIEdyb3VwLCBLaW5nIEFiZHVsYXppeiBVbml2ZXJz

aXR5LCBKZWRkYWgsIFNhdWRpIEFyYWJpYS4mI3hEO0FnaW5nIFJlc2VhcmNoIENlbnRlciwgRGVw

YXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIEthcm9s

aW5za2EgSW5zdGl0dXRldCwgYW5kIFN0b2NraG9sbSBVbml2ZXJzaXR5LCBTdG9ja2hvbG0sIFN3

ZWRlbjsgRGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoIFNvbHV0aW9ucywgQ2hyb25pYyBEaXNl

YXNlIFByZXZlbnRpb24gVW5pdCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5kIFdl

bGZhcmUsIEhlbHNpbmtpLCBGaW5sYW5kOyBJbnN0aXR1dGUgb2YgQ2xpbmljYWwgTWVkaWNpbmUv

TmV1cm9sb2d5LCBVbml2ZXJzaXR5IG9mIEVhc3Rlcm4gRmlubGFuZCwgS3VvcGlvLCBGaW5sYW5k

OyBEaXZpc2lvbiBvZiBDbGluaWNhbCBHZXJpYXRyaWNzLCBDZW50ZXIgZm9yIEFsemhlaW1lciBS

ZXNlYXJjaCwgRGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNv

Y2lldHksIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW47IFN0b2NraG9s

bXMgU2p1a2hlbSwgUmVzZWFyY2ggJmFtcDsgRGV2ZWxvcG1lbnQgdW5pdCwgU3RvY2tob2xtLCBT

d2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFsdGggU29sdXRpb25zLCBDaHJvbmlj

IERpc2Vhc2UgUHJldmVudGlvbiBVbml0LCBOYXRpb25hbCBJbnN0aXR1dGUgZm9yIEhlYWx0aCBh

bmQgV2VsZmFyZSwgSGVsc2lua2ksIEZpbmxhbmQ7IERpdmlzaW9uIG9mIENsaW5pY2FsIEdlcmlh

dHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5ldXJv

YmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0

LCBTdG9ja2hvbG0sIFN3ZWRlbi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5UaGUgRWZm

ZWN0IG9mIGEgMi1ZZWFyIEludGVydmVudGlvbiBDb25zaXN0aW5nIG9mIERpZXQsIFBoeXNpY2Fs

IEV4ZXJjaXNlLCBDb2duaXRpdmUgVHJhaW5pbmcsIGFuZCBNb25pdG9yaW5nIG9mIFZhc2N1bGFy

IFJpc2sgb24gQ2hyb25pYyBNb3JiaWRpdHktdGhlIEZJTkdFUiBSYW5kb21pemVkIENvbnRyb2xs

ZWQgVHJpYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBBbSBNZWQgRGlyIEFzc29jPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjM1NS0zNjAgZTE8L3BhZ2VzPjx2b2x1bWU+MTk8

L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+RGlldDwva2V5d29y

ZD48a2V5d29yZD5jaHJvbmljIG1vcmJpZGl0eTwva2V5d29yZD48a2V5d29yZD5jb2duaXRpdmUg

dHJhaW5pbmc8L2tleXdvcmQ+PGtleXdvcmQ+cGh5c2ljYWwgZXhlcmNpc2U8L2tleXdvcmQ+PGtl

eXdvcmQ+cmFuZG9taXplZCBjbGluaWNhbCB0cmlhbDwva2V5d29yZD48a2V5d29yZD52YXNjdWxh

ciByaXNrPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1k

YXRlcz48ZGF0ZT5BcHI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTM4LTkzNzUg

KEVsZWN0cm9uaWMpJiN4RDsxNTI1LTg2MTAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVt

PjI5MTA4ODg4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8v

d3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI5MTA4ODg4PC91cmw+PC9yZWxhdGVkLXVybHM+

PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ouamFtZGEuMjAxNy4wOS4w

MjA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9y

PlJvc2VuYmVyZzwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJlY051bT4zNjA8L1JlY051bT48

cmVjb3JkPjxyZWMtbnVtYmVyPjM2MDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0

YW1wPSIxNTMyNTQ4NjM0Ij4zNjA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPlJvc2VuYmVyZywgQS48L2F1dGhvcj48YXV0aG9yPk5nYW5kdSwgVC48L2F1dGhvcj48YXV0

aG9yPlJ1c2FuZW4sIE0uPC9hdXRob3I+PGF1dGhvcj5BbnRpa2FpbmVuLCBSLjwvYXV0aG9yPjxh

dXRob3I+QmFja21hbiwgTC48L2F1dGhvcj48YXV0aG9yPkhhdnVsaW5uYSwgUy48L2F1dGhvcj48

YXV0aG9yPkhhbm5pbmVuLCBULjwvYXV0aG9yPjxhdXRob3I+TGFhdGlrYWluZW4sIFQuPC9hdXRo

b3I+PGF1dGhvcj5MZWh0aXNhbG8sIEouPC9hdXRob3I+PGF1dGhvcj5MZXZhbGFodGksIEUuPC9h

dXRob3I+PGF1dGhvcj5MaW5kc3Ryb20sIEouPC9hdXRob3I+PGF1dGhvcj5QYWFqYW5lbiwgVC48

L2F1dGhvcj48YXV0aG9yPlBlbHRvbmVuLCBNLjwvYXV0aG9yPjxhdXRob3I+U29pbmluZW4sIEgu

PC9hdXRob3I+PGF1dGhvcj5TdGlnc2RvdHRlci1OZWVseSwgQS48L2F1dGhvcj48YXV0aG9yPlN0

cmFuZGJlcmcsIFQuPC9hdXRob3I+PGF1dGhvcj5UdW9taWxlaHRvLCBKLjwvYXV0aG9yPjxhdXRo

b3I+U29sb21vbiwgQS48L2F1dGhvcj48YXV0aG9yPktpdmlwZWx0bywgTS48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5JbnN0aXR1dGUgb2YgQ2xpbmljYWwg

TWVkaWNpbmUsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IG9mIEVhc3Rlcm4g

RmlubGFuZCwgS3VvcGlvLCBGaW5sYW5kLiBFbGVjdHJvbmljIGFkZHJlc3M6IGFubmEucm9zZW5i

ZXJnQHVlZi5maS4mI3hEO0RlcGFydG1lbnQgb2YgUHVibGljIEhlYWx0aCBTb2x1dGlvbnMsIENo

cm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVh

bHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlubGFuZDsgRGl2aXNpb24gb2YgQ2xpbmljYWwg

R2VyaWF0cmljcywgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIE5WUywgS2Fyb2xpbnNr

YSBJbnN0aXR1dGV0LCBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0RlcGFydG1lbnQgb2YgUHVibGlj

IEhlYWx0aCBTb2x1dGlvbnMsIENocm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQsIE5hdGlv

bmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlubGFuZDsg

RGl2aXNpb24gb2YgQ2xpbmljYWwgR2VyaWF0cmljcywgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVz

ZWFyY2gsIE5WUywgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBTdG9ja2hvbG0sIFN3ZWRlbjsgRGVw

YXJ0bWVudCBvZiBOZXVyb2xvZ3ksIE5vcnRoIEthcmVsaWEgQ2VudHJhbCBIb3NwaXRhbCwgSm9l

bnN1dSwgRmlubGFuZC4mI3hEO0NlbnRlciBmb3IgTGlmZSBDb3Vyc2UgSGVhbHRoIFJlc2VhcmNo

L0dlcmlhdHJpY3MsIFVuaXZlcnNpdHkgb2YgT3VsdSwgT3VsdSwgRmlubGFuZDsgTWVkaWNhbCBS

ZXNlYXJjaCBDZW50ZXIgT3VsdSwgT3VsdSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBPdWx1LCBGaW5s

YW5kOyBPdWx1IENpdHkgSG9zcGl0YWwsIE91bHUsIEZpbmxhbmQuJiN4RDtBZ2luZyBSZXNlYXJj

aCBDZW50ZXIsIEthcm9saW5za2EgSW5zdGl0dXRldC1TdG9ja2hvbG0gVW5pdmVyc2l0eSwgU3Rv

Y2tob2xtLCBTd2VkZW4uJiN4RDtBZ2luZywgRGlzYWJpbGl0eSBhbmQgRnVuY3Rpb25pbmcgVW5p

dCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5kIFdlbGZhcmUsIEhlbHNpbmtpLCBG

aW5sYW5kLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIEt1b3BpbyBVbml2ZXJzaXR5IEhv

c3BpdGFsLCBLdW9waW8sIEZpbmxhbmQuJiN4RDtEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFsdGgg

U29sdXRpb25zLCBDaHJvbmljIERpc2Vhc2UgUHJldmVudGlvbiBVbml0LCBOYXRpb25hbCBJbnN0

aXR1dGUgZm9yIEhlYWx0aCBhbmQgV2VsZmFyZSwgSGVsc2lua2ksIEZpbmxhbmQ7IEluc3RpdHV0

ZSBvZiBQdWJsaWMgSGVhbHRoIGFuZCBDbGluaWNhbCBOdXRyaXRpb24sIFVuaXZlcnNpdHkgb2Yg

RWFzdGVybiBGaW5sYW5kLCBLdW9waW8sIEZpbmxhbmQ7IEpvaW50IG11bmljaXBhbCBhdXRob3Jp

dHkgZm9yIE5vcnRoIEthcmVsaWEgU29jaWFsIGFuZCBIZWFsdGggc2VydmljZXMsIEpvZW5zdXUs

IEZpbmxhbmQuJiN4RDtEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFsdGggU29sdXRpb25zLCBDaHJv

bmljIERpc2Vhc2UgUHJldmVudGlvbiBVbml0LCBOYXRpb25hbCBJbnN0aXR1dGUgZm9yIEhlYWx0

aCBhbmQgV2VsZmFyZSwgSGVsc2lua2ksIEZpbmxhbmQ7IERlcGFydG1lbnQgb2YgUHVibGljIEhl

YWx0aCwgVW5pdmVyc2l0eSBvZiBIZWxzaW5raSwgSGVsc2lua2ksIEZpbmxhbmQuJiN4RDtEZXBh

cnRtZW50IG9mIFB1YmxpYyBIZWFsdGggU29sdXRpb25zLCBDaHJvbmljIERpc2Vhc2UgUHJldmVu

dGlvbiBVbml0LCBOYXRpb25hbCBJbnN0aXR1dGUgZm9yIEhlYWx0aCBhbmQgV2VsZmFyZSwgSGVs

c2lua2ksIEZpbmxhbmQuJiN4RDtGaW5uaXNoIEluc3RpdHV0ZSBvZiBPY2N1cGF0aW9uYWwgSGVh

bHRoLCBIZWxzaW5raSwgRmlubGFuZC4mI3hEO0luc3RpdHV0ZSBvZiBDbGluaWNhbCBNZWRpY2lu

ZSwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIFVuaXZlcnNpdHkgb2YgRWFzdGVybiBGaW5sYW5k

LCBLdW9waW8sIEZpbmxhbmQ7IE5ldXJvY2VudGVyLCBOZXVyb2xvZ3ksIEt1b3BpbyBVbml2ZXJz

aXR5IEhvc3BpdGFsLCBLdW9waW8sIEZpbmxhbmQuJiN4RDtEZXBhcnRtZW50IG9mIFBzeWNob2xv

Z3ksIFVtZWEgVW5pdmVyc2l0eSwgVW1lYSwgU3dlZGVuOyBEZXBhcnRtZW50IG9mIFNvY2lhbCBh

bmQgUHN5Y2hvbG9naWNhbCBTY2llbmNlcywgS2FybHN0YWQgVW5pdmVyc2l0eSwgS2FybHN0YWQs

IFN3ZWRlbi4mI3hEO0NlbnRlciBmb3IgTGlmZSBDb3Vyc2UgSGVhbHRoIFJlc2VhcmNoL0dlcmlh

dHJpY3MsIFVuaXZlcnNpdHkgb2YgT3VsdSwgT3VsdSwgRmlubGFuZDsgTWVkaWNhbCBSZXNlYXJj

aCBDZW50ZXIgT3VsdSwgT3VsdSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBPdWx1LCBGaW5sYW5kOyBV

bml2ZXJzaXR5IG9mIEhlbHNpbmtpLCBIZWxzaW5raSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIZWxz

aW5raSwgRmlubGFuZC4mI3hEO0RlcGFydG1lbnQgb2YgUHVibGljIEhlYWx0aCBTb2x1dGlvbnMs

IENocm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0ZSBmb3Ig

SGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlubGFuZDsgRGVwYXJ0bWVudCBvZiBQdWJs

aWMgSGVhbHRoLCBVbml2ZXJzaXR5IG9mIEhlbHNpbmtpLCBIZWxzaW5raSwgRmlubGFuZDsgU291

dGggT3N0cm9ib3RobmlhIENlbnRyYWwgSG9zcGl0YWwsIFNlaW5ham9raSwgRmlubGFuZC4mI3hE

O0luc3RpdHV0ZSBvZiBDbGluaWNhbCBNZWRpY2luZSwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ks

IFVuaXZlcnNpdHkgb2YgRWFzdGVybiBGaW5sYW5kLCBLdW9waW8sIEZpbmxhbmQ7IERpdmlzaW9u

IG9mIENsaW5pY2FsIEdlcmlhdHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBO

VlMsIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW47IEFnaW5nIFJlc2Vh

cmNoIENlbnRlciwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LVN0b2NraG9sbSBVbml2ZXJzaXR5LCBT

dG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0luc3RpdHV0ZSBvZiBDbGluaWNhbCBNZWRpY2luZSwgRGVw

YXJ0bWVudCBvZiBOZXVyb2xvZ3ksIFVuaXZlcnNpdHkgb2YgRWFzdGVybiBGaW5sYW5kLCBLdW9w

aW8sIEZpbmxhbmQ7IERlcGFydG1lbnQgb2YgUHVibGljIEhlYWx0aCBTb2x1dGlvbnMsIENocm9u

aWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRo

IGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlubGFuZDsgRGl2aXNpb24gb2YgQ2xpbmljYWwgR2Vy

aWF0cmljcywgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIE5WUywgS2Fyb2xpbnNrYSBJ

bnN0aXR1dGV0LCBTdG9ja2hvbG0sIFN3ZWRlbjsgQWdpbmcgUmVzZWFyY2ggQ2VudGVyLCBLYXJv

bGluc2thIEluc3RpdHV0ZXQtU3RvY2tob2xtIFVuaXZlcnNpdHksIFN0b2NraG9sbSwgU3dlZGVu

OyBTdG9ja2hvbG1zIFNqdWtoZW0sIFJlc2VhcmNoICZhbXA7IERldmVsb3BtZW50IFVuaXQsIFN0

b2NraG9sbSwgU3dlZGVuLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPk11bHRpZG9tYWlu

IGxpZmVzdHlsZSBpbnRlcnZlbnRpb24gYmVuZWZpdHMgYSBsYXJnZSBlbGRlcmx5IHBvcHVsYXRp

b24gYXQgcmlzayBmb3IgY29nbml0aXZlIGRlY2xpbmUgYW5kIGRlbWVudGlhIHJlZ2FyZGxlc3Mg

b2YgYmFzZWxpbmUgY2hhcmFjdGVyaXN0aWNzOiBUaGUgRklOR0VSIHRyaWFsPC90aXRsZT48c2Vj

b25kYXJ5LXRpdGxlPkFsemhlaW1lcnMgRGVtZW50PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBhZ2VzPjI2My0yNzA8L3BhZ2VzPjx2b2x1bWU+MTQ8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJl

cj48a2V5d29yZHM+PGtleXdvcmQ+KkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48

a2V5d29yZD4qQ29nbml0aXZlIGltcGFpcm1lbnQ8L2tleXdvcmQ+PGtleXdvcmQ+KkRlbWVudGlh

PC9rZXl3b3JkPjxrZXl3b3JkPipJbnRlcnZlbnRpb248L2tleXdvcmQ+PGtleXdvcmQ+KkxpZmVz

dHlsZTwva2V5d29yZD48a2V5d29yZD4qTXVsdGlkb21haW48L2tleXdvcmQ+PGtleXdvcmQ+KlBy

ZXZlbnRpb248L2tleXdvcmQ+PGtleXdvcmQ+KlJhbmRvbWl6ZWQgY29udHJvbGxlZCB0cmlhbDwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+TWFyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU1Mi01Mjc5IChFbGVjdHJv

bmljKSYjeEQ7MTU1Mi01MjYwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yOTA1NTgx

NDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3B1Ym1lZC8yOTA1NTgxNDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmphbHouMjAxNy4wOS4wMDY8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk5nYW5kdTwv

QXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJlY051bT4zNjU8L1JlY051bT48cmVjb3JkPjxyZWMt

bnVtYmVyPjM2NTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9

ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTQ4

NjM0Ij4zNjU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRp

Y2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk5nYW5kdSwg

VC48L2F1dGhvcj48YXV0aG9yPkxlaHRpc2FsbywgSi48L2F1dGhvcj48YXV0aG9yPlNvbG9tb24s

IEEuPC9hdXRob3I+PGF1dGhvcj5MZXZhbGFodGksIEUuPC9hdXRob3I+PGF1dGhvcj5BaHRpbHVv

dG8sIFMuPC9hdXRob3I+PGF1dGhvcj5BbnRpa2FpbmVuLCBSLjwvYXV0aG9yPjxhdXRob3I+QmFj

a21hbiwgTC48L2F1dGhvcj48YXV0aG9yPkhhbm5pbmVuLCBULjwvYXV0aG9yPjxhdXRob3I+SnVs

YSwgQS48L2F1dGhvcj48YXV0aG9yPkxhYXRpa2FpbmVuLCBULjwvYXV0aG9yPjxhdXRob3I+TGlu

ZHN0cm9tLCBKLjwvYXV0aG9yPjxhdXRob3I+TWFuZ2lhbGFzY2hlLCBGLjwvYXV0aG9yPjxhdXRo

b3I+UGFhamFuZW4sIFQuPC9hdXRob3I+PGF1dGhvcj5QYWphbGEsIFMuPC9hdXRob3I+PGF1dGhv

cj5QZWx0b25lbiwgTS48L2F1dGhvcj48YXV0aG9yPlJhdXJhbWFhLCBSLjwvYXV0aG9yPjxhdXRo

b3I+U3RpZ3Nkb3R0ZXItTmVlbHksIEEuPC9hdXRob3I+PGF1dGhvcj5TdHJhbmRiZXJnLCBULjwv

YXV0aG9yPjxhdXRob3I+VHVvbWlsZWh0bywgSi48L2F1dGhvcj48YXV0aG9yPlNvaW5pbmVuLCBI

LjwvYXV0aG9yPjxhdXRob3I+S2l2aXBlbHRvLCBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy

aWJ1dG9ycz48YXV0aC1hZGRyZXNzPkNocm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQsIE5h

dGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlubGFu

ZDsgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0IENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBT

dG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0Nocm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQsIE5h

dGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlubGFu

ZC4mI3hEO0thcm9saW5za2EgSW5zdGl0dXRldCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJj

aCwgU3RvY2tob2xtLCBTd2VkZW47IEluc3RpdHV0ZSBvZiBDbGluaWNhbCBNZWRpY2luZS9OZXVy

b2xvZ3ksIFVuaXZlcnNpdHkgb2YgRWFzdGVybiBGaW5sYW5kLCBLdW9waW8sIEZpbmxhbmQ7IEFn

aW5nIFJlc2VhcmNoIENlbnRlciwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LVN0b2NraG9sbSBVbml2

ZXJzaXR5LCBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0luc3RpdHV0ZSBvZiBIZWFsdGggU2NpZW5j

ZXMvR2VyaWF0cmljcywgVW5pdmVyc2l0eSBvZiBPdWx1IGFuZCBPdWx1IFVuaXZlcnNpdHkgSG9z

cGl0YWwsIE91bHUsIEZpbmxhbmQ7IE1lZGljYWwgUmVzZWFyY2ggQ2VudGVyIE91bHUsIE91bHUg

VW5pdmVyc2l0eSBIb3NwaXRhbCwgT3VsdSwgRmlubGFuZDsgT3VsdSBDaXR5IEhvc3BpdGFsLCBP

dWx1LCBGaW5sYW5kLiYjeEQ7QWdpbmcgUmVzZWFyY2ggQ2VudGVyLCBLYXJvbGluc2thIEluc3Rp

dHV0ZXQtU3RvY2tob2xtIFVuaXZlcnNpdHksIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7RGVwYXJ0

bWVudCBvZiBOZXVyb2xvZ3ksIEt1b3BpbyBVbml2ZXJzaXR5IEhvc3BpdGFsLCBLdW9waW8sIEZp

bmxhbmQuJiN4RDtDaHJvbmljIERpc2Vhc2UgUHJldmVudGlvbiBVbml0LCBOYXRpb25hbCBJbnN0

aXR1dGUgZm9yIEhlYWx0aCBhbmQgV2VsZmFyZSwgSGVsc2lua2ksIEZpbmxhbmQ7IEluc3RpdHV0

ZSBvZiBQdWJsaWMgSGVhbHRoIGFuZCBDbGluaWNhbCBOdXRyaXRpb24sIFVuaXZlcnNpdHkgb2Yg

RWFzdGVybiBGaW5sYW5kLCBLdW9waW8sIEZpbmxhbmQuJiN4RDtGaW5uaXNoIEluc3RpdHV0ZSBv

ZiBPY2N1cGF0aW9uYWwgSGVhbHRoLCBIZWxzaW5raSwgRmlubGFuZC4mI3hEO1dlbGZhcmUgYW5k

IEhlYWx0aCBQcm9tb3Rpb24gVW5pdCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5k

IFdlbGZhcmUsIEhlbHNpbmtpLCBGaW5sYW5kLiYjeEQ7RGVwYXJ0bWVudCBvZiBDbGluaWNhbCBQ

aHlzaW9sb2d5IGFuZCBOdWNsZWFyIE1lZGljaW5lLCBLdW9waW8gVW5pdmVyc2l0eSBIb3NwaXRh

bCwgS3VvcGlvLCBGaW5sYW5kOyBLdW9waW8gUmVzZWFyY2ggSW5zdGl0dXRlIG9mIEV4ZXJjaXNl

IE1lZGljaW5lLCBLdW9waW8sIEZpbmxhbmQuJiN4RDtEZXBhcnRtZW50IG9mIFBzeWNob2xvZ3ks

IFVtZWEgVW5pdmVyc2l0eSwgVW1lYSwgU3dlZGVuLiYjeEQ7SW5zdGl0dXRlIG9mIEhlYWx0aCBT

Y2llbmNlcy9HZXJpYXRyaWNzLCBVbml2ZXJzaXR5IG9mIE91bHUgYW5kIE91bHUgVW5pdmVyc2l0

eSBIb3NwaXRhbCwgT3VsdSwgRmlubGFuZDsgRGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgR2VyaWF0

cmljIENsaW5pYywgVW5pdmVyc2l0eSBvZiBIZWxzaW5raSwgSGVsc2lua2kgVW5pdmVyc2l0eSBD

ZW50cmFsIEhvc3BpdGFsLCBIZWxzaW5raSwgRmlubGFuZC4mI3hEO0Nocm9uaWMgRGlzZWFzZSBQ

cmV2ZW50aW9uIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJl

LCBIZWxzaW5raSwgRmlubGFuZDsgRGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoLCBISkVMVCBJ

bnN0aXR1dGUsIFVuaXZlcnNpdHkgb2YgSGVsc2lua2ksIEhlbHNpbmtpIFVuaXZlcnNpdHkgQ2Vu

dHJhbCBIb3NwaXRhbCwgSGVsc2lua2ksIEZpbmxhbmQ7IFNvdXRoIE9zdHJvYm90aG5pYSBDZW50

cmFsIEhvc3BpdGFsLCBTZWluYWpva2ksIEZpbmxhbmQ7IENlbnRlciBmb3IgVmFzY3VsYXIgUHJl

dmVudGlvbiwgRGFudWJlLVVuaXZlcnNpdHkgS3JlbXMsIEtyZW1zLCBBdXN0cmlhOyBEaWFiZXRl

cyBSZXNlYXJjaCBHcm91cCwgS2luZyBBYmR1bGF6aXogVW5pdmVyc2l0eSwgSmVkZGFoLCBTYXVk

aSBBcmFiaWEuJiN4RDtJbnN0aXR1dGUgb2YgQ2xpbmljYWwgTWVkaWNpbmUvTmV1cm9sb2d5LCBV

bml2ZXJzaXR5IG9mIEVhc3Rlcm4gRmlubGFuZCwgS3VvcGlvLCBGaW5sYW5kOyBEZXBhcnRtZW50

IG9mIE5ldXJvbG9neSwgS3VvcGlvIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEt1b3BpbywgRmlubGFu

ZC4mI3hEO0Nocm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0

ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlubGFuZDsgS2Fyb2xpbnNrYSBJ

bnN0aXR1dGV0IENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBTdG9ja2hvbG0sIFN3ZWRl

bjsgSW5zdGl0dXRlIG9mIENsaW5pY2FsIE1lZGljaW5lL05ldXJvbG9neSwgVW5pdmVyc2l0eSBv

ZiBFYXN0ZXJuIEZpbmxhbmQsIEt1b3BpbywgRmlubGFuZDsgQWdpbmcgUmVzZWFyY2ggQ2VudGVy

LCBLYXJvbGluc2thIEluc3RpdHV0ZXQtU3RvY2tob2xtIFVuaXZlcnNpdHksIFN0b2NraG9sbSwg

U3dlZGVuLiBFbGVjdHJvbmljIGFkZHJlc3M6IG1paWEua2l2aXBlbHRvQGtpLnNlLjwvYXV0aC1h

ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkEgMiB5ZWFyIG11bHRpZG9tYWluIGludGVydmVudGlvbiBv

ZiBkaWV0LCBleGVyY2lzZSwgY29nbml0aXZlIHRyYWluaW5nLCBhbmQgdmFzY3VsYXIgcmlzayBt

b25pdG9yaW5nIHZlcnN1cyBjb250cm9sIHRvIHByZXZlbnQgY29nbml0aXZlIGRlY2xpbmUgaW4g

YXQtcmlzayBlbGRlcmx5IHBlb3BsZSAoRklOR0VSKTogYSByYW5kb21pc2VkIGNvbnRyb2xsZWQg

dHJpYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TGFuY2V0PC9zZWNvbmRhcnktdGl0bGU+PC90

aXRsZXM+PHBhZ2VzPjIyNTUtNjM8L3BhZ2VzPjx2b2x1bWU+Mzg1PC92b2x1bWU+PG51bWJlcj45

OTg0PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+Q29n

bml0aW9uIERpc29yZGVycy9lcGlkZW1pb2xvZ3kvKnByZXZlbnRpb24gJmFtcDsgY29udHJvbDwv

a2V5d29yZD48a2V5d29yZD4qRGlldDwva2V5d29yZD48a2V5d29yZD5Eb3VibGUtQmxpbmQgTWV0

aG9kPC9rZXl3b3JkPjxrZXl3b3JkPipFeGVyY2lzZTwva2V5d29yZD48a2V5d29yZD4qRXhlcmNp

c2UgVGhlcmFweTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFs

ZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5OZXVyb3Bz

eWNob2xvZ2ljYWwgVGVzdHM8L2tleXdvcmQ+PGtleXdvcmQ+UmlzayBBc3Nlc3NtZW50PC9rZXl3

b3JkPjxrZXl3b3JkPlZhc2N1bGFyIERpc2Vhc2VzLyplcGlkZW1pb2xvZ3kvcHJldmVudGlvbiAm

YW1wOyBjb250cm9sPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5KdW4gNjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0

NzQtNTQ3WCAoRWxlY3Ryb25pYykmI3hEOzAxNDAtNjczNiAoTGlua2luZyk8L2lzYm4+PGFjY2Vz

c2lvbi1udW0+MjU3NzEyNDk8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJs

Pmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjU3NzEyNDk8L3VybD48L3JlbGF0

ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvUzAxNDAtNjcz

NigxNSk2MDQ2MS01PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPgB=

ADDIN EN.CITE.DATA 236,400-402, more evidence points out that AD is a heterogeneous disease and might not be caused by a single entity or even by a reduced number of entities PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJkeTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl

Y051bT4yODM8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4y

NCw0Niw0MDMtNDA1PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mjgz

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzMiPjI4Mzwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SGFyZHksIEouPC9hdXRob3I+

PGF1dGhvcj5Cb2dkYW5vdmljLCBOLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhv

cj48YXV0aG9yPlBvcnRlbGl1cywgRS48L2F1dGhvcj48YXV0aG9yPkFuZHJlYXNlbiwgTi48L2F1

dGhvcj48YXV0aG9yPkNlZGF6by1NaW5ndWV6LCBBLjwvYXV0aG9yPjxhdXRob3I+WmV0dGVyYmVy

ZywgSC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+UGF0

aHdheXMgdG8gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PkogSW50ZXJuIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxs

LXRpdGxlPkogSW50ZXJuIE1lZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjI5Ni0z

MDM8L3BhZ2VzPjx2b2x1bWU+Mjc1PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGtleXdvcmRz

PjxrZXl3b3JkPipBbHpoZWltZXIgRGlzZWFzZS9nZW5ldGljcy9tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPipBbXlsb2lkL2dlbmV0aWNzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZCBiZXRhLVBlcHRpZGVzLyphbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzPC9rZXl3

b3JkPjxrZXl3b3JkPkJyYWluL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+RWFybHkgTWVk

aWNhbCBJbnRlcnZlbnRpb248L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXRpYyBQcmVkaXNwb3NpdGlv

biB0byBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5J

bW11bm90aGVyYXB5L21ldGhvZHM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAx

NDwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1hcjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxp

c2JuPjEzNjUtMjc5NiAoRWxlY3Ryb25pYykmI3hEOzA5NTQtNjgyMCAoTGlua2luZyk8L2lzYm4+

PGFjY2Vzc2lvbi1udW0+MjQ3NDkxNzM8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJs

cz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjQ3NDkxNzM8L3VybD48

dXJsPmh0dHBzOi8vb25saW5lbGlicmFyeS53aWxleS5jb20vZG9pL3BkZi8xMC4xMTExL2pvaW0u

MTIxOTI8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjEwLjExMTEvam9pbS4xMjE5MjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9D

aXRlPjxDaXRlPjxBdXRob3I+TWVkaW5hPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48UmVjTnVt

PjI2MDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MjYwPC9yZWMtbnVtYmVyPjxmb3JlaWdu

LWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpw

cnB0NWF2IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzEiPjI2MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxy

ZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3Jz

PjxhdXRob3JzPjxhdXRob3I+TWVkaW5hLCBNLjwvYXV0aG9yPjxhdXRob3I+S2hhY2hhdHVyaWFu

LCBaLiBTLjwvYXV0aG9yPjxhdXRob3I+Um9zc29yLCBNLjwvYXV0aG9yPjxhdXRob3I+QXZpbGEs

IEouPC9hdXRob3I+PGF1dGhvcj5DZWRhem8tTWluZ3VleiwgQS48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DSUJFUk5FRCAoTmV0d29yayBDZW50ZXIgZm9y

IEJpb21lZGljYWwgUmVzZWFyY2ggaW4gTmV1cm9kZWdlbmVyYXRpdmUgRGlzZWFzZXMpLCBJU0NJ

SUksIE1hZHJpZCwgU3BhaW4uJiN4RDtDSUVOIEZvdW5kYXRpb24sIFJlaW5hIFNvZmlhIEZvdW5k

YXRpb24gQWx6aGVpbWVyIENlbnRlciwgTWFkcmlkLCBTcGFpbi4mI3hEO1BBRDIwMjAsIFBvdG9t

YWMsIE1ELCBVU0EuJiN4RDtJbnN0aXR1dGUgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IENvbGxl

Z2UgTG9uZG9uLCBMb25kb24sIFVLLiYjeEQ7TmV1cm9iaW9sb2d5IExhYm9yYXRvcnksIENlbnRl

ciBmb3IgTW9sZWN1bGFyIEJpb2xvZ3kgJnF1b3Q7U2V2ZXJvIE9jaG9hJnF1b3Q7IENTSUMtVUFN

LCBNYWRyaWQsIFNwYWluLiYjeEQ7RGl2aXNpb24gb2YgTmV1cm9nZXJpYXRyaWNzLCBEZXBhcnRt

ZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgQ2VudGVyIGZv

ciBBbHpoZWltZXIgUmVzZWFyY2gsIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBT

d2VkZW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VG93YXJkIGNvbW1vbiBtZWNoYW5p

c21zIGZvciByaXNrIGZhY3RvcnMgaW4gQWx6aGVpbWVyJmFwb3M7cyBzeW5kcm9tZTwvdGl0bGU+

PHNlY29uZGFyeS10aXRsZT5BbHpoZWltZXJzIERlbWVudCAoTiBZKTwvc2Vjb25kYXJ5LXRpdGxl

PjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFsemhlaW1lcnMgRGVtZW50IChOIFkp

PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NTcxLTU3ODwvcGFnZXM+PHZvbHVtZT4z

PC92b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciZh

cG9zO3M8L2tleXdvcmQ+PGtleXdvcmQ+RGVtZW50aWE8L2tleXdvcmQ+PGtleXdvcmQ+UGF0aG9n

ZW5lc2lzPC9rZXl3b3JkPjxrZXl3b3JkPlByZXZlbnRpb248L2tleXdvcmQ+PGtleXdvcmQ+Umlz

ayBmYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlN5bmRyb21lPC9rZXl3b3JkPjwva2V5d29yZHM+

PGRhdGVzPjx5ZWFyPjIwMTc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5Ob3Y8L2RhdGU+PC9wdWIt

ZGF0ZXM+PC9kYXRlcz48aXNibj4yMzUyLTg3MzcgKEVsZWN0cm9uaWMpJiN4RDsyMzUyLTg3Mzcg

KExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5MTI0MTE2PC9hY2Nlc3Npb24tbnVtPjx1

cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVk

LzI5MTI0MTE2PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzU2NzE2Mjg8

L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai50cmNpLjIwMTcuMDgu

MDA5PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhv

cj5IYXJkeTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJlY051bT4yODM8L1JlY051bT48cmVj

b3JkPjxyZWMtbnVtYmVyPjI4MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1w

PSIxNTMxNzc1MjczIj4yODM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PkhhcmR5LCBKLjwvYXV0aG9yPjxhdXRob3I+Qm9nZGFub3ZpYywgTi48L2F1dGhvcj48YXV0aG9y

PldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5Qb3J0ZWxpdXMsIEUuPC9hdXRob3I+PGF1dGhv

cj5BbmRyZWFzZW4sIE4uPC9hdXRob3I+PGF1dGhvcj5DZWRhem8tTWluZ3VleiwgQS48L2F1dGhv

cj48YXV0aG9yPlpldHRlcmJlcmcsIEguPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

Pjx0aXRsZXM+PHRpdGxlPlBhdGh3YXlzIHRvIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5KIEludGVybiBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxl

cz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIEludGVybiBNZWQ8L2Z1bGwtdGl0bGU+PC9wZXJp

b2RpY2FsPjxwYWdlcz4yOTYtMzAzPC9wYWdlcz48dm9sdW1lPjI3NTwvdm9sdW1lPjxudW1iZXI+

MzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD4qQWx6aGVpbWVyIERpc2Vhc2UvZ2VuZXRpY3Mv

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD4qQW15bG9pZC9nZW5ldGljcy9tZXRhYm9saXNt

PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy8qYW50YWdvbmlzdHMgJmFt

cDsgaW5oaWJpdG9yczwva2V5d29yZD48a2V5d29yZD5CcmFpbi9tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPkVhcmx5IE1lZGljYWwgSW50ZXJ2ZW50aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkdl

bmV0aWMgUHJlZGlzcG9zaXRpb24gdG8gRGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8

L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vdGhlcmFweS9tZXRob2RzPC9rZXl3b3JkPjwva2V5d29y

ZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXI8L2RhdGU+PC9w

dWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMzY1LTI3OTYgKEVsZWN0cm9uaWMpJiN4RDswOTU0LTY4

MjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI0NzQ5MTczPC9hY2Nlc3Npb24tbnVt

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVi

bWVkLzI0NzQ5MTczPC91cmw+PHVybD5odHRwczovL29ubGluZWxpYnJhcnkud2lsZXkuY29tL2Rv

aS9wZGYvMTAuMTExMS9qb2ltLjEyMTkyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVj

dHJvbmljLXJlc291cmNlLW51bT4xMC4xMTExL2pvaW0uMTIxOTI8L2VsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPktpdmlwZWx0bzwvQXV0aG9yPjxZ

ZWFyPjIwMTQ8L1llYXI+PFJlY051bT4zNDI8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM0

MjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUy

cHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTQ4NTk0Ij4zNDI8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPktpdmlwZWx0bywgTS48L2F1

dGhvcj48YXV0aG9yPk1hbmdpYWxhc2NoZSwgRi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli

dXRvcnM+PGF1dGgtYWRkcmVzcz5LYXJvbGluc2thIEluc3RpdHV0ZXQgQ2VudGVyIGZvciBBbHpo

ZWltZXIgUmVzZWFyY2gsIE5vdnVtIEZsb29yIDUsIFNFLTE0MSA1NyBIdWRkaW5nZSwgU3dlZGVu

LiYjeEQ7QWdpbmcgUmVzZWFyY2ggQ2VudGVyLCBLYXJvbGluc2thIEluc3RpdHV0ZXQtU3RvY2to

b2xtIFVuaXZlcnNpdHksIEdhdmxlZ2F0YW4gMTYsIFNFLTExMyAzMCBTdG9ja2hvbG0sIFN3ZWRl

bi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BbHpoZWltZXIgZGlzZWFzZTogVG8gd2hh

dCBleHRlbnQgY2FuIEFsemhlaW1lciBkaXNlYXNlIGJlIHByZXZlbnRlZD88L3RpdGxlPjxzZWNv

bmRhcnktdGl0bGU+TmF0IFJldiBOZXVyb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5OYXQgUmV2IE5ldXJvbDwvZnVsbC10aXRsZT48L3BlcmlvZGlj

YWw+PHBhZ2VzPjU1Mi0zPC9wYWdlcz48dm9sdW1lPjEwPC92b2x1bWU+PG51bWJlcj4xMDwvbnVt

YmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qZXBpZGVtaW9sb2d5Lypw

cmV2ZW50aW9uICZhbXA7IGNvbnRyb2w8L2tleXdvcmQ+PGtleXdvcmQ+RGF0YWJhc2VzLCBGYWN0

dWFsLyp0cmVuZHM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPipQ

b3B1bGF0aW9uIFN1cnZlaWxsYW5jZTwva2V5d29yZD48a2V5d29yZD5QcmltYXJ5IFByZXZlbnRp

b24vKm1ldGhvZHM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48

cHViLWRhdGVzPjxkYXRlPk9jdDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE3NTkt

NDc2NiAoRWxlY3Ryb25pYykmI3hEOzE3NTktNDc1OCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lv

bi1udW0+MjUyNDUxNTQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0

dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjUyNDUxNTQ8L3VybD48L3JlbGF0ZWQt

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMzgvbnJuZXVyb2wuMjAx

NC4xNzA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPlNvbG9tb248L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxSZWNOdW0+MzQ2PC9SZWNOdW0+

PHJlY29yZD48cmVjLW51bWJlcj4zNDY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw

cD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVz

dGFtcD0iMTUzMjU0ODU5NCI+MzQ2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5Tb2xvbW9uLCBBLjwvYXV0aG9yPjxhdXRob3I+QWtlbmluZSwgVS48L2F1dGhvcj48YXV0

aG9yPkFuZHJlYXNlbiwgTi48L2F1dGhvcj48YXV0aG9yPk1hbmdpYWxhc2NoZSwgRi48L2F1dGhv

cj48YXV0aG9yPldpbW8sIEEuPC9hdXRob3I+PGF1dGhvcj5KZWxpYywgVi48L2F1dGhvcj48YXV0

aG9yPktpdmlwZWx0bywgTS48L2F1dGhvcj48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+QWdpbmcgUmVzZWFyY2ggQ2VudGVy

IChBUkMpLCBEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29j

aWV0eSBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVuLjwvYXV0aC1hZGRy

ZXNzPjx0aXRsZXM+PHRpdGxlPlByYWN0aWNhbCBsZXNzb25zIGZyb20gYW15bG9pZCBpbW11bm90

aGVyYXB5IHRyaWFscyBpbiBBbHpoZWltZXIgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5DdXJyIEFsemhlaW1lciBSZXM8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh

bD48ZnVsbC10aXRsZT5DdXJyIEFsemhlaW1lciBSZXM8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz4xMTI2LTM0PC9wYWdlcz48dm9sdW1lPjk8L3ZvbHVtZT48bnVtYmVyPjEwPC9udW1i

ZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERp

c2Vhc2UvKmltbXVub2xvZ3kvKnRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZC8qaW1t

dW5vbG9neTwva2V5d29yZD48a2V5d29yZD5DYXJlZ2l2ZXJzPC9rZXl3b3JkPjxrZXl3b3JkPkRv

dWJsZS1CbGluZCBNZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3

b3JkPkZvbGxvdy1VcCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48

a2V5d29yZD4qSW1tdW5vdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxr

ZXl3b3JkPk1lbnRhbCBTdGF0dXMgU2NoZWR1bGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFn

ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UmV0cm9zcGVjdGl2ZSBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3

b3JkPlN3ZWRlbjwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEyPC95ZWFyPjxw

dWItZGF0ZXM+PGRhdGU+RGVjPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTg3NS01

ODI4IChFbGVjdHJvbmljKSYjeEQ7MTU2Ny0yMDUwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yMjYzMTQ0MjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMjYzMTQ0MjwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5Mb2VyYS1WYWxlbmNpYTwv

QXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJlY051bT4zNjg8L1JlY051bT48cmVjb3JkPjxyZWMt

bnVtYmVyPjM2ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9

ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTQ5

MDEyIj4zNjg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRp

Y2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkxvZXJhLVZh

bGVuY2lhLCBSLjwvYXV0aG9yPjxhdXRob3I+UGlyYXMsIEEuPC9hdXRob3I+PGF1dGhvcj5Jc21h

aWwsIE0uIEEuIE0uPC9hdXRob3I+PGF1dGhvcj5NYW5jaGFuZGEsIFMuPC9hdXRob3I+PGF1dGhv

cj5FeWpvbGZzZG90dGlyLCBILjwvYXV0aG9yPjxhdXRob3I+U2FpZG8sIFQuIEMuPC9hdXRob3I+

PGF1dGhvcj5Kb2hhbnNzb24sIEouPC9hdXRob3I+PGF1dGhvcj5Fcmlrc2RvdHRlciwgTS48L2F1

dGhvcj48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5OaWxzc29uLCBQLjwvYXV0

aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIE5l

dXJvZ2VyaWF0cmljcywgRGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMg

YW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBLYXJvbGluc2thIElu

c3RpdHV0ZXQsIFNvbG5hLCBTd2VkZW4uJiN4RDtUaGVtZSBOZXVybywgRGlzZWFzZXMgb2YgdGhl

IE5lcnZvdXMgU3lzdGVtIFBhdGllbnQgRmxvdywgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3Bp

dGFsLCBIdWRkaW5nZSwgU3dlZGVuLiYjeEQ7RGl2aXNpb24gb2YgQ2xpbmljYWwgR2VyaWF0cmlj

cywgRGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHks

IEthcm9saW5za2EgSW5zdGl0dXRldCwgSHVkZGluZ2UsIFN3ZWRlbi4mI3hEO1RoZW1lIEFnaW5n

LCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtS

SUtFTiBCcmFpbiBTY2llbmNlIEluc3RpdHV0ZSwgV2FrbywgU2FpdGFtYSwgSmFwYW4uPC9hdXRo

LWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGFyZ2V0aW5nIEFsemhlaW1lciZhcG9zO3MgZGlzZWFz

ZSB3aXRoIGdlbmUgYW5kIGNlbGwgdGhlcmFwaWVzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkog

SW50ZXJuIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRp

dGxlPkogSW50ZXJuIE1lZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjItMzY8L3Bh

Z2VzPjx2b2x1bWU+Mjg0PC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3

b3JkPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5jZWxsIHRoZXJh

cHk8L2tleXdvcmQ+PGtleXdvcmQ+Z2VuZSB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPmluZHVj

ZWQgbmV1cm9nZW5lc2lzPC9rZXl3b3JkPjxrZXl3b3JkPm5lcHJpbHlzaW48L2tleXdvcmQ+PGtl

eXdvcmQ+dGF1PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT5KdWw8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMzY1LTI3

OTYgKEVsZWN0cm9uaWMpJiN4RDswOTU0LTY4MjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24t

bnVtPjI5NTgyNDk1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRw

Oi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI5NTgyNDk1PC91cmw+PHVybD5odHRwczov

L29ubGluZWxpYnJhcnkud2lsZXkuY29tL2RvaS9wZGYvMTAuMTExMS9qb2ltLjEyNzU5PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTExL2pv

aW0uMTI3NTk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5v

dGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJkeTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl

Y051bT4yODM8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4y

NCw0Niw0MDMtNDA1PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mjgz

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzMiPjI4Mzwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SGFyZHksIEouPC9hdXRob3I+

PGF1dGhvcj5Cb2dkYW5vdmljLCBOLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhv

cj48YXV0aG9yPlBvcnRlbGl1cywgRS48L2F1dGhvcj48YXV0aG9yPkFuZHJlYXNlbiwgTi48L2F1

dGhvcj48YXV0aG9yPkNlZGF6by1NaW5ndWV6LCBBLjwvYXV0aG9yPjxhdXRob3I+WmV0dGVyYmVy

ZywgSC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+UGF0

aHdheXMgdG8gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PkogSW50ZXJuIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxs

LXRpdGxlPkogSW50ZXJuIE1lZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjI5Ni0z

MDM8L3BhZ2VzPjx2b2x1bWU+Mjc1PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGtleXdvcmRz

PjxrZXl3b3JkPipBbHpoZWltZXIgRGlzZWFzZS9nZW5ldGljcy9tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPipBbXlsb2lkL2dlbmV0aWNzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZCBiZXRhLVBlcHRpZGVzLyphbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzPC9rZXl3

b3JkPjxrZXl3b3JkPkJyYWluL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+RWFybHkgTWVk

aWNhbCBJbnRlcnZlbnRpb248L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXRpYyBQcmVkaXNwb3NpdGlv

biB0byBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5J

bW11bm90aGVyYXB5L21ldGhvZHM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAx

NDwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1hcjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxp

c2JuPjEzNjUtMjc5NiAoRWxlY3Ryb25pYykmI3hEOzA5NTQtNjgyMCAoTGlua2luZyk8L2lzYm4+

PGFjY2Vzc2lvbi1udW0+MjQ3NDkxNzM8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJs

cz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjQ3NDkxNzM8L3VybD48

dXJsPmh0dHBzOi8vb25saW5lbGlicmFyeS53aWxleS5jb20vZG9pL3BkZi8xMC4xMTExL2pvaW0u

MTIxOTI8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjEwLjExMTEvam9pbS4xMjE5MjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9D

aXRlPjxDaXRlPjxBdXRob3I+TWVkaW5hPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48UmVjTnVt

PjI2MDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MjYwPC9yZWMtbnVtYmVyPjxmb3JlaWdu

LWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpw

cnB0NWF2IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzEiPjI2MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxy

ZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3Jz

PjxhdXRob3JzPjxhdXRob3I+TWVkaW5hLCBNLjwvYXV0aG9yPjxhdXRob3I+S2hhY2hhdHVyaWFu

LCBaLiBTLjwvYXV0aG9yPjxhdXRob3I+Um9zc29yLCBNLjwvYXV0aG9yPjxhdXRob3I+QXZpbGEs

IEouPC9hdXRob3I+PGF1dGhvcj5DZWRhem8tTWluZ3VleiwgQS48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DSUJFUk5FRCAoTmV0d29yayBDZW50ZXIgZm9y

IEJpb21lZGljYWwgUmVzZWFyY2ggaW4gTmV1cm9kZWdlbmVyYXRpdmUgRGlzZWFzZXMpLCBJU0NJ

SUksIE1hZHJpZCwgU3BhaW4uJiN4RDtDSUVOIEZvdW5kYXRpb24sIFJlaW5hIFNvZmlhIEZvdW5k

YXRpb24gQWx6aGVpbWVyIENlbnRlciwgTWFkcmlkLCBTcGFpbi4mI3hEO1BBRDIwMjAsIFBvdG9t

YWMsIE1ELCBVU0EuJiN4RDtJbnN0aXR1dGUgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IENvbGxl

Z2UgTG9uZG9uLCBMb25kb24sIFVLLiYjeEQ7TmV1cm9iaW9sb2d5IExhYm9yYXRvcnksIENlbnRl

ciBmb3IgTW9sZWN1bGFyIEJpb2xvZ3kgJnF1b3Q7U2V2ZXJvIE9jaG9hJnF1b3Q7IENTSUMtVUFN

LCBNYWRyaWQsIFNwYWluLiYjeEQ7RGl2aXNpb24gb2YgTmV1cm9nZXJpYXRyaWNzLCBEZXBhcnRt

ZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgQ2VudGVyIGZv

ciBBbHpoZWltZXIgUmVzZWFyY2gsIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBT

d2VkZW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VG93YXJkIGNvbW1vbiBtZWNoYW5p

c21zIGZvciByaXNrIGZhY3RvcnMgaW4gQWx6aGVpbWVyJmFwb3M7cyBzeW5kcm9tZTwvdGl0bGU+

PHNlY29uZGFyeS10aXRsZT5BbHpoZWltZXJzIERlbWVudCAoTiBZKTwvc2Vjb25kYXJ5LXRpdGxl

PjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFsemhlaW1lcnMgRGVtZW50IChOIFkp

PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NTcxLTU3ODwvcGFnZXM+PHZvbHVtZT4z

PC92b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciZh

cG9zO3M8L2tleXdvcmQ+PGtleXdvcmQ+RGVtZW50aWE8L2tleXdvcmQ+PGtleXdvcmQ+UGF0aG9n

ZW5lc2lzPC9rZXl3b3JkPjxrZXl3b3JkPlByZXZlbnRpb248L2tleXdvcmQ+PGtleXdvcmQ+Umlz

ayBmYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlN5bmRyb21lPC9rZXl3b3JkPjwva2V5d29yZHM+

PGRhdGVzPjx5ZWFyPjIwMTc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5Ob3Y8L2RhdGU+PC9wdWIt

ZGF0ZXM+PC9kYXRlcz48aXNibj4yMzUyLTg3MzcgKEVsZWN0cm9uaWMpJiN4RDsyMzUyLTg3Mzcg

KExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5MTI0MTE2PC9hY2Nlc3Npb24tbnVtPjx1

cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVk

LzI5MTI0MTE2PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzU2NzE2Mjg8

L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai50cmNpLjIwMTcuMDgu

MDA5PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhv

cj5IYXJkeTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJlY051bT4yODM8L1JlY051bT48cmVj

b3JkPjxyZWMtbnVtYmVyPjI4MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1w

PSIxNTMxNzc1MjczIj4yODM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PkhhcmR5LCBKLjwvYXV0aG9yPjxhdXRob3I+Qm9nZGFub3ZpYywgTi48L2F1dGhvcj48YXV0aG9y

PldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5Qb3J0ZWxpdXMsIEUuPC9hdXRob3I+PGF1dGhv

cj5BbmRyZWFzZW4sIE4uPC9hdXRob3I+PGF1dGhvcj5DZWRhem8tTWluZ3VleiwgQS48L2F1dGhv

cj48YXV0aG9yPlpldHRlcmJlcmcsIEguPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

Pjx0aXRsZXM+PHRpdGxlPlBhdGh3YXlzIHRvIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5KIEludGVybiBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxl

cz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIEludGVybiBNZWQ8L2Z1bGwtdGl0bGU+PC9wZXJp

b2RpY2FsPjxwYWdlcz4yOTYtMzAzPC9wYWdlcz48dm9sdW1lPjI3NTwvdm9sdW1lPjxudW1iZXI+

MzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD4qQWx6aGVpbWVyIERpc2Vhc2UvZ2VuZXRpY3Mv

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD4qQW15bG9pZC9nZW5ldGljcy9tZXRhYm9saXNt

PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy8qYW50YWdvbmlzdHMgJmFt

cDsgaW5oaWJpdG9yczwva2V5d29yZD48a2V5d29yZD5CcmFpbi9tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPkVhcmx5IE1lZGljYWwgSW50ZXJ2ZW50aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkdl

bmV0aWMgUHJlZGlzcG9zaXRpb24gdG8gRGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8

L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vdGhlcmFweS9tZXRob2RzPC9rZXl3b3JkPjwva2V5d29y

ZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXI8L2RhdGU+PC9w

dWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMzY1LTI3OTYgKEVsZWN0cm9uaWMpJiN4RDswOTU0LTY4

MjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI0NzQ5MTczPC9hY2Nlc3Npb24tbnVt

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVi

bWVkLzI0NzQ5MTczPC91cmw+PHVybD5odHRwczovL29ubGluZWxpYnJhcnkud2lsZXkuY29tL2Rv

aS9wZGYvMTAuMTExMS9qb2ltLjEyMTkyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVj

dHJvbmljLXJlc291cmNlLW51bT4xMC4xMTExL2pvaW0uMTIxOTI8L2VsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPktpdmlwZWx0bzwvQXV0aG9yPjxZ

ZWFyPjIwMTQ8L1llYXI+PFJlY051bT4zNDI8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM0

MjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUy

cHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTQ4NTk0Ij4zNDI8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPktpdmlwZWx0bywgTS48L2F1

dGhvcj48YXV0aG9yPk1hbmdpYWxhc2NoZSwgRi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli

dXRvcnM+PGF1dGgtYWRkcmVzcz5LYXJvbGluc2thIEluc3RpdHV0ZXQgQ2VudGVyIGZvciBBbHpo

ZWltZXIgUmVzZWFyY2gsIE5vdnVtIEZsb29yIDUsIFNFLTE0MSA1NyBIdWRkaW5nZSwgU3dlZGVu

LiYjeEQ7QWdpbmcgUmVzZWFyY2ggQ2VudGVyLCBLYXJvbGluc2thIEluc3RpdHV0ZXQtU3RvY2to

b2xtIFVuaXZlcnNpdHksIEdhdmxlZ2F0YW4gMTYsIFNFLTExMyAzMCBTdG9ja2hvbG0sIFN3ZWRl

bi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BbHpoZWltZXIgZGlzZWFzZTogVG8gd2hh

dCBleHRlbnQgY2FuIEFsemhlaW1lciBkaXNlYXNlIGJlIHByZXZlbnRlZD88L3RpdGxlPjxzZWNv

bmRhcnktdGl0bGU+TmF0IFJldiBOZXVyb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5OYXQgUmV2IE5ldXJvbDwvZnVsbC10aXRsZT48L3BlcmlvZGlj

YWw+PHBhZ2VzPjU1Mi0zPC9wYWdlcz48dm9sdW1lPjEwPC92b2x1bWU+PG51bWJlcj4xMDwvbnVt

YmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qZXBpZGVtaW9sb2d5Lypw

cmV2ZW50aW9uICZhbXA7IGNvbnRyb2w8L2tleXdvcmQ+PGtleXdvcmQ+RGF0YWJhc2VzLCBGYWN0

dWFsLyp0cmVuZHM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPipQ

b3B1bGF0aW9uIFN1cnZlaWxsYW5jZTwva2V5d29yZD48a2V5d29yZD5QcmltYXJ5IFByZXZlbnRp

b24vKm1ldGhvZHM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48

cHViLWRhdGVzPjxkYXRlPk9jdDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE3NTkt

NDc2NiAoRWxlY3Ryb25pYykmI3hEOzE3NTktNDc1OCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lv

bi1udW0+MjUyNDUxNTQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0

dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjUyNDUxNTQ8L3VybD48L3JlbGF0ZWQt

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMzgvbnJuZXVyb2wuMjAx

NC4xNzA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPlNvbG9tb248L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxSZWNOdW0+MzQ2PC9SZWNOdW0+

PHJlY29yZD48cmVjLW51bWJlcj4zNDY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw

cD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVz

dGFtcD0iMTUzMjU0ODU5NCI+MzQ2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5Tb2xvbW9uLCBBLjwvYXV0aG9yPjxhdXRob3I+QWtlbmluZSwgVS48L2F1dGhvcj48YXV0

aG9yPkFuZHJlYXNlbiwgTi48L2F1dGhvcj48YXV0aG9yPk1hbmdpYWxhc2NoZSwgRi48L2F1dGhv

cj48YXV0aG9yPldpbW8sIEEuPC9hdXRob3I+PGF1dGhvcj5KZWxpYywgVi48L2F1dGhvcj48YXV0

aG9yPktpdmlwZWx0bywgTS48L2F1dGhvcj48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+QWdpbmcgUmVzZWFyY2ggQ2VudGVy

IChBUkMpLCBEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29j

aWV0eSBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVuLjwvYXV0aC1hZGRy

ZXNzPjx0aXRsZXM+PHRpdGxlPlByYWN0aWNhbCBsZXNzb25zIGZyb20gYW15bG9pZCBpbW11bm90

aGVyYXB5IHRyaWFscyBpbiBBbHpoZWltZXIgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5DdXJyIEFsemhlaW1lciBSZXM8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh

bD48ZnVsbC10aXRsZT5DdXJyIEFsemhlaW1lciBSZXM8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz4xMTI2LTM0PC9wYWdlcz48dm9sdW1lPjk8L3ZvbHVtZT48bnVtYmVyPjEwPC9udW1i

ZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERp

c2Vhc2UvKmltbXVub2xvZ3kvKnRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZC8qaW1t

dW5vbG9neTwva2V5d29yZD48a2V5d29yZD5DYXJlZ2l2ZXJzPC9rZXl3b3JkPjxrZXl3b3JkPkRv

dWJsZS1CbGluZCBNZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3

b3JkPkZvbGxvdy1VcCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48

a2V5d29yZD4qSW1tdW5vdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxr

ZXl3b3JkPk1lbnRhbCBTdGF0dXMgU2NoZWR1bGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFn

ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UmV0cm9zcGVjdGl2ZSBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3

b3JkPlN3ZWRlbjwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEyPC95ZWFyPjxw

dWItZGF0ZXM+PGRhdGU+RGVjPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTg3NS01

ODI4IChFbGVjdHJvbmljKSYjeEQ7MTU2Ny0yMDUwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4yMjYzMTQ0MjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMjYzMTQ0MjwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5Mb2VyYS1WYWxlbmNpYTwv

QXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJlY051bT4zNjg8L1JlY051bT48cmVjb3JkPjxyZWMt

bnVtYmVyPjM2ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9

ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTQ5

MDEyIj4zNjg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRp

Y2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkxvZXJhLVZh

bGVuY2lhLCBSLjwvYXV0aG9yPjxhdXRob3I+UGlyYXMsIEEuPC9hdXRob3I+PGF1dGhvcj5Jc21h

aWwsIE0uIEEuIE0uPC9hdXRob3I+PGF1dGhvcj5NYW5jaGFuZGEsIFMuPC9hdXRob3I+PGF1dGhv

cj5FeWpvbGZzZG90dGlyLCBILjwvYXV0aG9yPjxhdXRob3I+U2FpZG8sIFQuIEMuPC9hdXRob3I+

PGF1dGhvcj5Kb2hhbnNzb24sIEouPC9hdXRob3I+PGF1dGhvcj5Fcmlrc2RvdHRlciwgTS48L2F1

dGhvcj48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRob3I+PGF1dGhvcj5OaWxzc29uLCBQLjwvYXV0

aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIE5l

dXJvZ2VyaWF0cmljcywgRGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMg

YW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBLYXJvbGluc2thIElu

c3RpdHV0ZXQsIFNvbG5hLCBTd2VkZW4uJiN4RDtUaGVtZSBOZXVybywgRGlzZWFzZXMgb2YgdGhl

IE5lcnZvdXMgU3lzdGVtIFBhdGllbnQgRmxvdywgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3Bp

dGFsLCBIdWRkaW5nZSwgU3dlZGVuLiYjeEQ7RGl2aXNpb24gb2YgQ2xpbmljYWwgR2VyaWF0cmlj

cywgRGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHks

IEthcm9saW5za2EgSW5zdGl0dXRldCwgSHVkZGluZ2UsIFN3ZWRlbi4mI3hEO1RoZW1lIEFnaW5n

LCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtS

SUtFTiBCcmFpbiBTY2llbmNlIEluc3RpdHV0ZSwgV2FrbywgU2FpdGFtYSwgSmFwYW4uPC9hdXRo

LWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGFyZ2V0aW5nIEFsemhlaW1lciZhcG9zO3MgZGlzZWFz

ZSB3aXRoIGdlbmUgYW5kIGNlbGwgdGhlcmFwaWVzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkog

SW50ZXJuIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRp

dGxlPkogSW50ZXJuIE1lZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjItMzY8L3Bh

Z2VzPjx2b2x1bWU+Mjg0PC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3

b3JkPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5jZWxsIHRoZXJh

cHk8L2tleXdvcmQ+PGtleXdvcmQ+Z2VuZSB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPmluZHVj

ZWQgbmV1cm9nZW5lc2lzPC9rZXl3b3JkPjxrZXl3b3JkPm5lcHJpbHlzaW48L2tleXdvcmQ+PGtl

eXdvcmQ+dGF1PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT5KdWw8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMzY1LTI3

OTYgKEVsZWN0cm9uaWMpJiN4RDswOTU0LTY4MjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24t

bnVtPjI5NTgyNDk1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRw

Oi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI5NTgyNDk1PC91cmw+PHVybD5odHRwczov

L29ubGluZWxpYnJhcnkud2lsZXkuY29tL2RvaS9wZGYvMTAuMTExMS9qb2ltLjEyNzU5PC91cmw+

PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTExL2pv

aW0uMTI3NTk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5v

dGU+AG==

ADDIN EN.CITE.DATA 24,46,403-405. This heterogeneity in pathogenesis may lead to different evolution roads of disease and could be the cause of improper clinical trial design and lack of translation between animal models and patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KdWNrZXI8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

ZWNOdW0+MzcyPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDA2LTQwOTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM3MjwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTQ5MTEwIj4zNzI8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkp1Y2tlciwgTS48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIENlbGx1bGFy

IE5ldXJvbG9neSwgSGVydGllIEluc3RpdHV0ZSBmb3IgQ2xpbmljYWwgQnJhaW4gUmVzZWFyY2gs

IFVuaXZlcnNpdHkgb2YgVHViaW5nZW4sIFR1YmluZ2VuLCBHZXJtYW55LiBtYXRoaWFzLmp1Y2tl

ckB1bmktdHVlYmluZ2VuLmRlPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGhlIGJlbmVm

aXRzIGFuZCBsaW1pdGF0aW9ucyBvZiBhbmltYWwgbW9kZWxzIGZvciB0cmFuc2xhdGlvbmFsIHJl

c2VhcmNoIGluIG5ldXJvZGVnZW5lcmF0aXZlIGRpc2Vhc2VzPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPk5hdCBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTIxMC00PC9wYWdl

cz48dm9sdW1lPjE2PC92b2x1bWU+PG51bWJlcj4xMTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29y

ZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkNsaW5pY2FsIFRyaWFscyBhcyBUb3BpYzwva2V5

d29yZD48a2V5d29yZD5HZW5ldGljIEVuZ2luZWVyaW5nPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFu

czwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPipNb2RlbHMsIEFuaW1h

bDwva2V5d29yZD48a2V5d29yZD5OZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcy8qcGF0aG9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPlJlcHJvZHVjaWJpbGl0eSBvZiBSZXN1bHRzPC9rZXl3b3JkPjxr

ZXl3b3JkPipUcmFuc2xhdGlvbmFsIE1lZGljYWwgUmVzZWFyY2g8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxMDwveWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdjwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NDYtMTcwWCAoRWxlY3Ryb25pYykmI3hEOzEwNzgtODk1

NiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjEwNTIwNzU8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMjEwNTIwNzU8L3VybD48dXJsPmh0dHA6Ly93d3cubmF0dXJlLmNvbS9hcnRpY2xlcy9ubS4y

MjI0LnBkZjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+MTAuMTAzOC9ubS4yMjI0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TcGVybGluZzwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJlY051

bT4zNzM8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3MzwvcmVjLW51bWJlcj48Zm9yZWln

bi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6

cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTQ5MzM0Ij4zNzM8L2tleT48L2ZvcmVpZ24ta2V5cz48

cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9y

cz48YXV0aG9ycz48YXV0aG9yPlNwZXJsaW5nLCBSLiBBLjwvYXV0aG9yPjxhdXRob3I+QWlzZW4s

IFAuIFMuPC9hdXRob3I+PGF1dGhvcj5CZWNrZXR0LCBMLiBBLjwvYXV0aG9yPjxhdXRob3I+QmVu

bmV0dCwgRC4gQS48L2F1dGhvcj48YXV0aG9yPkNyYWZ0LCBTLjwvYXV0aG9yPjxhdXRob3I+RmFn

YW4sIEEuIE0uPC9hdXRob3I+PGF1dGhvcj5Jd2F0c3VibywgVC48L2F1dGhvcj48YXV0aG9yPkph

Y2ssIEMuIFIuLCBKci48L2F1dGhvcj48YXV0aG9yPktheWUsIEouPC9hdXRob3I+PGF1dGhvcj5N

b250aW5lLCBULiBKLjwvYXV0aG9yPjxhdXRob3I+UGFyaywgRC4gQy48L2F1dGhvcj48YXV0aG9y

PlJlaW1hbiwgRS4gTS48L2F1dGhvcj48YXV0aG9yPlJvd2UsIEMuIEMuPC9hdXRob3I+PGF1dGhv

cj5TaWVtZXJzLCBFLjwvYXV0aG9yPjxhdXRob3I+U3Rlcm4sIFkuPC9hdXRob3I+PGF1dGhvcj5Z

YWZmZSwgSy48L2F1dGhvcj48YXV0aG9yPkNhcnJpbGxvLCBNLiBDLjwvYXV0aG9yPjxhdXRob3I+

VGhpZXMsIEIuPC9hdXRob3I+PGF1dGhvcj5Nb3JyaXNvbi1Cb2dvcmFkLCBNLjwvYXV0aG9yPjxh

dXRob3I+V2Fnc3RlciwgTS4gVi48L2F1dGhvcj48YXV0aG9yPlBoZWxwcywgQy4gSC48L2F1dGhv

cj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DZW50ZXIgZm9yIEFsemhl

aW1lciBSZXNlYXJjaCBhbmQgVHJlYXRtZW50LCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgQnJp

Z2hhbSBhbmQgV29tZW4mYXBvcztzIEhvc3BpdGFsLCBIYXJ2YXJkIE1lZGljYWwgU2Nob29sLCBC

b3N0b24sIE1BLCBVU0EuIHJlaXNhQHJpY3MuYndoLmhhcnZhcmQuZWR1PC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+VG93YXJkIGRlZmluaW5nIHRoZSBwcmVjbGluaWNhbCBzdGFnZXMgb2Yg

QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlOiByZWNvbW1lbmRhdGlvbnMgZnJvbSB0aGUgTmF0aW9u

YWwgSW5zdGl0dXRlIG9uIEFnaW5nLUFsemhlaW1lciZhcG9zO3MgQXNzb2NpYXRpb24gd29ya2dy

b3VwcyBvbiBkaWFnbm9zdGljIGd1aWRlbGluZXMgZm9yIEFsemhlaW1lciZhcG9zO3MgZGlzZWFz

ZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbHpoZWltZXJzIERlbWVudDwvc2Vjb25kYXJ5LXRp

dGxlPjwvdGl0bGVzPjxwYWdlcz4yODAtOTI8L3BhZ2VzPjx2b2x1bWU+Nzwvdm9sdW1lPjxudW1i

ZXI+MzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qZGlhZ25v

c2lzL3BoeXNpb3BhdGhvbG9neS9wc3ljaG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJpb21hcmtl

cnMvYW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+Q29nbml0aW9uIERpc29yZGVycy8qZGlhZ25v

c2lzL3BoeXNpb3BhdGhvbG9neS9wc3ljaG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwv

a2V5d29yZD48a2V5d29yZD5OYXRpb25hbCBJbnN0aXR1dGUgb24gQWdpbmcgKFUuUy4pLypzdGFu

ZGFyZHM8L2tleXdvcmQ+PGtleXdvcmQ+UHJhY3RpY2UgR3VpZGVsaW5lcyBhcyBUb3BpYy8qc3Rh

bmRhcmRzPC9rZXl3b3JkPjxrZXl3b3JkPlVuaXRlZCBTdGF0ZXM8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1heTwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTItNTI3OSAoRWxlY3Ryb25pYykmI3hEOzE1NTItNTI2

MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjE1MTQyNDg8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMjE1MTQyNDg8L3VybD48dXJsPmh0dHBzOi8vYWMuZWxzLWNkbi5jb20vUzE1NTI1MjYwMTEw

MDA5OTkvMS1zMi4wLVMxNTUyNTI2MDExMDAwOTk5LW1haW4ucGRmP190aWQ9YWNjMDkyMmMtMzU2

MS00YjNjLTgyZWMtMDA1OTBlM2FmNmQyJmFtcDthY2RuYXQ9MTUzNDQ5NDgyMF8wZTI1N2I3YTRl

MzdkNzM2NzQ0M2QxZGVjNTA5NGZhMTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9t

Mj5QTUMzMjIwOTQ2PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ou

amFsei4yMDExLjAzLjAwMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRl

PjxDaXRlPjxBdXRob3I+VmVsbGFzPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVtPjM3

NzwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc3PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtl

eXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0

NWF2IiB0aW1lc3RhbXA9IjE1MzI1NDk0MDgiPjM3Nzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYt

dHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxh

dXRob3JzPjxhdXRob3I+VmVsbGFzLCBCLjwvYXV0aG9yPjxhdXRob3I+Q2FycmlsbG8sIE0uIEMu

PC9hdXRob3I+PGF1dGhvcj5TYW1wYWlvLCBDLjwvYXV0aG9yPjxhdXRob3I+QnJhc2hlYXIsIEgu

IFIuPC9hdXRob3I+PGF1dGhvcj5TaWVtZXJzLCBFLjwvYXV0aG9yPjxhdXRob3I+SGFtcGVsLCBI

LjwvYXV0aG9yPjxhdXRob3I+U2NobmVpZGVyLCBMLiBTLjwvYXV0aG9yPjxhdXRob3I+V2VpbmVy

LCBNLjwvYXV0aG9yPjxhdXRob3I+RG9vZHksIFIuPC9hdXRob3I+PGF1dGhvcj5LaGFjaGF0dXJp

YW4sIFouPC9hdXRob3I+PGF1dGhvcj5DZWRhcmJhdW0sIEouPC9hdXRob3I+PGF1dGhvcj5HcnVu

ZG1hbiwgTS48L2F1dGhvcj48YXV0aG9yPkJyb2ljaCwgSy48L2F1dGhvcj48YXV0aG9yPkdpYWNv

YmluaSwgRS48L2F1dGhvcj48YXV0aG9yPkR1Ym9pcywgQi48L2F1dGhvcj48YXV0aG9yPlNwZXJs

aW5nLCBSLjwvYXV0aG9yPjxhdXRob3I+V2lsY29jaywgRy4gSy48L2F1dGhvcj48YXV0aG9yPkZv

eCwgTi48L2F1dGhvcj48YXV0aG9yPlNjaGVsdGVucywgUC48L2F1dGhvcj48YXV0aG9yPlRvdWNo

b24sIEouPC9hdXRob3I+PGF1dGhvcj5IZW5kcml4LCBTLjwvYXV0aG9yPjxhdXRob3I+QW5kcmll

dSwgUy48L2F1dGhvcj48YXV0aG9yPkFpc2VuLCBQLjwvYXV0aG9yPjxhdXRob3I+RXUgVXMgQ3Rh

ZCBUYXNrIEZvcmNlIE1lbWJlcnM8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1

dGgtYWRkcmVzcz5VTVIxMDI3IEluc2VybSwgVG91bG91c2UsIEZyYW5jZS4gdmVsbGFzLmJydW5v

QGdtYWlsLmNvbTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkRlc2lnbmluZyBkcnVnIHRy

aWFscyBmb3IgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlOiB3aGF0IHdlIGhhdmUgbGVhcm5lZCBm

cm9tIHRoZSByZWxlYXNlIG9mIHRoZSBwaGFzZSBJSUkgYW50aWJvZHkgdHJpYWxzOiBhIHJlcG9y

dCBmcm9tIHRoZSBFVS9VUy9DVEFEIFRhc2sgRm9yY2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+

QWx6aGVpbWVycyBEZW1lbnQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NDM4LTQ0

PC9wYWdlcz48dm9sdW1lPjk8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48a2V5d29yZHM+PGtl

eXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48

a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9kcnVnIHRoZXJhcHkvbWV0YWJvbGlzbS8qcHJldmVu

dGlvbiAmYW1wOyBjb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRl

cy9hbmFseXNpczwva2V5d29yZD48a2V5d29yZD5BbnRpYm9kaWVzLCBNb25vY2xvbmFsLCBIdW1h

bml6ZWQvKnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMg

RS9hbmFseXNpcy9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5BdHJvcGh5L2V0aW9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPkJpb21hcmtlcnM8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vcGF0aG9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluIENoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5C

cmFpbiBFZGVtYS9ldGlvbG9neTwva2V5d29yZD48a2V5d29yZD5DbGluaWNhbCBUcmlhbHMsIFBo

YXNlIElJIGFzIFRvcGljL3N0YXRpc3RpY3MgJmFtcDsgbnVtZXJpY2FsIGRhdGE8L2tleXdvcmQ+

PGtleXdvcmQ+Q2xpbmljYWwgVHJpYWxzLCBQaGFzZSBJSUkgYXMgVG9waWMvKm1ldGhvZHM8L2tl

eXdvcmQ+PGtleXdvcmQ+Q29nbml0aXZlIER5c2Z1bmN0aW9uL2RydWcgdGhlcmFweTwva2V5d29y

ZD48a2V5d29yZD5EaXNlYXNlIFByb2dyZXNzaW9uPC9rZXl3b3JkPjxrZXl3b3JkPkVuZHBvaW50

IERldGVybWluYXRpb24vbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+

PGtleXdvcmQ+TXVsdGljZW50ZXIgU3R1ZGllcyBhcyBUb3BpYy8qbWV0aG9kczwva2V5d29yZD48

a2V5d29yZD5OZXVyb2ltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+Tm9vdHJvcGljIEFnZW50cy8q

dGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPlBhdGllbnQgU2VsZWN0aW9uPC9rZXl3

b3JkPjxrZXl3b3JkPlJhbmRvbWl6ZWQgQ29udHJvbGxlZCBUcmlhbHMgYXMgVG9waWMvKm1ldGhv

ZHM8L2tleXdvcmQ+PGtleXdvcmQ+VHJlYXRtZW50IEZhaWx1cmU8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bDwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTItNTI3OSAoRWxlY3Ryb25pYykmI3hEOzE1NTItNTI2

MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjM4MDkzNjQ8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMjM4MDkzNjQ8L3VybD48dXJsPmh0dHBzOi8vYWMuZWxzLWNkbi5jb20vUzE1NTI1MjYwMTMw

MDEzNDkvMS1zMi4wLVMxNTUyNTI2MDEzMDAxMzQ5LW1haW4ucGRmP190aWQ9NjYwN2E3OTUtMWFl

MC00NTM0LTgyNDAtN2JmNzI4NDcxMDgyJmFtcDthY2RuYXQ9MTUzNDQ5NDgzN180NTIxMWQzNGIz

NWU2MmYxM2IxNDk3YzFjNWU3Yzg4NDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmphbHouMjAxMy4wMy4wMDc8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlZlbGxhczwvQXV0aG9y

PjxZZWFyPjIwMDc8L1llYXI+PFJlY051bT4zOTI8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVy

PjM5MjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTBy

eDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTQ5NTU2Ij4z

OTI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x

NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlZlbGxhcywgQi48L2F1

dGhvcj48YXV0aG9yPkFuZHJpZXUsIFMuPC9hdXRob3I+PGF1dGhvcj5TYW1wYWlvLCBDLjwvYXV0

aG9yPjxhdXRob3I+V2lsY29jaywgRy48L2F1dGhvcj48YXV0aG9yPkV1cm9wZWFuIFRhc2sgRm9y

Y2UsIGdyb3VwPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+

QWx6aGVpbWVyIERpc2Vhc2UgUmVzZWFyY2ggYW5kIENsaW5pY2FsIENlbnRlciwgVW5pdmVyc2l0

eSBvZiBUb3Vsb3VzZSwgVG91bG91c2UsIEZyYW5jZS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0

aXRsZT5EaXNlYXNlLW1vZGlmeWluZyB0cmlhbHMgaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNl

OiBhIEV1cm9wZWFuIHRhc2sgZm9yY2UgY29uc2Vuc3VzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PkxhbmNldCBOZXVyb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NTYtNjI8L3Bh

Z2VzPjx2b2x1bWU+Njwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29y

ZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2RydWcgdGhlcmFweS9l

Y29ub21pY3MvcHN5Y2hvbG9neS8qdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5CaW9tYXJrZXJz

PC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbi9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PkNvbnNlbnN1cyBEZXZlbG9wbWVudCBDb25mZXJlbmNlcyBhcyBUb3BpYzwva2V5d29yZD48a2V5

d29yZD5EcnVnIENvc3RzPC9rZXl3b3JkPjxrZXl3b3JkPkVuZHBvaW50IERldGVybWluYXRpb248

L2tleXdvcmQ+PGtleXdvcmQ+RXVyb3BlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29y

ZD48a2V5d29yZD5SZXNlYXJjaCBEZXNpZ248L2tleXdvcmQ+PGtleXdvcmQ+UmlzayBBc3Nlc3Nt

ZW50PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDc8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT5KYW48L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDc0LTQ0MjIgKFBy

aW50KSYjeEQ7MTQ3NC00NDIyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xNzE2Njgw

MjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3B1Ym1lZC8xNzE2NjgwMjwvdXJsPjx1cmw+aHR0cHM6Ly9hYy5lbHMtY2Ru

LmNvbS9TMTQ3NDQ0MjIwNjcwNjc3OS8xLXMyLjAtUzE0NzQ0NDIyMDY3MDY3NzktbWFpbi5wZGY/

X3RpZD0wZGUwODc5YS1lY2I0LTQ2NTMtYmFmYi1iMDBhMzAzYTFkZTEmYW1wO2FjZG5hdD0xNTM0

NDk0ODMyX2Y2ZmM5OGY1ZGIzMDBiMzYxMGIwYjg5NGIwYjA0ZTQwPC91cmw+PC9yZWxhdGVkLXVy

bHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L1MxNDc0LTQ0MjIoMDYp

NzA2NzctOTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90

ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KdWNrZXI8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

ZWNOdW0+MzcyPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDA2LTQwOTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM3MjwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTQ5MTEwIj4zNzI8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkp1Y2tlciwgTS48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIENlbGx1bGFy

IE5ldXJvbG9neSwgSGVydGllIEluc3RpdHV0ZSBmb3IgQ2xpbmljYWwgQnJhaW4gUmVzZWFyY2gs

IFVuaXZlcnNpdHkgb2YgVHViaW5nZW4sIFR1YmluZ2VuLCBHZXJtYW55LiBtYXRoaWFzLmp1Y2tl

ckB1bmktdHVlYmluZ2VuLmRlPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGhlIGJlbmVm

aXRzIGFuZCBsaW1pdGF0aW9ucyBvZiBhbmltYWwgbW9kZWxzIGZvciB0cmFuc2xhdGlvbmFsIHJl

c2VhcmNoIGluIG5ldXJvZGVnZW5lcmF0aXZlIGRpc2Vhc2VzPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPk5hdCBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTIxMC00PC9wYWdl

cz48dm9sdW1lPjE2PC92b2x1bWU+PG51bWJlcj4xMTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29y

ZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkNsaW5pY2FsIFRyaWFscyBhcyBUb3BpYzwva2V5

d29yZD48a2V5d29yZD5HZW5ldGljIEVuZ2luZWVyaW5nPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFu

czwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPipNb2RlbHMsIEFuaW1h

bDwva2V5d29yZD48a2V5d29yZD5OZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcy8qcGF0aG9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPlJlcHJvZHVjaWJpbGl0eSBvZiBSZXN1bHRzPC9rZXl3b3JkPjxr

ZXl3b3JkPipUcmFuc2xhdGlvbmFsIE1lZGljYWwgUmVzZWFyY2g8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxMDwveWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdjwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NDYtMTcwWCAoRWxlY3Ryb25pYykmI3hEOzEwNzgtODk1

NiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjEwNTIwNzU8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMjEwNTIwNzU8L3VybD48dXJsPmh0dHA6Ly93d3cubmF0dXJlLmNvbS9hcnRpY2xlcy9ubS4y

MjI0LnBkZjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+MTAuMTAzOC9ubS4yMjI0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5TcGVybGluZzwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJlY051

bT4zNzM8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM3MzwvcmVjLW51bWJlcj48Zm9yZWln

bi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6

cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTQ5MzM0Ij4zNzM8L2tleT48L2ZvcmVpZ24ta2V5cz48

cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9y

cz48YXV0aG9ycz48YXV0aG9yPlNwZXJsaW5nLCBSLiBBLjwvYXV0aG9yPjxhdXRob3I+QWlzZW4s

IFAuIFMuPC9hdXRob3I+PGF1dGhvcj5CZWNrZXR0LCBMLiBBLjwvYXV0aG9yPjxhdXRob3I+QmVu

bmV0dCwgRC4gQS48L2F1dGhvcj48YXV0aG9yPkNyYWZ0LCBTLjwvYXV0aG9yPjxhdXRob3I+RmFn

YW4sIEEuIE0uPC9hdXRob3I+PGF1dGhvcj5Jd2F0c3VibywgVC48L2F1dGhvcj48YXV0aG9yPkph

Y2ssIEMuIFIuLCBKci48L2F1dGhvcj48YXV0aG9yPktheWUsIEouPC9hdXRob3I+PGF1dGhvcj5N

b250aW5lLCBULiBKLjwvYXV0aG9yPjxhdXRob3I+UGFyaywgRC4gQy48L2F1dGhvcj48YXV0aG9y

PlJlaW1hbiwgRS4gTS48L2F1dGhvcj48YXV0aG9yPlJvd2UsIEMuIEMuPC9hdXRob3I+PGF1dGhv

cj5TaWVtZXJzLCBFLjwvYXV0aG9yPjxhdXRob3I+U3Rlcm4sIFkuPC9hdXRob3I+PGF1dGhvcj5Z

YWZmZSwgSy48L2F1dGhvcj48YXV0aG9yPkNhcnJpbGxvLCBNLiBDLjwvYXV0aG9yPjxhdXRob3I+

VGhpZXMsIEIuPC9hdXRob3I+PGF1dGhvcj5Nb3JyaXNvbi1Cb2dvcmFkLCBNLjwvYXV0aG9yPjxh

dXRob3I+V2Fnc3RlciwgTS4gVi48L2F1dGhvcj48YXV0aG9yPlBoZWxwcywgQy4gSC48L2F1dGhv

cj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DZW50ZXIgZm9yIEFsemhl

aW1lciBSZXNlYXJjaCBhbmQgVHJlYXRtZW50LCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgQnJp

Z2hhbSBhbmQgV29tZW4mYXBvcztzIEhvc3BpdGFsLCBIYXJ2YXJkIE1lZGljYWwgU2Nob29sLCBC

b3N0b24sIE1BLCBVU0EuIHJlaXNhQHJpY3MuYndoLmhhcnZhcmQuZWR1PC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+VG93YXJkIGRlZmluaW5nIHRoZSBwcmVjbGluaWNhbCBzdGFnZXMgb2Yg

QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlOiByZWNvbW1lbmRhdGlvbnMgZnJvbSB0aGUgTmF0aW9u

YWwgSW5zdGl0dXRlIG9uIEFnaW5nLUFsemhlaW1lciZhcG9zO3MgQXNzb2NpYXRpb24gd29ya2dy

b3VwcyBvbiBkaWFnbm9zdGljIGd1aWRlbGluZXMgZm9yIEFsemhlaW1lciZhcG9zO3MgZGlzZWFz

ZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbHpoZWltZXJzIERlbWVudDwvc2Vjb25kYXJ5LXRp

dGxlPjwvdGl0bGVzPjxwYWdlcz4yODAtOTI8L3BhZ2VzPjx2b2x1bWU+Nzwvdm9sdW1lPjxudW1i

ZXI+MzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qZGlhZ25v

c2lzL3BoeXNpb3BhdGhvbG9neS9wc3ljaG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJpb21hcmtl

cnMvYW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+Q29nbml0aW9uIERpc29yZGVycy8qZGlhZ25v

c2lzL3BoeXNpb3BhdGhvbG9neS9wc3ljaG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwv

a2V5d29yZD48a2V5d29yZD5OYXRpb25hbCBJbnN0aXR1dGUgb24gQWdpbmcgKFUuUy4pLypzdGFu

ZGFyZHM8L2tleXdvcmQ+PGtleXdvcmQ+UHJhY3RpY2UgR3VpZGVsaW5lcyBhcyBUb3BpYy8qc3Rh

bmRhcmRzPC9rZXl3b3JkPjxrZXl3b3JkPlVuaXRlZCBTdGF0ZXM8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1heTwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTItNTI3OSAoRWxlY3Ryb25pYykmI3hEOzE1NTItNTI2

MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjE1MTQyNDg8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMjE1MTQyNDg8L3VybD48dXJsPmh0dHBzOi8vYWMuZWxzLWNkbi5jb20vUzE1NTI1MjYwMTEw

MDA5OTkvMS1zMi4wLVMxNTUyNTI2MDExMDAwOTk5LW1haW4ucGRmP190aWQ9YWNjMDkyMmMtMzU2

MS00YjNjLTgyZWMtMDA1OTBlM2FmNmQyJmFtcDthY2RuYXQ9MTUzNDQ5NDgyMF8wZTI1N2I3YTRl

MzdkNzM2NzQ0M2QxZGVjNTA5NGZhMTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9t

Mj5QTUMzMjIwOTQ2PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ou

amFsei4yMDExLjAzLjAwMzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRl

PjxDaXRlPjxBdXRob3I+VmVsbGFzPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVtPjM3

NzwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+Mzc3PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtl

eXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0

NWF2IiB0aW1lc3RhbXA9IjE1MzI1NDk0MDgiPjM3Nzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYt

dHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxh

dXRob3JzPjxhdXRob3I+VmVsbGFzLCBCLjwvYXV0aG9yPjxhdXRob3I+Q2FycmlsbG8sIE0uIEMu

PC9hdXRob3I+PGF1dGhvcj5TYW1wYWlvLCBDLjwvYXV0aG9yPjxhdXRob3I+QnJhc2hlYXIsIEgu

IFIuPC9hdXRob3I+PGF1dGhvcj5TaWVtZXJzLCBFLjwvYXV0aG9yPjxhdXRob3I+SGFtcGVsLCBI

LjwvYXV0aG9yPjxhdXRob3I+U2NobmVpZGVyLCBMLiBTLjwvYXV0aG9yPjxhdXRob3I+V2VpbmVy

LCBNLjwvYXV0aG9yPjxhdXRob3I+RG9vZHksIFIuPC9hdXRob3I+PGF1dGhvcj5LaGFjaGF0dXJp

YW4sIFouPC9hdXRob3I+PGF1dGhvcj5DZWRhcmJhdW0sIEouPC9hdXRob3I+PGF1dGhvcj5HcnVu

ZG1hbiwgTS48L2F1dGhvcj48YXV0aG9yPkJyb2ljaCwgSy48L2F1dGhvcj48YXV0aG9yPkdpYWNv

YmluaSwgRS48L2F1dGhvcj48YXV0aG9yPkR1Ym9pcywgQi48L2F1dGhvcj48YXV0aG9yPlNwZXJs

aW5nLCBSLjwvYXV0aG9yPjxhdXRob3I+V2lsY29jaywgRy4gSy48L2F1dGhvcj48YXV0aG9yPkZv

eCwgTi48L2F1dGhvcj48YXV0aG9yPlNjaGVsdGVucywgUC48L2F1dGhvcj48YXV0aG9yPlRvdWNo

b24sIEouPC9hdXRob3I+PGF1dGhvcj5IZW5kcml4LCBTLjwvYXV0aG9yPjxhdXRob3I+QW5kcmll

dSwgUy48L2F1dGhvcj48YXV0aG9yPkFpc2VuLCBQLjwvYXV0aG9yPjxhdXRob3I+RXUgVXMgQ3Rh

ZCBUYXNrIEZvcmNlIE1lbWJlcnM8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1

dGgtYWRkcmVzcz5VTVIxMDI3IEluc2VybSwgVG91bG91c2UsIEZyYW5jZS4gdmVsbGFzLmJydW5v

QGdtYWlsLmNvbTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkRlc2lnbmluZyBkcnVnIHRy

aWFscyBmb3IgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlOiB3aGF0IHdlIGhhdmUgbGVhcm5lZCBm

cm9tIHRoZSByZWxlYXNlIG9mIHRoZSBwaGFzZSBJSUkgYW50aWJvZHkgdHJpYWxzOiBhIHJlcG9y

dCBmcm9tIHRoZSBFVS9VUy9DVEFEIFRhc2sgRm9yY2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+

QWx6aGVpbWVycyBEZW1lbnQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NDM4LTQ0

PC9wYWdlcz48dm9sdW1lPjk8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48a2V5d29yZHM+PGtl

eXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48

a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9kcnVnIHRoZXJhcHkvbWV0YWJvbGlzbS8qcHJldmVu

dGlvbiAmYW1wOyBjb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRl

cy9hbmFseXNpczwva2V5d29yZD48a2V5d29yZD5BbnRpYm9kaWVzLCBNb25vY2xvbmFsLCBIdW1h

bml6ZWQvKnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMg

RS9hbmFseXNpcy9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5BdHJvcGh5L2V0aW9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPkJpb21hcmtlcnM8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vcGF0aG9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluIENoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5C

cmFpbiBFZGVtYS9ldGlvbG9neTwva2V5d29yZD48a2V5d29yZD5DbGluaWNhbCBUcmlhbHMsIFBo

YXNlIElJIGFzIFRvcGljL3N0YXRpc3RpY3MgJmFtcDsgbnVtZXJpY2FsIGRhdGE8L2tleXdvcmQ+

PGtleXdvcmQ+Q2xpbmljYWwgVHJpYWxzLCBQaGFzZSBJSUkgYXMgVG9waWMvKm1ldGhvZHM8L2tl

eXdvcmQ+PGtleXdvcmQ+Q29nbml0aXZlIER5c2Z1bmN0aW9uL2RydWcgdGhlcmFweTwva2V5d29y

ZD48a2V5d29yZD5EaXNlYXNlIFByb2dyZXNzaW9uPC9rZXl3b3JkPjxrZXl3b3JkPkVuZHBvaW50

IERldGVybWluYXRpb24vbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+

PGtleXdvcmQ+TXVsdGljZW50ZXIgU3R1ZGllcyBhcyBUb3BpYy8qbWV0aG9kczwva2V5d29yZD48

a2V5d29yZD5OZXVyb2ltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+Tm9vdHJvcGljIEFnZW50cy8q

dGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPlBhdGllbnQgU2VsZWN0aW9uPC9rZXl3

b3JkPjxrZXl3b3JkPlJhbmRvbWl6ZWQgQ29udHJvbGxlZCBUcmlhbHMgYXMgVG9waWMvKm1ldGhv

ZHM8L2tleXdvcmQ+PGtleXdvcmQ+VHJlYXRtZW50IEZhaWx1cmU8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bDwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTItNTI3OSAoRWxlY3Ryb25pYykmI3hEOzE1NTItNTI2

MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjM4MDkzNjQ8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMjM4MDkzNjQ8L3VybD48dXJsPmh0dHBzOi8vYWMuZWxzLWNkbi5jb20vUzE1NTI1MjYwMTMw

MDEzNDkvMS1zMi4wLVMxNTUyNTI2MDEzMDAxMzQ5LW1haW4ucGRmP190aWQ9NjYwN2E3OTUtMWFl

MC00NTM0LTgyNDAtN2JmNzI4NDcxMDgyJmFtcDthY2RuYXQ9MTUzNDQ5NDgzN180NTIxMWQzNGIz

NWU2MmYxM2IxNDk3YzFjNWU3Yzg4NDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmphbHouMjAxMy4wMy4wMDc8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlZlbGxhczwvQXV0aG9y

PjxZZWFyPjIwMDc8L1llYXI+PFJlY051bT4zOTI8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVy

PjM5MjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTBy

eDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTQ5NTU2Ij4z

OTI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x

NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlZlbGxhcywgQi48L2F1

dGhvcj48YXV0aG9yPkFuZHJpZXUsIFMuPC9hdXRob3I+PGF1dGhvcj5TYW1wYWlvLCBDLjwvYXV0

aG9yPjxhdXRob3I+V2lsY29jaywgRy48L2F1dGhvcj48YXV0aG9yPkV1cm9wZWFuIFRhc2sgRm9y

Y2UsIGdyb3VwPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+

QWx6aGVpbWVyIERpc2Vhc2UgUmVzZWFyY2ggYW5kIENsaW5pY2FsIENlbnRlciwgVW5pdmVyc2l0

eSBvZiBUb3Vsb3VzZSwgVG91bG91c2UsIEZyYW5jZS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0

aXRsZT5EaXNlYXNlLW1vZGlmeWluZyB0cmlhbHMgaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNl

OiBhIEV1cm9wZWFuIHRhc2sgZm9yY2UgY29uc2Vuc3VzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PkxhbmNldCBOZXVyb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NTYtNjI8L3Bh

Z2VzPjx2b2x1bWU+Njwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29y

ZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2RydWcgdGhlcmFweS9l

Y29ub21pY3MvcHN5Y2hvbG9neS8qdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5CaW9tYXJrZXJz

PC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbi9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PkNvbnNlbnN1cyBEZXZlbG9wbWVudCBDb25mZXJlbmNlcyBhcyBUb3BpYzwva2V5d29yZD48a2V5

d29yZD5EcnVnIENvc3RzPC9rZXl3b3JkPjxrZXl3b3JkPkVuZHBvaW50IERldGVybWluYXRpb248

L2tleXdvcmQ+PGtleXdvcmQ+RXVyb3BlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29y

ZD48a2V5d29yZD5SZXNlYXJjaCBEZXNpZ248L2tleXdvcmQ+PGtleXdvcmQ+UmlzayBBc3Nlc3Nt

ZW50PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDc8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT5KYW48L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDc0LTQ0MjIgKFBy

aW50KSYjeEQ7MTQ3NC00NDIyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xNzE2Njgw

MjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3B1Ym1lZC8xNzE2NjgwMjwvdXJsPjx1cmw+aHR0cHM6Ly9hYy5lbHMtY2Ru

LmNvbS9TMTQ3NDQ0MjIwNjcwNjc3OS8xLXMyLjAtUzE0NzQ0NDIyMDY3MDY3NzktbWFpbi5wZGY/

X3RpZD0wZGUwODc5YS1lY2I0LTQ2NTMtYmFmYi1iMDBhMzAzYTFkZTEmYW1wO2FjZG5hdD0xNTM0

NDk0ODMyX2Y2ZmM5OGY1ZGIzMDBiMzYxMGIwYjg5NGIwYjA0ZTQwPC91cmw+PC9yZWxhdGVkLXVy

bHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L1MxNDc0LTQ0MjIoMDYp

NzA2NzctOTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90

ZT5=

ADDIN EN.CITE.DATA 406-409. For these reasons, efforts should be directed to identify disease pathways that are related to specific clusters of patients. Several reports have looked at patients with altered cholesterol metabolism in the brain and their susceptibility to developing AD. Peripheral hypercholesterolemia is a contributing factor in the risk of developing AD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PcnRoPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVj

TnVtPjgzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+NDEw

LTQxNDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjgzPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE0MjQwOTc2OTIiPjgzPC9rZXk+PGtleSBh

cHA9IkVOV2ViIiBkYi1pZD0iIj4wPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5PcnRoLCBNLjwvYXV0aG9yPjxhdXRob3I+QmVsbG9zdGEsIFMuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+SW5zdGl0dXQgZnVyIExhYm9yYXRvcml1

bXNtZWRpemluLCBWaW56ZW56IHZvbiBQYXVsIEtsaW5pa2VuIGdHbWJILCBBZGxlcnN0cmEgYmV0

YSBlIDcsIFBvc3RmYWNoIDEwMzE2MywgNzAxOTkgU3R1dHRnYXJ0LCBHZXJtYW55LjwvYXV0aC1h

ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNob2xlc3Rlcm9sOiBpdHMgcmVndWxhdGlvbiBhbmQgcm9s

ZSBpbiBjZW50cmFsIG5lcnZvdXMgc3lzdGVtIGRpc29yZGVyczwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5DaG9sZXN0ZXJvbDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+Q2hvbGVzdGVyb2w8

L2FsdC10aXRsZT48L3RpdGxlcz48cGFnZXM+MjkyNTk4PC9wYWdlcz48dm9sdW1lPjIwMTI8L3Zv

bHVtZT48ZGF0ZXM+PHllYXI+MjAxMjwveWVhcj48L2RhdGVzPjxpc2JuPjIwOTAtMTI5MSAoRWxl

Y3Ryb25pYykmI3hEOzIwOTAtMTI4MyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjMx

MTkxNDk8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjMxMTkxNDk8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGN1c3RvbTI+MzQ4MzY1MjwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu

MTE1NS8yMDEyLzI5MjU5ODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRl

PjxDaXRlPjxBdXRob3I+Q2VkYXpvLU1pbmd1ZXo8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

ZWNOdW0+MzAyPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zMDI8L3JlYy1udW1iZXI+PGZv

cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6

dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMTc3NTI3NiI+MzAyPC9rZXk+PC9mb3JlaWduLWtl

eXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmli

dXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DZWRhem8tTWluZ3VleiwgQS48L2F1dGhvcj48YXV0aG9y

PklzbWFpbCwgTS4gQS48L2F1dGhvcj48YXV0aG9yPk1hdGVvcywgTC48L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9n

eSwgQ2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LUFsemhl

aW1lciZhcG9zO3MgRGlzZWFzZSBSZXNlYXJjaCBDZW50ZXIsIE5PVlVNLCA1dGggZmxvb3IsIFNF

LTE0MTg2IFN0b2NraG9sbSwgU3dlZGVuLiBhbmdlbC5jZWRhem8tbWluZ3VlekBraS5zZTwvYXV0

aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlBsYXNtYSBjaG9sZXN0ZXJvbCBhbmQgcmlzayBmb3Ig

bGF0ZS1vbnNldCBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0

bGU+RXhwZXJ0IFJldiBOZXVyb3RoZXI8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+

NDk1LTg8L3BhZ2VzPjx2b2x1bWU+MTE8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZGF0ZXM+

PHllYXI+MjAxMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkFwcjwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjE3NDQtODM2MCAoRWxlY3Ryb25pYykmI3hEOzE0NzMtNzE3NSAoTGlua2lu

Zyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjE0Njk5MjI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJl

bGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjE0Njk5

MjI8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEw

LjE1ODYvZXJuLjExLjM2PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+

PENpdGU+PEF1dGhvcj5LaXZpcGVsdG88L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxSZWNOdW0+

MzU1PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zNTU8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBy

cHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjU0ODU5NCI+MzU1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5LaXZpcGVsdG8sIE0uPC9hdXRob3I+PGF1dGhvcj5OZ2FuZHUsIFQu

PC9hdXRob3I+PGF1dGhvcj5GcmF0aWdsaW9uaSwgTC48L2F1dGhvcj48YXV0aG9yPlZpaXRhbmVu

LCBNLjwvYXV0aG9yPjxhdXRob3I+S2FyZWhvbHQsIEkuPC9hdXRob3I+PGF1dGhvcj5XaW5ibGFk

LCBCLjwvYXV0aG9yPjxhdXRob3I+SGVsa2FsYSwgRS4gTC48L2F1dGhvcj48YXV0aG9yPlR1b21p

bGVodG8sIEouPC9hdXRob3I+PGF1dGhvcj5Tb2luaW5lbiwgSC48L2F1dGhvcj48YXV0aG9yPk5p

c3NpbmVuLCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNz

PkFnaW5nIFJlc2VhcmNoIENlbnRlciwgRGl2aXNpb24gb2YgR2VyaWF0cmljIEVwaWRlbWlvbG9n

eSwgTmV1cm90ZWMsIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW4uIG1p

aWEua2l2aXBlbHRvQG5ldXJvdGVjLmtpLnNlPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+

T2Jlc2l0eSBhbmQgdmFzY3VsYXIgcmlzayBmYWN0b3JzIGF0IG1pZGxpZmUgYW5kIHRoZSByaXNr

IG9mIGRlbWVudGlhIGFuZCBBbHpoZWltZXIgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5BcmNoIE5ldXJvbDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xNTU2LTYwPC9w

YWdlcz48dm9sdW1lPjYyPC92b2x1bWU+PG51bWJlcj4xMDwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5

d29yZD5BZ2UgRmFjdG9yczwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3Jk

PkFsemhlaW1lciBEaXNlYXNlLypldGlvbG9neTwva2V5d29yZD48a2V5d29yZD5Cb2R5IE1hc3Mg

SW5kZXg8L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGVzdGVyb2wvYmxvb2Q8L2tleXdvcmQ+PGtleXdv

cmQ+RGVtZW50aWEvKmV0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48

a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlwZXJ0ZW5zaW9uLypjb21wbGljYXRp

b25zPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8

L2tleXdvcmQ+PGtleXdvcmQ+T2Jlc2l0eS8qY29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5d29y

ZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNTwveWVh

cj48cHViLWRhdGVzPjxkYXRlPk9jdDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAw

MDMtOTk0MiAoUHJpbnQpJiN4RDswMDAzLTk5NDIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24t

bnVtPjE2MjE2OTM4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRw

Oi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE2MjE2OTM4PC91cmw+PC9yZWxhdGVkLXVy

bHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDAxL2FyY2huZXVyLjYyLjEw

LjE1NTY8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPktpdmlwZWx0bzwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+PFJlY051bT4zNTc8L1JlY051

bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM1NzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg

YXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGlt

ZXN0YW1wPSIxNTMyNTQ4NTk0Ij4zNTc8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt

ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48

YXV0aG9yPktpdmlwZWx0bywgTS48L2F1dGhvcj48YXV0aG9yPkhlbGthbGEsIEUuIEwuPC9hdXRo

b3I+PGF1dGhvcj5MYWFrc28sIE0uIFAuPC9hdXRob3I+PGF1dGhvcj5IYW5uaW5lbiwgVC48L2F1

dGhvcj48YXV0aG9yPkhhbGxpa2FpbmVuLCBNLjwvYXV0aG9yPjxhdXRob3I+QWxoYWluZW4sIEsu

PC9hdXRob3I+PGF1dGhvcj5JaXZvbmVuLCBTLjwvYXV0aG9yPjxhdXRob3I+TWFubmVybWFhLCBB

LjwvYXV0aG9yPjxhdXRob3I+VHVvbWlsZWh0bywgSi48L2F1dGhvcj48YXV0aG9yPk5pc3NpbmVu

LCBBLjwvYXV0aG9yPjxhdXRob3I+U29pbmluZW4sIEguPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+VW5pdmVyc2l0eSBvZiBLdW9waW8sIERlcGFydG1lbnQg

b2YgTmV1cm9zY2llbmNlIGFuZCBOZXVyb2xvZ3ksIFBPIEJveCAxNjI3LCA3MDIxMSBLdW9waW8s

IEZpbmxhbmQuIG1paWEua2l2aXBlbHRvQHVrdS5maTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRp

dGxlPkFwb2xpcG9wcm90ZWluIEUgZXBzaWxvbjQgYWxsZWxlLCBlbGV2YXRlZCBtaWRsaWZlIHRv

dGFsIGNob2xlc3Rlcm9sIGxldmVsLCBhbmQgaGlnaCBtaWRsaWZlIHN5c3RvbGljIGJsb29kIHBy

ZXNzdXJlIGFyZSBpbmRlcGVuZGVudCByaXNrIGZhY3RvcnMgZm9yIGxhdGUtbGlmZSBBbHpoZWlt

ZXIgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Bbm4gSW50ZXJuIE1lZDwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xNDktNTU8L3BhZ2VzPjx2b2x1bWU+MTM3PC92b2x1

bWU+PG51bWJlcj4zPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+KkFsbGVsZXM8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvZGlhZ25v

c2lzLypldGlvbG9neS8qcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9w

cm90ZWlucyBFLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5CbG9vZCBQcmVzc3VyZS8qcGh5

c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0ZXJvbC8qYmxvb2Q8L2tleXdvcmQ+PGtl

eXdvcmQ+RGVtZW50aWEvZGlhZ25vc2lzL2V0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZvbGxv

dy1VcCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmV0aWMgUHJlZGlzcG9zaXRpb24gdG8g

RGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5HZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5IdW1h

bnM8L2tleXdvcmQ+PGtleXdvcmQ+TG9uZ2l0dWRpbmFsIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdv

cmQ+UHJvc3BlY3RpdmUgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5SZWdyZXNzaW9uIEFuYWx5

c2lzPC9rZXl3b3JkPjxrZXl3b3JkPlJpc2sgRmFjdG9yczwva2V5d29yZD48L2tleXdvcmRzPjxk

YXRlcz48eWVhcj4yMDAyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXVnIDY8L2RhdGU+PC9wdWIt

ZGF0ZXM+PC9kYXRlcz48aXNibj4xNTM5LTM3MDQgKEVsZWN0cm9uaWMpJiN4RDswMDAzLTQ4MTkg

KExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjEyMTYwMzYyPC9hY2Nlc3Npb24tbnVtPjx1

cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVk

LzEyMTYwMzYyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0

ZT48QXV0aG9yPkNlZGF6by1NaW5ndWV6PC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVjTnVt

PjMzMTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MzMxPC9yZWMtbnVtYmVyPjxmb3JlaWdu

LWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpw

cnB0NWF2IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzgiPjMzMTwva2V5PjwvZm9yZWlnbi1rZXlzPjxy

ZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3Jz

PjxhdXRob3JzPjxhdXRob3I+Q2VkYXpvLU1pbmd1ZXosIEEuPC9hdXRob3I+PGF1dGhvcj5Db3di

dXJuLCBSLiBGLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNz

Pkthcm9saW5za2EgSW5zdGl0dXRldCwgTkVVUk9URUMsIERpdmlzaW9uIG9mIEV4cGVyaW1lbnRh

bCBHZXJpYXRyaWNzLCBOb3Z1bSwgS0ZDLCBIdWRkaW5nZSwgU3RvY2tob2xtLCBTd2VkZW4uIEFu

Z2VsLkNlZGF6by1NaW5ndWV6QG5ldXJvdGVjLmtpLnNlPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48

dGl0bGU+QXBvbGlwb3Byb3RlaW4gRTogYSBtYWpvciBwaWVjZSBpbiB0aGUgQWx6aGVpbWVyJmFw

b3M7cyBkaXNlYXNlIHB1enpsZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIENlbGwgTW9sIE1l

ZDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4yNTQtNjY8L3BhZ2VzPjx2b2x1bWU+

NTwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIg

RGlzZWFzZS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMgRS8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0ZXJvbC9tZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5MaXBpZCBNZXRhYm9saXNtPC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5KdWwtU2VwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU4Mi0xODM4IChQcmlu

dCkmI3hEOzE1ODItMTgzOCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTIwNjc0ODQ8

L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5u

bG0ubmloLmdvdi9wdWJtZWQvMTIwNjc0ODQ8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9y

ZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PcnRoPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVj

TnVtPjgzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+NDEw

LTQxNDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjgzPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE0MjQwOTc2OTIiPjgzPC9rZXk+PGtleSBh

cHA9IkVOV2ViIiBkYi1pZD0iIj4wPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5PcnRoLCBNLjwvYXV0aG9yPjxhdXRob3I+QmVsbG9zdGEsIFMuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+SW5zdGl0dXQgZnVyIExhYm9yYXRvcml1

bXNtZWRpemluLCBWaW56ZW56IHZvbiBQYXVsIEtsaW5pa2VuIGdHbWJILCBBZGxlcnN0cmEgYmV0

YSBlIDcsIFBvc3RmYWNoIDEwMzE2MywgNzAxOTkgU3R1dHRnYXJ0LCBHZXJtYW55LjwvYXV0aC1h

ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNob2xlc3Rlcm9sOiBpdHMgcmVndWxhdGlvbiBhbmQgcm9s

ZSBpbiBjZW50cmFsIG5lcnZvdXMgc3lzdGVtIGRpc29yZGVyczwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5DaG9sZXN0ZXJvbDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+Q2hvbGVzdGVyb2w8

L2FsdC10aXRsZT48L3RpdGxlcz48cGFnZXM+MjkyNTk4PC9wYWdlcz48dm9sdW1lPjIwMTI8L3Zv

bHVtZT48ZGF0ZXM+PHllYXI+MjAxMjwveWVhcj48L2RhdGVzPjxpc2JuPjIwOTAtMTI5MSAoRWxl

Y3Ryb25pYykmI3hEOzIwOTAtMTI4MyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjMx

MTkxNDk8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjMxMTkxNDk8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGN1c3RvbTI+MzQ4MzY1MjwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu

MTE1NS8yMDEyLzI5MjU5ODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRl

PjxDaXRlPjxBdXRob3I+Q2VkYXpvLU1pbmd1ZXo8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

ZWNOdW0+MzAyPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zMDI8L3JlYy1udW1iZXI+PGZv

cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6

dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMTc3NTI3NiI+MzAyPC9rZXk+PC9mb3JlaWduLWtl

eXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmli

dXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DZWRhem8tTWluZ3VleiwgQS48L2F1dGhvcj48YXV0aG9y

PklzbWFpbCwgTS4gQS48L2F1dGhvcj48YXV0aG9yPk1hdGVvcywgTC48L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9n

eSwgQ2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LUFsemhl

aW1lciZhcG9zO3MgRGlzZWFzZSBSZXNlYXJjaCBDZW50ZXIsIE5PVlVNLCA1dGggZmxvb3IsIFNF

LTE0MTg2IFN0b2NraG9sbSwgU3dlZGVuLiBhbmdlbC5jZWRhem8tbWluZ3VlekBraS5zZTwvYXV0

aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlBsYXNtYSBjaG9sZXN0ZXJvbCBhbmQgcmlzayBmb3Ig

bGF0ZS1vbnNldCBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0

bGU+RXhwZXJ0IFJldiBOZXVyb3RoZXI8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+

NDk1LTg8L3BhZ2VzPjx2b2x1bWU+MTE8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZGF0ZXM+

PHllYXI+MjAxMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkFwcjwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjE3NDQtODM2MCAoRWxlY3Ryb25pYykmI3hEOzE0NzMtNzE3NSAoTGlua2lu

Zyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjE0Njk5MjI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJl

bGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjE0Njk5

MjI8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEw

LjE1ODYvZXJuLjExLjM2PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+

PENpdGU+PEF1dGhvcj5LaXZpcGVsdG88L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxSZWNOdW0+

MzU1PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zNTU8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBy

cHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjU0ODU5NCI+MzU1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5LaXZpcGVsdG8sIE0uPC9hdXRob3I+PGF1dGhvcj5OZ2FuZHUsIFQu

PC9hdXRob3I+PGF1dGhvcj5GcmF0aWdsaW9uaSwgTC48L2F1dGhvcj48YXV0aG9yPlZpaXRhbmVu

LCBNLjwvYXV0aG9yPjxhdXRob3I+S2FyZWhvbHQsIEkuPC9hdXRob3I+PGF1dGhvcj5XaW5ibGFk

LCBCLjwvYXV0aG9yPjxhdXRob3I+SGVsa2FsYSwgRS4gTC48L2F1dGhvcj48YXV0aG9yPlR1b21p

bGVodG8sIEouPC9hdXRob3I+PGF1dGhvcj5Tb2luaW5lbiwgSC48L2F1dGhvcj48YXV0aG9yPk5p

c3NpbmVuLCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNz

PkFnaW5nIFJlc2VhcmNoIENlbnRlciwgRGl2aXNpb24gb2YgR2VyaWF0cmljIEVwaWRlbWlvbG9n

eSwgTmV1cm90ZWMsIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW4uIG1p

aWEua2l2aXBlbHRvQG5ldXJvdGVjLmtpLnNlPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+

T2Jlc2l0eSBhbmQgdmFzY3VsYXIgcmlzayBmYWN0b3JzIGF0IG1pZGxpZmUgYW5kIHRoZSByaXNr

IG9mIGRlbWVudGlhIGFuZCBBbHpoZWltZXIgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5BcmNoIE5ldXJvbDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xNTU2LTYwPC9w

YWdlcz48dm9sdW1lPjYyPC92b2x1bWU+PG51bWJlcj4xMDwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5

d29yZD5BZ2UgRmFjdG9yczwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3Jk

PkFsemhlaW1lciBEaXNlYXNlLypldGlvbG9neTwva2V5d29yZD48a2V5d29yZD5Cb2R5IE1hc3Mg

SW5kZXg8L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGVzdGVyb2wvYmxvb2Q8L2tleXdvcmQ+PGtleXdv

cmQ+RGVtZW50aWEvKmV0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48

a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlwZXJ0ZW5zaW9uLypjb21wbGljYXRp

b25zPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8

L2tleXdvcmQ+PGtleXdvcmQ+T2Jlc2l0eS8qY29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5d29y

ZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNTwveWVh

cj48cHViLWRhdGVzPjxkYXRlPk9jdDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAw

MDMtOTk0MiAoUHJpbnQpJiN4RDswMDAzLTk5NDIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24t

bnVtPjE2MjE2OTM4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRw

Oi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE2MjE2OTM4PC91cmw+PC9yZWxhdGVkLXVy

bHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDAxL2FyY2huZXVyLjYyLjEw

LjE1NTY8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPktpdmlwZWx0bzwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+PFJlY051bT4zNTc8L1JlY051

bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM1NzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg

YXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGlt

ZXN0YW1wPSIxNTMyNTQ4NTk0Ij4zNTc8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt

ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48

YXV0aG9yPktpdmlwZWx0bywgTS48L2F1dGhvcj48YXV0aG9yPkhlbGthbGEsIEUuIEwuPC9hdXRo

b3I+PGF1dGhvcj5MYWFrc28sIE0uIFAuPC9hdXRob3I+PGF1dGhvcj5IYW5uaW5lbiwgVC48L2F1

dGhvcj48YXV0aG9yPkhhbGxpa2FpbmVuLCBNLjwvYXV0aG9yPjxhdXRob3I+QWxoYWluZW4sIEsu

PC9hdXRob3I+PGF1dGhvcj5JaXZvbmVuLCBTLjwvYXV0aG9yPjxhdXRob3I+TWFubmVybWFhLCBB

LjwvYXV0aG9yPjxhdXRob3I+VHVvbWlsZWh0bywgSi48L2F1dGhvcj48YXV0aG9yPk5pc3NpbmVu

LCBBLjwvYXV0aG9yPjxhdXRob3I+U29pbmluZW4sIEguPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+VW5pdmVyc2l0eSBvZiBLdW9waW8sIERlcGFydG1lbnQg

b2YgTmV1cm9zY2llbmNlIGFuZCBOZXVyb2xvZ3ksIFBPIEJveCAxNjI3LCA3MDIxMSBLdW9waW8s

IEZpbmxhbmQuIG1paWEua2l2aXBlbHRvQHVrdS5maTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRp

dGxlPkFwb2xpcG9wcm90ZWluIEUgZXBzaWxvbjQgYWxsZWxlLCBlbGV2YXRlZCBtaWRsaWZlIHRv

dGFsIGNob2xlc3Rlcm9sIGxldmVsLCBhbmQgaGlnaCBtaWRsaWZlIHN5c3RvbGljIGJsb29kIHBy

ZXNzdXJlIGFyZSBpbmRlcGVuZGVudCByaXNrIGZhY3RvcnMgZm9yIGxhdGUtbGlmZSBBbHpoZWlt

ZXIgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Bbm4gSW50ZXJuIE1lZDwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xNDktNTU8L3BhZ2VzPjx2b2x1bWU+MTM3PC92b2x1

bWU+PG51bWJlcj4zPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+KkFsbGVsZXM8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvZGlhZ25v

c2lzLypldGlvbG9neS8qcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9w

cm90ZWlucyBFLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5CbG9vZCBQcmVzc3VyZS8qcGh5

c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0ZXJvbC8qYmxvb2Q8L2tleXdvcmQ+PGtl

eXdvcmQ+RGVtZW50aWEvZGlhZ25vc2lzL2V0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZvbGxv

dy1VcCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmV0aWMgUHJlZGlzcG9zaXRpb24gdG8g

RGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5HZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5IdW1h

bnM8L2tleXdvcmQ+PGtleXdvcmQ+TG9uZ2l0dWRpbmFsIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdv

cmQ+UHJvc3BlY3RpdmUgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5SZWdyZXNzaW9uIEFuYWx5

c2lzPC9rZXl3b3JkPjxrZXl3b3JkPlJpc2sgRmFjdG9yczwva2V5d29yZD48L2tleXdvcmRzPjxk

YXRlcz48eWVhcj4yMDAyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXVnIDY8L2RhdGU+PC9wdWIt

ZGF0ZXM+PC9kYXRlcz48aXNibj4xNTM5LTM3MDQgKEVsZWN0cm9uaWMpJiN4RDswMDAzLTQ4MTkg

KExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjEyMTYwMzYyPC9hY2Nlc3Npb24tbnVtPjx1

cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVk

LzEyMTYwMzYyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0

ZT48QXV0aG9yPkNlZGF6by1NaW5ndWV6PC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVjTnVt

PjMzMTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MzMxPC9yZWMtbnVtYmVyPjxmb3JlaWdu

LWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpw

cnB0NWF2IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzgiPjMzMTwva2V5PjwvZm9yZWlnbi1rZXlzPjxy

ZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3Jz

PjxhdXRob3JzPjxhdXRob3I+Q2VkYXpvLU1pbmd1ZXosIEEuPC9hdXRob3I+PGF1dGhvcj5Db3di

dXJuLCBSLiBGLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNz

Pkthcm9saW5za2EgSW5zdGl0dXRldCwgTkVVUk9URUMsIERpdmlzaW9uIG9mIEV4cGVyaW1lbnRh

bCBHZXJpYXRyaWNzLCBOb3Z1bSwgS0ZDLCBIdWRkaW5nZSwgU3RvY2tob2xtLCBTd2VkZW4uIEFu

Z2VsLkNlZGF6by1NaW5ndWV6QG5ldXJvdGVjLmtpLnNlPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48

dGl0bGU+QXBvbGlwb3Byb3RlaW4gRTogYSBtYWpvciBwaWVjZSBpbiB0aGUgQWx6aGVpbWVyJmFw

b3M7cyBkaXNlYXNlIHB1enpsZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIENlbGwgTW9sIE1l

ZDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4yNTQtNjY8L3BhZ2VzPjx2b2x1bWU+

NTwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIg

RGlzZWFzZS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMgRS8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0ZXJvbC9tZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5MaXBpZCBNZXRhYm9saXNtPC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5KdWwtU2VwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU4Mi0xODM4IChQcmlu

dCkmI3hEOzE1ODItMTgzOCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTIwNjc0ODQ8

L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5u

bG0ubmloLmdvdi9wdWJtZWQvMTIwNjc0ODQ8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9y

ZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 410-414; however, cholesterol is unable to cross the blood-brain barrier. In the last two decades, BBB permeable cholesterol metabolites (known collectively as oxysterols) have been identified as well as their role in cholesterol metabolism regulation in the brain PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cam9ya2hlbTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+

PFJlY051bT4zMTM8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zOTQsNDE1LTQxOTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjMx

MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUy

cHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMxNzc1Mjc2Ij4zMTM8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJqb3JraGVtLCBJLjwvYXV0

aG9yPjxhdXRob3I+Q2VkYXpvLU1pbmd1ZXosIEEuPC9hdXRob3I+PGF1dGhvcj5MZW9uaSwgVi48

L2F1dGhvcj48YXV0aG9yPk1lYW5leSwgUy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIExhYm9yYXRvcnkgTWVkaWNpbmUsIEthcm9s

aW5za2EgSW5zdGl0dXRldCwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIdWRkaW5n

ZSwgU3dlZGVuLiBpbmdlbWFyLmJqb3JraGVtQGthcm9saW5za2Euc2U8L2F1dGgtYWRkcmVzcz48

dGl0bGVzPjx0aXRsZT5PeHlzdGVyb2xzIGFuZCBuZXVyb2RlZ2VuZXJhdGl2ZSBkaXNlYXNlczwv

dGl0bGU+PHNlY29uZGFyeS10aXRsZT5Nb2wgQXNwZWN0cyBNZWQ8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTcxLTk8L3BhZ2VzPjx2b2x1bWU+MzA8L3ZvbHVtZT48bnVtYmVyPjM8

L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzLyptZXRhYm9s

aXNtPC9rZXl3b3JkPjxrZXl3b3JkPkJsb29kLUJyYWluIEJhcnJpZXIvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5DeXRvc2tlbGV0YWwgUHJvdGVpbnMvbWV0YWJvbGlzbTwva2V5d29yZD48

a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy8qbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5OZXJ2ZSBUaXNzdWUgUHJvdGVpbnMvbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5OZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcy8qbWV0YWJvbGlz

bTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA5PC95ZWFyPjxwdWItZGF0ZXM+

PGRhdGU+SnVuPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTg3Mi05NDUyIChFbGVj

dHJvbmljKSYjeEQ7MDA5OC0yOTk3IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xOTI0

ODgwMzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xOTI0ODgwMzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLm1hbS4yMDA5LjAyLjAwMTwvZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Qmpvcmto

ZW08L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxSZWNOdW0+NDQwPC9SZWNOdW0+PHJlY29yZD48

cmVjLW51bWJlcj40NDA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRi

LWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUz

MjU0OTk0NCI+NDQwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwg

QXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Cam9y

a2hlbSwgSS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5E

aXZpc2lvbiBvZiBDbGluaWNhbCBDaGVtaXN0cnksIERlcGFydG1lbnQgb2YgTGFib3JhdG9yeSBN

ZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIdWRkaW5nZSwgU3dlZGVu

LiBpbmdlbWFyLmJqb3JraGVtQGthcm9saW5za2Euc2U8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0

aXRsZT5Dcm9zc2luZyB0aGUgYmFycmllcjogb3h5c3Rlcm9scyBhcyBjaG9sZXN0ZXJvbCB0cmFu

c3BvcnRlcnMgYW5kIG1ldGFib2xpYyBtb2R1bGF0b3JzIGluIHRoZSBicmFpbjwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5KIEludGVybiBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5KIEludGVybiBNZWQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz40OTMtNTA4PC9wYWdlcz48dm9sdW1lPjI2MDwvdm9sdW1lPjxudW1iZXI+NjwvbnVt

YmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9tZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9iaW9zeW50aGVzaXM8L2tleXdvcmQ+

PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CaW9sb2dpY2FsIFRyYW5zcG9ydC9w

aHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJsb29kLUJyYWluIEJhcnJpZXIvbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5CcmFpbi8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5C

cmFpbiBEaXNlYXNlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sLypt

ZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sIDI0LUh5ZHJveHlsYXNlPC9r

ZXl3b3JkPjxrZXl3b3JkPkhvbWVvc3Rhc2lzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5ZHJveHljaG9sZXN0ZXJvbHMvYmxvb2QvKm1ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SW5mYW50PC9rZXl3b3JkPjxrZXl3b3JkPlJhdHM8L2tl

eXdvcmQ+PGtleXdvcmQ+U3Rlcm9pZCBIeWRyb3h5bGFzZXMvZ2VuZXRpY3MvbWV0YWJvbGlzbTwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA2PC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+RGVjPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDk1NC02ODIwIChQcmludCkm

I3hEOzA5NTQtNjgyMCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTcxMTYwMDA8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMTcxMTYwMDA8L3VybD48dXJsPmh0dHBzOi8vb25saW5lbGlicmFyeS53

aWxleS5jb20vZG9pL3BkZi8xMC4xMTExL2ouMTM2NS0yNzk2LjIwMDYuMDE3MjUueDwvdXJsPjwv

cmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTExMS9qLjEz

NjUtMjc5Ni4yMDA2LjAxNzI1Lng8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48Q2l0ZT48QXV0aG9yPkx1dGpvaGFubjwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+PFJl

Y051bT40NjM8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjQ2MzwvcmVjLW51bWJlcj48Zm9y

ZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0

c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTQ5OTQ3Ij40NjM8L2tleT48L2ZvcmVpZ24ta2V5

cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1

dG9ycz48YXV0aG9ycz48YXV0aG9yPkx1dGpvaGFubiwgRC48L2F1dGhvcj48YXV0aG9yPkJqb3Jr

aGVtLCBJLjwvYXV0aG9yPjxhdXRob3I+TG9jYXRlbGxpLCBTLjwvYXV0aG9yPjxhdXRob3I+RGFt

ZSwgQy48L2F1dGhvcj48YXV0aG9yPlNjaG1vbGxpbmcsIEouPC9hdXRob3I+PGF1dGhvcj52b24g

QmVyZ21hbm4sIEsuPC9hdXRob3I+PGF1dGhvcj5GYWhuZW5zdGljaCwgSC48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIENsaW5pY2Fs

IFBoYXJtYWNvbG9neSwgVW5pdmVyc2l0eSBvZiBCb25uLCBHZXJtYW55LiBkLmx1ZXRqb2hhbm5A

dW5pLWJvbm4uZGU8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5DaG9sZXN0ZXJvbCBkeW5h

bWljcyBpbiB0aGUgZm9ldGFsIGFuZCBuZW9uYXRhbCBicmFpbiBhcyByZWZsZWN0ZWQgYnkgY2ly

Y3VsYXRvcnkgbGV2ZWxzIG9mIDI0Uy1oeWRyb3h5Y2hvbGVzdGVyb2w8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+QWN0YSBQYWVkaWF0cjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2Rp

Y2FsPjxmdWxsLXRpdGxlPkFjdGEgUGFlZGlhdHI8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxw

YWdlcz42NTItNzwvcGFnZXM+PHZvbHVtZT45MDwvdm9sdW1lPjxudW1iZXI+NjwvbnVtYmVyPjxr

ZXl3b3Jkcz48a2V5d29yZD5CcmFpbi8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DaG9s

ZXN0ZXJvbC8qcGhhcm1hY29raW5ldGljczwva2V5d29yZD48a2V5d29yZD5Fcnl0aHJvYmxhc3Rv

c2lzLCBGZXRhbC9ibG9vZDwva2V5d29yZD48a2V5d29yZD5GZXR1cy8qbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9s

cy8qYmxvb2Q8L2tleXdvcmQ+PGtleXdvcmQ+SW5mYW50LCBOZXdib3JuLyptZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPkluZmFudCwgUHJlbWF0dXJlL2Jsb29kPC9rZXl3b3JkPjxrZXl3b3Jk

PkluZmFudCwgU21hbGwgZm9yIEdlc3RhdGlvbmFsIEFnZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxr

ZXl3b3JkPkxvbmdpdHVkaW5hbCBTdHVkaWVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5

ZWFyPjIwMDE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdW48L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4wODAzLTUyNTMgKFByaW50KSYjeEQ7MDgwMy01MjUzIChMaW5raW5nKTwvaXNi

bj48YWNjZXNzaW9uLW51bT4xMTQ0MDA5OTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11

cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xMTQ0MDA5OTwvdXJs

PjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5NZWFu

ZXk8L0F1dGhvcj48WWVhcj4yMDAxPC9ZZWFyPjxSZWNOdW0+NDY1PC9SZWNOdW0+PHJlY29yZD48

cmVjLW51bWJlcj40NjU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRi

LWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUz

MjU0OTk0OSI+NDY1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwg

QXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5NZWFu

ZXksIFMuPC9hdXRob3I+PGF1dGhvcj5IYXNzYW4sIE0uPC9hdXRob3I+PGF1dGhvcj5TYWtpbmlz

LCBBLjwvYXV0aG9yPjxhdXRob3I+THV0am9oYW5uLCBELjwvYXV0aG9yPjxhdXRob3I+dm9uIEJl

cmdtYW5uLCBLLjwvYXV0aG9yPjxhdXRob3I+V2Vubm1hbG0sIEEuPC9hdXRob3I+PGF1dGhvcj5E

aWN6ZmFsdXN5LCBVLjwvYXV0aG9yPjxhdXRob3I+QmpvcmtoZW0sIEkuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGl2aXNpb24gb2YgQ2xpbmljYWwgQ2hl

bWlzdHJ5LCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIEh1ZGRpbmdlIFVuaXZlcnNpdHkgSG9zcGl0

YWwsIFNFLTE0MSA4NiBIdWRkaW5nZSwgU3dlZGVuLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRp

dGxlPkV2aWRlbmNlIHRoYXQgdGhlIG1ham9yIG94eXN0ZXJvbHMgaW4gaHVtYW4gY2lyY3VsYXRp

b24gb3JpZ2luYXRlIGZyb20gZGlzdGluY3QgcG9vbHMgb2YgY2hvbGVzdGVyb2w6IGEgc3RhYmxl

IGlzb3RvcGUgc3R1ZHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBMaXBpZCBSZXM8L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NzAtODwvcGFnZXM+PHZvbHVtZT40Mjwvdm9sdW1l

PjxudW1iZXI+MTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5CbG9vZCBDaXJjdWxhdGlvbjwv

a2V5d29yZD48a2V5d29yZD5DaG9sZXN0ZXJvbC9hZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2Uv

KnBoYXJtYWNva2luZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+RGV1dGVyaXVtPC9rZXl3b3JkPjxr

ZXl3b3JkPkhhbGYtTGlmZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdv

cmQ+SHlkcm94eWNob2xlc3Rlcm9scy8qYmxvb2Q8L2tleXdvcmQ+PGtleXdvcmQ+T3JnYW4gU3Bl

Y2lmaWNpdHk8L2tleXdvcmQ+PGtleXdvcmQ+T3h5Z2VuL3BoYXJtYWNva2luZXRpY3M8L2tleXdv

cmQ+PGtleXdvcmQ+T3h5Z2VuIElzb3RvcGVzPC9rZXl3b3JkPjxrZXl3b3JkPlRpbWUgRmFjdG9y

czwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDAxPC95ZWFyPjxwdWItZGF0ZXM+

PGRhdGU+SmFuPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDAyMi0yMjc1IChQcmlu

dCkmI3hEOzAwMjItMjI3NSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTExNjAzNjc8

L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5u

bG0ubmloLmdvdi9wdWJtZWQvMTExNjAzNjc8L3VybD48dXJsPmh0dHA6Ly93d3cuamxyLm9yZy9j

b250ZW50LzQyLzEvNzAuZnVsbC5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNv

cmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TWVhbmV5PC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48

UmVjTnVtPjQ2NzwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+NDY3PC9yZWMtbnVtYmVyPjxm

b3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5

enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI1NDk5NDkiPjQ2Nzwva2V5PjwvZm9yZWlnbi1r

ZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJp

YnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWVhbmV5LCBTLjwvYXV0aG9yPjxhdXRob3I+THV0am9o

YW5uLCBELjwvYXV0aG9yPjxhdXRob3I+RGljemZhbHVzeSwgVS48L2F1dGhvcj48YXV0aG9yPkJq

b3JraGVtLCBJLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNz

PkRpdmlzaW9uIG9mIENsaW5pY2FsIENoZW1pc3RyeSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0IGF0

IEh1ZGRpbmdlIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCBTd2VkZW4uPC9hdXRoLWFk

ZHJlc3M+PHRpdGxlcz48dGl0bGU+Rm9ybWF0aW9uIG9mIG94eXN0ZXJvbHMgZnJvbSBkaWZmZXJl

bnQgcG9vbHMgb2YgY2hvbGVzdGVyb2wgYXMgc3R1ZGllZCBieSBzdGFibGUgaXNvdG9wZSB0ZWNo

bmlxdWU6IGNlcmVicmFsIG9yaWdpbiBvZiBtb3N0IGNpcmN1bGF0aW5nIDI0Uy1oeWRyb3h5Y2hv

bGVzdGVyb2wgaW4gcmF0cywgYnV0IG5vdCBpbiBtaWNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PkJpb2NoaW0gQmlvcGh5cyBBY3RhPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+QmlvY2hpbSBCaW9waHlzIEFjdGE8L2Z1bGwtdGl0bGU+PGFiYnItMT5C

aW9jaGltaWNhIGV0IGJpb3BoeXNpY2EgYWN0YTwvYWJici0xPjwvcGVyaW9kaWNhbD48cGFnZXM+

MjkzLTg8L3BhZ2VzPjx2b2x1bWU+MTQ4Njwvdm9sdW1lPjxudW1iZXI+Mi0zPC9udW1iZXI+PGtl

eXdvcmRzPjxrZXl3b3JkPkFkcmVuYWwgR2xhbmRzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CcmFpbi8qbWV0YWJvbGlzbTwva2V5d29yZD48

a2V5d29yZD5DaG9sZXN0ZXJvbCAyNC1IeWRyb3h5bGFzZTwva2V5d29yZD48a2V5d29yZD5DaG9s

ZXN0ZXJvbCwgRGlldGFyeS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5EZXV0ZXJpdW08

L2tleXdvcmQ+PGtleXdvcmQ+R2FzIENocm9tYXRvZ3JhcGh5LU1hc3MgU3BlY3Ryb21ldHJ5PC9r

ZXl3b3JkPjxrZXl3b3JkPkh5ZHJveHljaG9sZXN0ZXJvbHMvYmxvb2Q8L2tleXdvcmQ+PGtleXdv

cmQ+TGl2ZXIvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3

b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+UmF0czwva2V5d29yZD48a2V5d29yZD5SYXRzLCBT

cHJhZ3VlLURhd2xleTwva2V5d29yZD48a2V5d29yZD5TdGVyb2lkIEh5ZHJveHlsYXNlcy8qbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5UZXN0aXMvbWV0YWJvbGlzbTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDAwPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVsIDE5PC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDAwNi0zMDAyIChQcmludCkmI3hEOzAwMDYt

MzAwMiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTA5MDM0ODA8L2FjY2Vzc2lvbi1u

dW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9w

dWJtZWQvMTA5MDM0ODA8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRl

PjxDaXRlPjxBdXRob3I+THV0am9oYW5uPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48UmVjTnVt

PjQyMTQ8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjQyMTQ8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjc3NzQ1NCI+NDIxNDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+THV0am9oYW5uLCBELjwvYXV0aG9yPjxhdXRob3I+QnJldWVy

LCBPLjwvYXV0aG9yPjxhdXRob3I+QWhsYm9yZywgRy48L2F1dGhvcj48YXV0aG9yPk5lbm5lc21v

LCBJLjwvYXV0aG9yPjxhdXRob3I+U2lkZW4sIEEuPC9hdXRob3I+PGF1dGhvcj5EaWN6ZmFsdXN5

LCBVLjwvYXV0aG9yPjxhdXRob3I+QmpvcmtoZW0sIEkuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGl2aXNpb24gb2YgQ2xpbmljYWwgQ2hlbWlzdHJ5LCBL

YXJvbGluc2thIEluc3RpdHV0ZSwgSHVkZGluZ2UgVW5pdmVyc2l0eSBIb3NwaXRhbCwgU3dlZGVu

LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNob2xlc3Rlcm9sIGhvbWVvc3Rhc2lzIGlu

IGh1bWFuIGJyYWluOiBldmlkZW5jZSBmb3IgYW4gYWdlLWRlcGVuZGVudCBmbHV4IG9mIDI0Uy1o

eWRyb3h5Y2hvbGVzdGVyb2wgZnJvbSB0aGUgYnJhaW4gaW50byB0aGUgY2lyY3VsYXRpb248L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9zZWNvbmRhcnkt

dGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2Np

IFUgUyBBPC9mdWxsLXRpdGxlPjxhYmJyLTE+UHJvY2VlZGluZ3Mgb2YgdGhlIE5hdGlvbmFsIEFj

YWRlbXkgb2YgU2NpZW5jZXMgb2YgdGhlIFVuaXRlZCBTdGF0ZXMgb2YgQW1lcmljYTwvYWJici0x

PjwvcGVyaW9kaWNhbD48cGFnZXM+OTc5OS04MDQ8L3BhZ2VzPjx2b2x1bWU+OTM8L3ZvbHVtZT48

bnVtYmVyPjE4PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkb2xlc2NlbnQ8L2tleXdvcmQ+

PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5B

Z2luZy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3

b3JkPkJyYWluLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkNoaWxkPC9rZXl3b3JkPjxr

ZXl3b3JkPkNoaWxkLCBQcmVzY2hvb2w8L2tleXdvcmQ+PGtleXdvcmQ+Q2lyY2FkaWFuIFJoeXRo

bTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+KkhvbWVvc3Rhc2lz

PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IeWRyb3h5Y2hvbGVz

dGVyb2xzL2Jsb29kL2NlcmVicm9zcGluYWwgZmx1aWQvKm1ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+SW5mYW50PC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlk

ZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+T3h5Z2VuPC9rZXl3b3JkPjxrZXl3b3JkPlJhdHM8

L2tleXdvcmQ+PGtleXdvcmQ+UmVmZXJlbmNlIFZhbHVlczwva2V5d29yZD48a2V5d29yZD5TdGVy

ZW9pc29tZXJpc208L2tleXdvcmQ+PGtleXdvcmQ+VGlzc3VlIERpc3RyaWJ1dGlvbjwva2V5d29y

ZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2Vw

IDM8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDI3LTg0MjQgKFByaW50KSYjeEQ7

MDAyNy04NDI0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT44NzkwNDExPC9hY2Nlc3Np

b24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5n

b3YvcHVibWVkLzg3OTA0MTE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1D

Mzg1MDk8L2N1c3RvbTI+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cam9ya2hlbTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+

PFJlY051bT4zMTM8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zOTQsNDE1LTQxOTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjMx

MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUy

cHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMxNzc1Mjc2Ij4zMTM8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJqb3JraGVtLCBJLjwvYXV0

aG9yPjxhdXRob3I+Q2VkYXpvLU1pbmd1ZXosIEEuPC9hdXRob3I+PGF1dGhvcj5MZW9uaSwgVi48

L2F1dGhvcj48YXV0aG9yPk1lYW5leSwgUy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv

cnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIExhYm9yYXRvcnkgTWVkaWNpbmUsIEthcm9s

aW5za2EgSW5zdGl0dXRldCwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIdWRkaW5n

ZSwgU3dlZGVuLiBpbmdlbWFyLmJqb3JraGVtQGthcm9saW5za2Euc2U8L2F1dGgtYWRkcmVzcz48

dGl0bGVzPjx0aXRsZT5PeHlzdGVyb2xzIGFuZCBuZXVyb2RlZ2VuZXJhdGl2ZSBkaXNlYXNlczwv

dGl0bGU+PHNlY29uZGFyeS10aXRsZT5Nb2wgQXNwZWN0cyBNZWQ8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+MTcxLTk8L3BhZ2VzPjx2b2x1bWU+MzA8L3ZvbHVtZT48bnVtYmVyPjM8

L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzLyptZXRhYm9s

aXNtPC9rZXl3b3JkPjxrZXl3b3JkPkJsb29kLUJyYWluIEJhcnJpZXIvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5DeXRvc2tlbGV0YWwgUHJvdGVpbnMvbWV0YWJvbGlzbTwva2V5d29yZD48

a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy8qbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5OZXJ2ZSBUaXNzdWUgUHJvdGVpbnMvbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5OZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcy8qbWV0YWJvbGlz

bTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA5PC95ZWFyPjxwdWItZGF0ZXM+

PGRhdGU+SnVuPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTg3Mi05NDUyIChFbGVj

dHJvbmljKSYjeEQ7MDA5OC0yOTk3IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xOTI0

ODgwMzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xOTI0ODgwMzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLm1hbS4yMDA5LjAyLjAwMTwvZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Qmpvcmto

ZW08L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxSZWNOdW0+NDQwPC9SZWNOdW0+PHJlY29yZD48

cmVjLW51bWJlcj40NDA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRi

LWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUz

MjU0OTk0NCI+NDQwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwg

QXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Cam9y

a2hlbSwgSS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5E

aXZpc2lvbiBvZiBDbGluaWNhbCBDaGVtaXN0cnksIERlcGFydG1lbnQgb2YgTGFib3JhdG9yeSBN

ZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIdWRkaW5nZSwgU3dlZGVu

LiBpbmdlbWFyLmJqb3JraGVtQGthcm9saW5za2Euc2U8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0

aXRsZT5Dcm9zc2luZyB0aGUgYmFycmllcjogb3h5c3Rlcm9scyBhcyBjaG9sZXN0ZXJvbCB0cmFu

c3BvcnRlcnMgYW5kIG1ldGFib2xpYyBtb2R1bGF0b3JzIGluIHRoZSBicmFpbjwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5KIEludGVybiBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5KIEludGVybiBNZWQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz40OTMtNTA4PC9wYWdlcz48dm9sdW1lPjI2MDwvdm9sdW1lPjxudW1iZXI+NjwvbnVt

YmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9tZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9iaW9zeW50aGVzaXM8L2tleXdvcmQ+

PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CaW9sb2dpY2FsIFRyYW5zcG9ydC9w

aHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJsb29kLUJyYWluIEJhcnJpZXIvbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5CcmFpbi8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5C

cmFpbiBEaXNlYXNlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sLypt

ZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sIDI0LUh5ZHJveHlsYXNlPC9r

ZXl3b3JkPjxrZXl3b3JkPkhvbWVvc3Rhc2lzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5ZHJveHljaG9sZXN0ZXJvbHMvYmxvb2QvKm1ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SW5mYW50PC9rZXl3b3JkPjxrZXl3b3JkPlJhdHM8L2tl

eXdvcmQ+PGtleXdvcmQ+U3Rlcm9pZCBIeWRyb3h5bGFzZXMvZ2VuZXRpY3MvbWV0YWJvbGlzbTwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA2PC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+RGVjPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDk1NC02ODIwIChQcmludCkm

I3hEOzA5NTQtNjgyMCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTcxMTYwMDA8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMTcxMTYwMDA8L3VybD48dXJsPmh0dHBzOi8vb25saW5lbGlicmFyeS53

aWxleS5jb20vZG9pL3BkZi8xMC4xMTExL2ouMTM2NS0yNzk2LjIwMDYuMDE3MjUueDwvdXJsPjwv

cmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTExMS9qLjEz

NjUtMjc5Ni4yMDA2LjAxNzI1Lng8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwv

Q2l0ZT48Q2l0ZT48QXV0aG9yPkx1dGpvaGFubjwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+PFJl

Y051bT40NjM8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjQ2MzwvcmVjLW51bWJlcj48Zm9y

ZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0

c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTQ5OTQ3Ij40NjM8L2tleT48L2ZvcmVpZ24ta2V5

cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1

dG9ycz48YXV0aG9ycz48YXV0aG9yPkx1dGpvaGFubiwgRC48L2F1dGhvcj48YXV0aG9yPkJqb3Jr

aGVtLCBJLjwvYXV0aG9yPjxhdXRob3I+TG9jYXRlbGxpLCBTLjwvYXV0aG9yPjxhdXRob3I+RGFt

ZSwgQy48L2F1dGhvcj48YXV0aG9yPlNjaG1vbGxpbmcsIEouPC9hdXRob3I+PGF1dGhvcj52b24g

QmVyZ21hbm4sIEsuPC9hdXRob3I+PGF1dGhvcj5GYWhuZW5zdGljaCwgSC48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIENsaW5pY2Fs

IFBoYXJtYWNvbG9neSwgVW5pdmVyc2l0eSBvZiBCb25uLCBHZXJtYW55LiBkLmx1ZXRqb2hhbm5A

dW5pLWJvbm4uZGU8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5DaG9sZXN0ZXJvbCBkeW5h

bWljcyBpbiB0aGUgZm9ldGFsIGFuZCBuZW9uYXRhbCBicmFpbiBhcyByZWZsZWN0ZWQgYnkgY2ly

Y3VsYXRvcnkgbGV2ZWxzIG9mIDI0Uy1oeWRyb3h5Y2hvbGVzdGVyb2w8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+QWN0YSBQYWVkaWF0cjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2Rp

Y2FsPjxmdWxsLXRpdGxlPkFjdGEgUGFlZGlhdHI8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxw

YWdlcz42NTItNzwvcGFnZXM+PHZvbHVtZT45MDwvdm9sdW1lPjxudW1iZXI+NjwvbnVtYmVyPjxr

ZXl3b3Jkcz48a2V5d29yZD5CcmFpbi8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DaG9s

ZXN0ZXJvbC8qcGhhcm1hY29raW5ldGljczwva2V5d29yZD48a2V5d29yZD5Fcnl0aHJvYmxhc3Rv

c2lzLCBGZXRhbC9ibG9vZDwva2V5d29yZD48a2V5d29yZD5GZXR1cy8qbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9s

cy8qYmxvb2Q8L2tleXdvcmQ+PGtleXdvcmQ+SW5mYW50LCBOZXdib3JuLyptZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPkluZmFudCwgUHJlbWF0dXJlL2Jsb29kPC9rZXl3b3JkPjxrZXl3b3Jk

PkluZmFudCwgU21hbGwgZm9yIEdlc3RhdGlvbmFsIEFnZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxr

ZXl3b3JkPkxvbmdpdHVkaW5hbCBTdHVkaWVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5

ZWFyPjIwMDE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdW48L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4wODAzLTUyNTMgKFByaW50KSYjeEQ7MDgwMy01MjUzIChMaW5raW5nKTwvaXNi

bj48YWNjZXNzaW9uLW51bT4xMTQ0MDA5OTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11

cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xMTQ0MDA5OTwvdXJs

PjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5NZWFu

ZXk8L0F1dGhvcj48WWVhcj4yMDAxPC9ZZWFyPjxSZWNOdW0+NDY1PC9SZWNOdW0+PHJlY29yZD48

cmVjLW51bWJlcj40NjU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRi

LWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUz

MjU0OTk0OSI+NDY1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwg

QXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5NZWFu

ZXksIFMuPC9hdXRob3I+PGF1dGhvcj5IYXNzYW4sIE0uPC9hdXRob3I+PGF1dGhvcj5TYWtpbmlz

LCBBLjwvYXV0aG9yPjxhdXRob3I+THV0am9oYW5uLCBELjwvYXV0aG9yPjxhdXRob3I+dm9uIEJl

cmdtYW5uLCBLLjwvYXV0aG9yPjxhdXRob3I+V2Vubm1hbG0sIEEuPC9hdXRob3I+PGF1dGhvcj5E

aWN6ZmFsdXN5LCBVLjwvYXV0aG9yPjxhdXRob3I+QmpvcmtoZW0sIEkuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGl2aXNpb24gb2YgQ2xpbmljYWwgQ2hl

bWlzdHJ5LCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIEh1ZGRpbmdlIFVuaXZlcnNpdHkgSG9zcGl0

YWwsIFNFLTE0MSA4NiBIdWRkaW5nZSwgU3dlZGVuLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRp

dGxlPkV2aWRlbmNlIHRoYXQgdGhlIG1ham9yIG94eXN0ZXJvbHMgaW4gaHVtYW4gY2lyY3VsYXRp

b24gb3JpZ2luYXRlIGZyb20gZGlzdGluY3QgcG9vbHMgb2YgY2hvbGVzdGVyb2w6IGEgc3RhYmxl

IGlzb3RvcGUgc3R1ZHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBMaXBpZCBSZXM8L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NzAtODwvcGFnZXM+PHZvbHVtZT40Mjwvdm9sdW1l

PjxudW1iZXI+MTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5CbG9vZCBDaXJjdWxhdGlvbjwv

a2V5d29yZD48a2V5d29yZD5DaG9sZXN0ZXJvbC9hZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2Uv

KnBoYXJtYWNva2luZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+RGV1dGVyaXVtPC9rZXl3b3JkPjxr

ZXl3b3JkPkhhbGYtTGlmZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdv

cmQ+SHlkcm94eWNob2xlc3Rlcm9scy8qYmxvb2Q8L2tleXdvcmQ+PGtleXdvcmQ+T3JnYW4gU3Bl

Y2lmaWNpdHk8L2tleXdvcmQ+PGtleXdvcmQ+T3h5Z2VuL3BoYXJtYWNva2luZXRpY3M8L2tleXdv

cmQ+PGtleXdvcmQ+T3h5Z2VuIElzb3RvcGVzPC9rZXl3b3JkPjxrZXl3b3JkPlRpbWUgRmFjdG9y

czwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDAxPC95ZWFyPjxwdWItZGF0ZXM+

PGRhdGU+SmFuPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDAyMi0yMjc1IChQcmlu

dCkmI3hEOzAwMjItMjI3NSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTExNjAzNjc8

L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5u

bG0ubmloLmdvdi9wdWJtZWQvMTExNjAzNjc8L3VybD48dXJsPmh0dHA6Ly93d3cuamxyLm9yZy9j

b250ZW50LzQyLzEvNzAuZnVsbC5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNv

cmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TWVhbmV5PC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48

UmVjTnVtPjQ2NzwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+NDY3PC9yZWMtbnVtYmVyPjxm

b3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5

enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI1NDk5NDkiPjQ2Nzwva2V5PjwvZm9yZWlnbi1r

ZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJp

YnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWVhbmV5LCBTLjwvYXV0aG9yPjxhdXRob3I+THV0am9o

YW5uLCBELjwvYXV0aG9yPjxhdXRob3I+RGljemZhbHVzeSwgVS48L2F1dGhvcj48YXV0aG9yPkJq

b3JraGVtLCBJLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNz

PkRpdmlzaW9uIG9mIENsaW5pY2FsIENoZW1pc3RyeSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0IGF0

IEh1ZGRpbmdlIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCBTd2VkZW4uPC9hdXRoLWFk

ZHJlc3M+PHRpdGxlcz48dGl0bGU+Rm9ybWF0aW9uIG9mIG94eXN0ZXJvbHMgZnJvbSBkaWZmZXJl

bnQgcG9vbHMgb2YgY2hvbGVzdGVyb2wgYXMgc3R1ZGllZCBieSBzdGFibGUgaXNvdG9wZSB0ZWNo

bmlxdWU6IGNlcmVicmFsIG9yaWdpbiBvZiBtb3N0IGNpcmN1bGF0aW5nIDI0Uy1oeWRyb3h5Y2hv

bGVzdGVyb2wgaW4gcmF0cywgYnV0IG5vdCBpbiBtaWNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PkJpb2NoaW0gQmlvcGh5cyBBY3RhPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+QmlvY2hpbSBCaW9waHlzIEFjdGE8L2Z1bGwtdGl0bGU+PGFiYnItMT5C

aW9jaGltaWNhIGV0IGJpb3BoeXNpY2EgYWN0YTwvYWJici0xPjwvcGVyaW9kaWNhbD48cGFnZXM+

MjkzLTg8L3BhZ2VzPjx2b2x1bWU+MTQ4Njwvdm9sdW1lPjxudW1iZXI+Mi0zPC9udW1iZXI+PGtl

eXdvcmRzPjxrZXl3b3JkPkFkcmVuYWwgR2xhbmRzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CcmFpbi8qbWV0YWJvbGlzbTwva2V5d29yZD48

a2V5d29yZD5DaG9sZXN0ZXJvbCAyNC1IeWRyb3h5bGFzZTwva2V5d29yZD48a2V5d29yZD5DaG9s

ZXN0ZXJvbCwgRGlldGFyeS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5EZXV0ZXJpdW08

L2tleXdvcmQ+PGtleXdvcmQ+R2FzIENocm9tYXRvZ3JhcGh5LU1hc3MgU3BlY3Ryb21ldHJ5PC9r

ZXl3b3JkPjxrZXl3b3JkPkh5ZHJveHljaG9sZXN0ZXJvbHMvYmxvb2Q8L2tleXdvcmQ+PGtleXdv

cmQ+TGl2ZXIvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3

b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+UmF0czwva2V5d29yZD48a2V5d29yZD5SYXRzLCBT

cHJhZ3VlLURhd2xleTwva2V5d29yZD48a2V5d29yZD5TdGVyb2lkIEh5ZHJveHlsYXNlcy8qbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5UZXN0aXMvbWV0YWJvbGlzbTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDAwPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVsIDE5PC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDAwNi0zMDAyIChQcmludCkmI3hEOzAwMDYt

MzAwMiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTA5MDM0ODA8L2FjY2Vzc2lvbi1u

dW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9w

dWJtZWQvMTA5MDM0ODA8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRl

PjxDaXRlPjxBdXRob3I+THV0am9oYW5uPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48UmVjTnVt

PjQyMTQ8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjQyMTQ8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6

enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNjc3NzQ1NCI+NDIxNDwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+THV0am9oYW5uLCBELjwvYXV0aG9yPjxhdXRob3I+QnJldWVy

LCBPLjwvYXV0aG9yPjxhdXRob3I+QWhsYm9yZywgRy48L2F1dGhvcj48YXV0aG9yPk5lbm5lc21v

LCBJLjwvYXV0aG9yPjxhdXRob3I+U2lkZW4sIEEuPC9hdXRob3I+PGF1dGhvcj5EaWN6ZmFsdXN5

LCBVLjwvYXV0aG9yPjxhdXRob3I+QmpvcmtoZW0sIEkuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGl2aXNpb24gb2YgQ2xpbmljYWwgQ2hlbWlzdHJ5LCBL

YXJvbGluc2thIEluc3RpdHV0ZSwgSHVkZGluZ2UgVW5pdmVyc2l0eSBIb3NwaXRhbCwgU3dlZGVu

LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNob2xlc3Rlcm9sIGhvbWVvc3Rhc2lzIGlu

IGh1bWFuIGJyYWluOiBldmlkZW5jZSBmb3IgYW4gYWdlLWRlcGVuZGVudCBmbHV4IG9mIDI0Uy1o

eWRyb3h5Y2hvbGVzdGVyb2wgZnJvbSB0aGUgYnJhaW4gaW50byB0aGUgY2lyY3VsYXRpb248L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9zZWNvbmRhcnkt

dGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UHJvYyBOYXRsIEFjYWQgU2Np

IFUgUyBBPC9mdWxsLXRpdGxlPjxhYmJyLTE+UHJvY2VlZGluZ3Mgb2YgdGhlIE5hdGlvbmFsIEFj

YWRlbXkgb2YgU2NpZW5jZXMgb2YgdGhlIFVuaXRlZCBTdGF0ZXMgb2YgQW1lcmljYTwvYWJici0x

PjwvcGVyaW9kaWNhbD48cGFnZXM+OTc5OS04MDQ8L3BhZ2VzPjx2b2x1bWU+OTM8L3ZvbHVtZT48

bnVtYmVyPjE4PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkb2xlc2NlbnQ8L2tleXdvcmQ+

PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5B

Z2luZy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3

b3JkPkJyYWluLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkNoaWxkPC9rZXl3b3JkPjxr

ZXl3b3JkPkNoaWxkLCBQcmVzY2hvb2w8L2tleXdvcmQ+PGtleXdvcmQ+Q2lyY2FkaWFuIFJoeXRo

bTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+KkhvbWVvc3Rhc2lz

PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IeWRyb3h5Y2hvbGVz

dGVyb2xzL2Jsb29kL2NlcmVicm9zcGluYWwgZmx1aWQvKm1ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+SW5mYW50PC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlk

ZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+T3h5Z2VuPC9rZXl3b3JkPjxrZXl3b3JkPlJhdHM8

L2tleXdvcmQ+PGtleXdvcmQ+UmVmZXJlbmNlIFZhbHVlczwva2V5d29yZD48a2V5d29yZD5TdGVy

ZW9pc29tZXJpc208L2tleXdvcmQ+PGtleXdvcmQ+VGlzc3VlIERpc3RyaWJ1dGlvbjwva2V5d29y

ZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2Vw

IDM8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDI3LTg0MjQgKFByaW50KSYjeEQ7

MDAyNy04NDI0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT44NzkwNDExPC9hY2Nlc3Np

b24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5n

b3YvcHVibWVkLzg3OTA0MTE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1D

Mzg1MDk8L2N1c3RvbTI+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 394,415-419. The main oxysterol exchange between the brain and the periphery comes from 24-hydroxycholesterol (24-OH) and 27-hydroxycholesterol (27-OH) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cam9ya2hlbTwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+

PFJlY051bT40NDA8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zOTQsNDE2LDQxOCw0MTk8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJl

cj40NDA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ew

cng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjU0OTk0NCI+

NDQwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+

MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Cam9ya2hlbSwgSS48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EaXZpc2lvbiBv

ZiBDbGluaWNhbCBDaGVtaXN0cnksIERlcGFydG1lbnQgb2YgTGFib3JhdG9yeSBNZWRpY2luZSwg

S2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIdWRkaW5nZSwgU3dlZGVuLiBpbmdlbWFy

LmJqb3JraGVtQGthcm9saW5za2Euc2U8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Dcm9z

c2luZyB0aGUgYmFycmllcjogb3h5c3Rlcm9scyBhcyBjaG9sZXN0ZXJvbCB0cmFuc3BvcnRlcnMg

YW5kIG1ldGFib2xpYyBtb2R1bGF0b3JzIGluIHRoZSBicmFpbjwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5KIEludGVybiBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5KIEludGVybiBNZWQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz40

OTMtNTA4PC9wYWdlcz48dm9sdW1lPjI2MDwvdm9sdW1lPjxudW1iZXI+NjwvbnVtYmVyPjxrZXl3

b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3

b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9iaW9zeW50aGVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+

QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CaW9sb2dpY2FsIFRyYW5zcG9ydC9waHlzaW9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPkJsb29kLUJyYWluIEJhcnJpZXIvbWV0YWJvbGlzbTwva2V5d29y

ZD48a2V5d29yZD5CcmFpbi8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5CcmFpbiBEaXNl

YXNlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sLyptZXRhYm9saXNt

PC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sIDI0LUh5ZHJveHlsYXNlPC9rZXl3b3JkPjxr

ZXl3b3JkPkhvbWVvc3Rhc2lzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9r

ZXl3b3JkPjxrZXl3b3JkPkh5ZHJveHljaG9sZXN0ZXJvbHMvYmxvb2QvKm1ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+SW5mYW50PC9rZXl3b3JkPjxrZXl3b3JkPlJhdHM8L2tleXdvcmQ+PGtl

eXdvcmQ+U3Rlcm9pZCBIeWRyb3h5bGFzZXMvZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48

L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RGVjPC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDk1NC02ODIwIChQcmludCkmI3hEOzA5NTQt

NjgyMCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTcxMTYwMDA8L2FjY2Vzc2lvbi1u

dW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9w

dWJtZWQvMTcxMTYwMDA8L3VybD48dXJsPmh0dHBzOi8vb25saW5lbGlicmFyeS53aWxleS5jb20v

ZG9pL3BkZi8xMC4xMTExL2ouMTM2NS0yNzk2LjIwMDYuMDE3MjUueDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTExMS9qLjEzNjUtMjc5Ni4y

MDA2LjAxNzI1Lng8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0

ZT48QXV0aG9yPk1lYW5leTwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+PFJlY051bT40NjU8L1Jl

Y051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjQ2NTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxr

ZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIg

dGltZXN0YW1wPSIxNTMyNTQ5OTQ5Ij40NjU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUg

bmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9y

cz48YXV0aG9yPk1lYW5leSwgUy48L2F1dGhvcj48YXV0aG9yPkhhc3NhbiwgTS48L2F1dGhvcj48

YXV0aG9yPlNha2luaXMsIEEuPC9hdXRob3I+PGF1dGhvcj5MdXRqb2hhbm4sIEQuPC9hdXRob3I+

PGF1dGhvcj52b24gQmVyZ21hbm4sIEsuPC9hdXRob3I+PGF1dGhvcj5XZW5ubWFsbSwgQS48L2F1

dGhvcj48YXV0aG9yPkRpY3pmYWx1c3ksIFUuPC9hdXRob3I+PGF1dGhvcj5Cam9ya2hlbSwgSS48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EaXZpc2lvbiBv

ZiBDbGluaWNhbCBDaGVtaXN0cnksIEthcm9saW5za2EgSW5zdGl0dXRldCwgSHVkZGluZ2UgVW5p

dmVyc2l0eSBIb3NwaXRhbCwgU0UtMTQxIDg2IEh1ZGRpbmdlLCBTd2VkZW4uPC9hdXRoLWFkZHJl

c3M+PHRpdGxlcz48dGl0bGU+RXZpZGVuY2UgdGhhdCB0aGUgbWFqb3Igb3h5c3Rlcm9scyBpbiBo

dW1hbiBjaXJjdWxhdGlvbiBvcmlnaW5hdGUgZnJvbSBkaXN0aW5jdCBwb29scyBvZiBjaG9sZXN0

ZXJvbDogYSBzdGFibGUgaXNvdG9wZSBzdHVkeTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIExp

cGlkIFJlczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz43MC04PC9wYWdlcz48dm9s

dW1lPjQyPC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkJsb29k

IENpcmN1bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sL2FkbWluaXN0cmF0aW9u

ICZhbXA7IGRvc2FnZS8qcGhhcm1hY29raW5ldGljczwva2V5d29yZD48a2V5d29yZD5EZXV0ZXJp

dW08L2tleXdvcmQ+PGtleXdvcmQ+SGFsZi1MaWZlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwv

a2V5d29yZD48a2V5d29yZD5IeWRyb3h5Y2hvbGVzdGVyb2xzLypibG9vZDwva2V5d29yZD48a2V5

d29yZD5PcmdhbiBTcGVjaWZpY2l0eTwva2V5d29yZD48a2V5d29yZD5PeHlnZW4vcGhhcm1hY29r

aW5ldGljczwva2V5d29yZD48a2V5d29yZD5PeHlnZW4gSXNvdG9wZXM8L2tleXdvcmQ+PGtleXdv

cmQ+VGltZSBGYWN0b3JzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDE8L3ll

YXI+PHB1Yi1kYXRlcz48ZGF0ZT5KYW48L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4w

MDIyLTIyNzUgKFByaW50KSYjeEQ7MDAyMi0yMjc1IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4xMTE2MDM2NzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xMTE2MDM2NzwvdXJsPjx1cmw+aHR0cDov

L3d3dy5qbHIub3JnL2NvbnRlbnQvNDIvMS83MC5mdWxsLnBkZjwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5NZWFuZXk8L0F1dGhvcj48WWVh

cj4yMDAwPC9ZZWFyPjxSZWNOdW0+NDY3PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj40Njc8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjU0OTk0OSI+NDY3PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5NZWFuZXksIFMuPC9hdXRob3I+

PGF1dGhvcj5MdXRqb2hhbm4sIEQuPC9hdXRob3I+PGF1dGhvcj5EaWN6ZmFsdXN5LCBVLjwvYXV0

aG9yPjxhdXRob3I+QmpvcmtoZW0sIEkuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

PjxhdXRoLWFkZHJlc3M+RGl2aXNpb24gb2YgQ2xpbmljYWwgQ2hlbWlzdHJ5LCBLYXJvbGluc2th

IEluc3RpdHV0ZXQgYXQgSHVkZGluZ2UgVW5pdmVyc2l0eSBIb3NwaXRhbCwgSHVkZGluZ2UsIFN3

ZWRlbi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Gb3JtYXRpb24gb2Ygb3h5c3Rlcm9s

cyBmcm9tIGRpZmZlcmVudCBwb29scyBvZiBjaG9sZXN0ZXJvbCBhcyBzdHVkaWVkIGJ5IHN0YWJs

ZSBpc290b3BlIHRlY2huaXF1ZTogY2VyZWJyYWwgb3JpZ2luIG9mIG1vc3QgY2lyY3VsYXRpbmcg

MjRTLWh5ZHJveHljaG9sZXN0ZXJvbCBpbiByYXRzLCBidXQgbm90IGluIG1pY2U8L3RpdGxlPjxz

ZWNvbmRhcnktdGl0bGU+QmlvY2hpbSBCaW9waHlzIEFjdGE8L3NlY29uZGFyeS10aXRsZT48L3Rp

dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5CaW9jaGltIEJpb3BoeXMgQWN0YTwvZnVsbC10

aXRsZT48YWJici0xPkJpb2NoaW1pY2EgZXQgYmlvcGh5c2ljYSBhY3RhPC9hYmJyLTE+PC9wZXJp

b2RpY2FsPjxwYWdlcz4yOTMtODwvcGFnZXM+PHZvbHVtZT4xNDg2PC92b2x1bWU+PG51bWJlcj4y

LTM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWRyZW5hbCBHbGFuZHMvbWV0YWJvbGlzbTwv

a2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluLyptZXRhYm9s

aXNtPC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sIDI0LUh5ZHJveHlsYXNlPC9rZXl3b3Jk

PjxrZXl3b3JkPkNob2xlc3Rlcm9sLCBEaWV0YXJ5LyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3

b3JkPkRldXRlcml1bTwva2V5d29yZD48a2V5d29yZD5HYXMgQ2hyb21hdG9ncmFwaHktTWFzcyBT

cGVjdHJvbWV0cnk8L2tleXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy9ibG9vZDwv

a2V5d29yZD48a2V5d29yZD5MaXZlci9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8

L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5SYXRzPC9rZXl3b3JkPjxr

ZXl3b3JkPlJhdHMsIFNwcmFndWUtRGF3bGV5PC9rZXl3b3JkPjxrZXl3b3JkPlN0ZXJvaWQgSHlk

cm94eWxhc2VzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlRlc3Rpcy9tZXRhYm9saXNt

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDA8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5KdWwgMTk8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDA2LTMwMDIgKFBy

aW50KSYjeEQ7MDAwNi0zMDAyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xMDkwMzQ4

MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3B1Ym1lZC8xMDkwMzQ4MDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48

L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5MdXRqb2hhbm48L0F1dGhvcj48WWVhcj4xOTk2

PC9ZZWFyPjxSZWNOdW0+NDIxNDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+NDIxNDwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2Nzc3NDU0Ij40MjE0PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5MdXRqb2hhbm4sIEQuPC9hdXRob3I+

PGF1dGhvcj5CcmV1ZXIsIE8uPC9hdXRob3I+PGF1dGhvcj5BaGxib3JnLCBHLjwvYXV0aG9yPjxh

dXRob3I+TmVubmVzbW8sIEkuPC9hdXRob3I+PGF1dGhvcj5TaWRlbiwgQS48L2F1dGhvcj48YXV0

aG9yPkRpY3pmYWx1c3ksIFUuPC9hdXRob3I+PGF1dGhvcj5Cam9ya2hlbSwgSS48L2F1dGhvcj48

L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EaXZpc2lvbiBvZiBDbGluaWNh

bCBDaGVtaXN0cnksIEthcm9saW5za2EgSW5zdGl0dXRlLCBIdWRkaW5nZSBVbml2ZXJzaXR5IEhv

c3BpdGFsLCBTd2VkZW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Q2hvbGVzdGVyb2wg

aG9tZW9zdGFzaXMgaW4gaHVtYW4gYnJhaW46IGV2aWRlbmNlIGZvciBhbiBhZ2UtZGVwZW5kZW50

IGZsdXggb2YgMjRTLWh5ZHJveHljaG9sZXN0ZXJvbCBmcm9tIHRoZSBicmFpbiBpbnRvIHRoZSBj

aXJjdWxhdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Qcm9jIE5hdGwgQWNhZCBTY2kgVSBT

IEE8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Qcm9j

IE5hdGwgQWNhZCBTY2kgVSBTIEE8L2Z1bGwtdGl0bGU+PGFiYnItMT5Qcm9jZWVkaW5ncyBvZiB0

aGUgTmF0aW9uYWwgQWNhZGVteSBvZiBTY2llbmNlcyBvZiB0aGUgVW5pdGVkIFN0YXRlcyBvZiBB

bWVyaWNhPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxwYWdlcz45Nzk5LTgwNDwvcGFnZXM+PHZvbHVt

ZT45Mzwvdm9sdW1lPjxudW1iZXI+MTg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWRvbGVz

Y2VudDwva2V5d29yZD48a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3

b3JkPjxrZXl3b3JkPkFnaW5nLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8

L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q2hp

bGQ8L2tleXdvcmQ+PGtleXdvcmQ+Q2hpbGQsIFByZXNjaG9vbDwva2V5d29yZD48a2V5d29yZD5D

aXJjYWRpYW4gUmh5dGhtPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29y

ZD4qSG9tZW9zdGFzaXM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3Jk

Pkh5ZHJveHljaG9sZXN0ZXJvbHMvYmxvb2QvY2VyZWJyb3NwaW5hbCBmbHVpZC8qbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5JbmZhbnQ8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29y

ZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5PeHlnZW48L2tleXdvcmQ+

PGtleXdvcmQ+UmF0czwva2V5d29yZD48a2V5d29yZD5SZWZlcmVuY2UgVmFsdWVzPC9rZXl3b3Jk

PjxrZXl3b3JkPlN0ZXJlb2lzb21lcmlzbTwva2V5d29yZD48a2V5d29yZD5UaXNzdWUgRGlzdHJp

YnV0aW9uPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTY8L3llYXI+PHB1Yi1k

YXRlcz48ZGF0ZT5TZXAgMzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMjctODQy

NCAoUHJpbnQpJiN4RDswMDI3LTg0MjQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjg3

OTA0MTE8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvODc5MDQxMTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48Y3VzdG9tMj5QTUMzODUwOTwvY3VzdG9tMj48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cam9ya2hlbTwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+

PFJlY051bT40NDA8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij4zOTQsNDE2LDQxOCw0MTk8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJl

cj40NDA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ew

cng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjU0OTk0NCI+

NDQwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+

MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Cam9ya2hlbSwgSS48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EaXZpc2lvbiBv

ZiBDbGluaWNhbCBDaGVtaXN0cnksIERlcGFydG1lbnQgb2YgTGFib3JhdG9yeSBNZWRpY2luZSwg

S2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIdWRkaW5nZSwgU3dlZGVuLiBpbmdlbWFy

LmJqb3JraGVtQGthcm9saW5za2Euc2U8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Dcm9z

c2luZyB0aGUgYmFycmllcjogb3h5c3Rlcm9scyBhcyBjaG9sZXN0ZXJvbCB0cmFuc3BvcnRlcnMg

YW5kIG1ldGFib2xpYyBtb2R1bGF0b3JzIGluIHRoZSBicmFpbjwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5KIEludGVybiBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5KIEludGVybiBNZWQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz40

OTMtNTA4PC9wYWdlcz48dm9sdW1lPjI2MDwvdm9sdW1lPjxudW1iZXI+NjwvbnVtYmVyPjxrZXl3

b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3

b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9iaW9zeW50aGVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+

QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CaW9sb2dpY2FsIFRyYW5zcG9ydC9waHlzaW9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPkJsb29kLUJyYWluIEJhcnJpZXIvbWV0YWJvbGlzbTwva2V5d29y

ZD48a2V5d29yZD5CcmFpbi8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5CcmFpbiBEaXNl

YXNlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sLyptZXRhYm9saXNt

PC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sIDI0LUh5ZHJveHlsYXNlPC9rZXl3b3JkPjxr

ZXl3b3JkPkhvbWVvc3Rhc2lzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9r

ZXl3b3JkPjxrZXl3b3JkPkh5ZHJveHljaG9sZXN0ZXJvbHMvYmxvb2QvKm1ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+SW5mYW50PC9rZXl3b3JkPjxrZXl3b3JkPlJhdHM8L2tleXdvcmQ+PGtl

eXdvcmQ+U3Rlcm9pZCBIeWRyb3h5bGFzZXMvZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48

L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RGVjPC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDk1NC02ODIwIChQcmludCkmI3hEOzA5NTQt

NjgyMCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTcxMTYwMDA8L2FjY2Vzc2lvbi1u

dW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9w

dWJtZWQvMTcxMTYwMDA8L3VybD48dXJsPmh0dHBzOi8vb25saW5lbGlicmFyeS53aWxleS5jb20v

ZG9pL3BkZi8xMC4xMTExL2ouMTM2NS0yNzk2LjIwMDYuMDE3MjUueDwvdXJsPjwvcmVsYXRlZC11

cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTExMS9qLjEzNjUtMjc5Ni4y

MDA2LjAxNzI1Lng8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0

ZT48QXV0aG9yPk1lYW5leTwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+PFJlY051bT40NjU8L1Jl

Y051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjQ2NTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxr

ZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIg

dGltZXN0YW1wPSIxNTMyNTQ5OTQ5Ij40NjU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUg

bmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9y

cz48YXV0aG9yPk1lYW5leSwgUy48L2F1dGhvcj48YXV0aG9yPkhhc3NhbiwgTS48L2F1dGhvcj48

YXV0aG9yPlNha2luaXMsIEEuPC9hdXRob3I+PGF1dGhvcj5MdXRqb2hhbm4sIEQuPC9hdXRob3I+

PGF1dGhvcj52b24gQmVyZ21hbm4sIEsuPC9hdXRob3I+PGF1dGhvcj5XZW5ubWFsbSwgQS48L2F1

dGhvcj48YXV0aG9yPkRpY3pmYWx1c3ksIFUuPC9hdXRob3I+PGF1dGhvcj5Cam9ya2hlbSwgSS48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EaXZpc2lvbiBv

ZiBDbGluaWNhbCBDaGVtaXN0cnksIEthcm9saW5za2EgSW5zdGl0dXRldCwgSHVkZGluZ2UgVW5p

dmVyc2l0eSBIb3NwaXRhbCwgU0UtMTQxIDg2IEh1ZGRpbmdlLCBTd2VkZW4uPC9hdXRoLWFkZHJl

c3M+PHRpdGxlcz48dGl0bGU+RXZpZGVuY2UgdGhhdCB0aGUgbWFqb3Igb3h5c3Rlcm9scyBpbiBo

dW1hbiBjaXJjdWxhdGlvbiBvcmlnaW5hdGUgZnJvbSBkaXN0aW5jdCBwb29scyBvZiBjaG9sZXN0

ZXJvbDogYSBzdGFibGUgaXNvdG9wZSBzdHVkeTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIExp

cGlkIFJlczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz43MC04PC9wYWdlcz48dm9s

dW1lPjQyPC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkJsb29k

IENpcmN1bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sL2FkbWluaXN0cmF0aW9u

ICZhbXA7IGRvc2FnZS8qcGhhcm1hY29raW5ldGljczwva2V5d29yZD48a2V5d29yZD5EZXV0ZXJp

dW08L2tleXdvcmQ+PGtleXdvcmQ+SGFsZi1MaWZlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwv

a2V5d29yZD48a2V5d29yZD5IeWRyb3h5Y2hvbGVzdGVyb2xzLypibG9vZDwva2V5d29yZD48a2V5

d29yZD5PcmdhbiBTcGVjaWZpY2l0eTwva2V5d29yZD48a2V5d29yZD5PeHlnZW4vcGhhcm1hY29r

aW5ldGljczwva2V5d29yZD48a2V5d29yZD5PeHlnZW4gSXNvdG9wZXM8L2tleXdvcmQ+PGtleXdv

cmQ+VGltZSBGYWN0b3JzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDE8L3ll

YXI+PHB1Yi1kYXRlcz48ZGF0ZT5KYW48L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4w

MDIyLTIyNzUgKFByaW50KSYjeEQ7MDAyMi0yMjc1IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u

LW51bT4xMTE2MDM2NzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0

cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xMTE2MDM2NzwvdXJsPjx1cmw+aHR0cDov

L3d3dy5qbHIub3JnL2NvbnRlbnQvNDIvMS83MC5mdWxsLnBkZjwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5NZWFuZXk8L0F1dGhvcj48WWVh

cj4yMDAwPC9ZZWFyPjxSZWNOdW0+NDY3PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj40Njc8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjU0OTk0OSI+NDY3PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5NZWFuZXksIFMuPC9hdXRob3I+

PGF1dGhvcj5MdXRqb2hhbm4sIEQuPC9hdXRob3I+PGF1dGhvcj5EaWN6ZmFsdXN5LCBVLjwvYXV0

aG9yPjxhdXRob3I+QmpvcmtoZW0sIEkuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

PjxhdXRoLWFkZHJlc3M+RGl2aXNpb24gb2YgQ2xpbmljYWwgQ2hlbWlzdHJ5LCBLYXJvbGluc2th

IEluc3RpdHV0ZXQgYXQgSHVkZGluZ2UgVW5pdmVyc2l0eSBIb3NwaXRhbCwgSHVkZGluZ2UsIFN3

ZWRlbi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Gb3JtYXRpb24gb2Ygb3h5c3Rlcm9s

cyBmcm9tIGRpZmZlcmVudCBwb29scyBvZiBjaG9sZXN0ZXJvbCBhcyBzdHVkaWVkIGJ5IHN0YWJs

ZSBpc290b3BlIHRlY2huaXF1ZTogY2VyZWJyYWwgb3JpZ2luIG9mIG1vc3QgY2lyY3VsYXRpbmcg

MjRTLWh5ZHJveHljaG9sZXN0ZXJvbCBpbiByYXRzLCBidXQgbm90IGluIG1pY2U8L3RpdGxlPjxz

ZWNvbmRhcnktdGl0bGU+QmlvY2hpbSBCaW9waHlzIEFjdGE8L3NlY29uZGFyeS10aXRsZT48L3Rp

dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5CaW9jaGltIEJpb3BoeXMgQWN0YTwvZnVsbC10

aXRsZT48YWJici0xPkJpb2NoaW1pY2EgZXQgYmlvcGh5c2ljYSBhY3RhPC9hYmJyLTE+PC9wZXJp

b2RpY2FsPjxwYWdlcz4yOTMtODwvcGFnZXM+PHZvbHVtZT4xNDg2PC92b2x1bWU+PG51bWJlcj4y

LTM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWRyZW5hbCBHbGFuZHMvbWV0YWJvbGlzbTwv

a2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluLyptZXRhYm9s

aXNtPC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sIDI0LUh5ZHJveHlsYXNlPC9rZXl3b3Jk

PjxrZXl3b3JkPkNob2xlc3Rlcm9sLCBEaWV0YXJ5LyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3

b3JkPkRldXRlcml1bTwva2V5d29yZD48a2V5d29yZD5HYXMgQ2hyb21hdG9ncmFwaHktTWFzcyBT

cGVjdHJvbWV0cnk8L2tleXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy9ibG9vZDwv

a2V5d29yZD48a2V5d29yZD5MaXZlci9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8

L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5SYXRzPC9rZXl3b3JkPjxr

ZXl3b3JkPlJhdHMsIFNwcmFndWUtRGF3bGV5PC9rZXl3b3JkPjxrZXl3b3JkPlN0ZXJvaWQgSHlk

cm94eWxhc2VzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlRlc3Rpcy9tZXRhYm9saXNt

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDA8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5KdWwgMTk8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDA2LTMwMDIgKFBy

aW50KSYjeEQ7MDAwNi0zMDAyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xMDkwMzQ4

MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3B1Ym1lZC8xMDkwMzQ4MDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48

L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5MdXRqb2hhbm48L0F1dGhvcj48WWVhcj4xOTk2

PC9ZZWFyPjxSZWNOdW0+NDIxNDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+NDIxNDwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM2Nzc3NDU0Ij40MjE0PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5MdXRqb2hhbm4sIEQuPC9hdXRob3I+

PGF1dGhvcj5CcmV1ZXIsIE8uPC9hdXRob3I+PGF1dGhvcj5BaGxib3JnLCBHLjwvYXV0aG9yPjxh

dXRob3I+TmVubmVzbW8sIEkuPC9hdXRob3I+PGF1dGhvcj5TaWRlbiwgQS48L2F1dGhvcj48YXV0

aG9yPkRpY3pmYWx1c3ksIFUuPC9hdXRob3I+PGF1dGhvcj5Cam9ya2hlbSwgSS48L2F1dGhvcj48

L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EaXZpc2lvbiBvZiBDbGluaWNh

bCBDaGVtaXN0cnksIEthcm9saW5za2EgSW5zdGl0dXRlLCBIdWRkaW5nZSBVbml2ZXJzaXR5IEhv

c3BpdGFsLCBTd2VkZW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Q2hvbGVzdGVyb2wg

aG9tZW9zdGFzaXMgaW4gaHVtYW4gYnJhaW46IGV2aWRlbmNlIGZvciBhbiBhZ2UtZGVwZW5kZW50

IGZsdXggb2YgMjRTLWh5ZHJveHljaG9sZXN0ZXJvbCBmcm9tIHRoZSBicmFpbiBpbnRvIHRoZSBj

aXJjdWxhdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Qcm9jIE5hdGwgQWNhZCBTY2kgVSBT

IEE8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Qcm9j

IE5hdGwgQWNhZCBTY2kgVSBTIEE8L2Z1bGwtdGl0bGU+PGFiYnItMT5Qcm9jZWVkaW5ncyBvZiB0

aGUgTmF0aW9uYWwgQWNhZGVteSBvZiBTY2llbmNlcyBvZiB0aGUgVW5pdGVkIFN0YXRlcyBvZiBB

bWVyaWNhPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxwYWdlcz45Nzk5LTgwNDwvcGFnZXM+PHZvbHVt

ZT45Mzwvdm9sdW1lPjxudW1iZXI+MTg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWRvbGVz

Y2VudDwva2V5d29yZD48a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3

b3JkPjxrZXl3b3JkPkFnaW5nLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8

L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q2hp

bGQ8L2tleXdvcmQ+PGtleXdvcmQ+Q2hpbGQsIFByZXNjaG9vbDwva2V5d29yZD48a2V5d29yZD5D

aXJjYWRpYW4gUmh5dGhtPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29y

ZD4qSG9tZW9zdGFzaXM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3Jk

Pkh5ZHJveHljaG9sZXN0ZXJvbHMvYmxvb2QvY2VyZWJyb3NwaW5hbCBmbHVpZC8qbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5JbmZhbnQ8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29y

ZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5PeHlnZW48L2tleXdvcmQ+

PGtleXdvcmQ+UmF0czwva2V5d29yZD48a2V5d29yZD5SZWZlcmVuY2UgVmFsdWVzPC9rZXl3b3Jk

PjxrZXl3b3JkPlN0ZXJlb2lzb21lcmlzbTwva2V5d29yZD48a2V5d29yZD5UaXNzdWUgRGlzdHJp

YnV0aW9uPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTY8L3llYXI+PHB1Yi1k

YXRlcz48ZGF0ZT5TZXAgMzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMjctODQy

NCAoUHJpbnQpJiN4RDswMDI3LTg0MjQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjg3

OTA0MTE8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvODc5MDQxMTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs

cz48Y3VzdG9tMj5QTUMzODUwOTwvY3VzdG9tMj48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 394,416,418,419. Excessive 27-OH has been related to AD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYXlhPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48UmVj

TnVtPjg1NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjQy

MCw0MjE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj44NTc8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjU1MDk0MiI+ODU3PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5WYXlhLCBKLjwvYXV0aG9yPjxhdXRob3I+

U2NoaXBwZXIsIEguIE0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk

ZHJlc3M+VGhlIExhYm9yYXRvcnkgb2YgTmF0dXJhbCBNZWRpY2luYWwgQ29tcG91bmRzLCBNaWdh

bC1HYWxpbGVlIFRlY2hub2xvZ3kgQ2VudGVyLCBLaXJ5YXQtU2htb25hLCBhbmQgVGVsIEhhaSBB

Y2FkZW1pYyBDb2xsZWdlLCBJc3JhZWxEZXBhcnRtZW50IG9mIE5ldXJvbG9neSBhbmQgTmV1cm9z

dXJnZXJ5LCBNY0dpbGwgVW5pdmVyc2l0eSwgTW9udHJlYWwsIFF1ZWJlYywgQ2FuYWRhQ2VudHJl

IGZvciBOZXVyb3RyYW5zbGF0aW9uYWwgUmVzZWFyY2gsIExhZHkgRGF2aXMgSW5zdGl0dXRlIGZv

ciBNZWRpY2FsIFJlc2VhcmNoLCBTTUJEIEpld2lzaCBHZW5lcmFsIEhvc3BpdGFsLCBNb250cmVh

bCwgUXVlYmVjLCBDYW5hZGEuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+T3h5c3Rlcm9s

cywgY2hvbGVzdGVyb2wgaG9tZW9zdGFzaXMsIGFuZCBBbHpoZWltZXIgZGlzZWFzZTwvdGl0bGU+

PHNlY29uZGFyeS10aXRsZT5KIE5ldXJvY2hlbTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxw

ZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9jaGVtPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNh

bD48cGFnZXM+MTcyNy0xNzM3PC9wYWdlcz48dm9sdW1lPjEwMjwvdm9sdW1lPjxudW1iZXI+Njwv

bnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9kcnVnIHRoZXJhcHkv

Km1ldGFib2xpc20vcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0

YS1Qcm90ZWluIFByZWN1cnNvci9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8

L2tleXdvcmQ+PGtleXdvcmQ+QXBvbGlwb3Byb3RlaW5zIEUvbWV0YWJvbGlzbTwva2V5d29yZD48

a2V5d29yZD5CcmFpbi8qbWV0YWJvbGlzbS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+Q2hvbGVzdGVyb2wvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q3l0b3Byb3RlY3Rp

b24vZHJ1ZyBlZmZlY3RzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RE5BLUJpbmRpbmcg

UHJvdGVpbnMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SGVtZSBPeHlnZW5hc2UtMS9t

ZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5MaXZl

ciBYIFJlY2VwdG9yczwva2V5d29yZD48a2V5d29yZD5PcnBoYW4gTnVjbGVhciBSZWNlcHRvcnM8

L2tleXdvcmQ+PGtleXdvcmQ+UmVjZXB0b3JzLCBDeXRvcGxhc21pYyBhbmQgTnVjbGVhci8qbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5TdGVyb2xzLyptZXRhYm9saXNtPC9rZXl3b3JkPjwv

a2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5TZXA8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDIyLTMwNDIgKFByaW50KSYjeEQ7MDAyMi0z

MDQyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xNzU3MzgxOTwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8xNzU3MzgxOTwvdXJsPjx1cmw+aHR0cHM6Ly9vbmxpbmVsaWJyYXJ5LndpbGV5LmNvbS9k

b2kvcGRmLzEwLjExMTEvai4xNDcxLTQxNTkuMjAwNy4wNDY4OS54PC91cmw+PC9yZWxhdGVkLXVy

bHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTExL2ouMTQ3MS00MTU5LjIw

MDcuMDQ2ODkueDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRl

PjxBdXRob3I+TGF0aGU8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNOdW0+ODU2PC9SZWNO

dW0+PHJlY29yZD48cmVjLW51bWJlcj44NTY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5

IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRp

bWVzdGFtcD0iMTUzMjU1MDk0MiI+ODU2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5MYXRoZSwgUi48L2F1dGhvcj48YXV0aG9yPlNhcHJvbm92YSwgQS48L2F1dGhvcj48

YXV0aG9yPktvdGVsZXZ0c2V2LCBZLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48

YXV0aC1hZGRyZXNzPlN0YXRlIFVuaXZlcnNpdHkgb2YgUHVzaGNoaW5vLCBQcm9zcGVrdCBOYXVr

aSwgUHVzaGNoaW5vIDE0MjI5MCwgTW9zY293IFJlZ2lvbiwgUnVzc2lhLiBybGF0aGVAcGlldGEt

cmVzZWFyY2gub3JnLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkF0aGVyb3NjbGVyb3Np

cyBhbmQgQWx6aGVpbWVyLS1kaXNlYXNlcyB3aXRoIGEgY29tbW9uIGNhdXNlPyBJbmZsYW1tYXRp

b24sIG94eXN0ZXJvbHMsIHZhc2N1bGF0dXJlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkJNQyBH

ZXJpYXRyPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjM2PC9wYWdlcz48dm9sdW1l

PjE0PC92b2x1bWU+PGtleXdvcmRzPjxrZXl3b3JkPkFnaW5nL21ldGFib2xpc20vcGF0aG9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2Jsb29kLypldGlvbG9neS9wYXRo

b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL2Jsb29kPC9rZXl3

b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QXRoZXJvc2NsZXJvc2lzL2Js

b29kLypldGlvbG9neS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKmJsb29kIHN1

cHBseS9tZXRhYm9saXNtL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdv

cmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy9ibG9vZDwva2V5d29yZD48a2V5d29yZD5J

bmZsYW1tYXRpb24vYmxvb2QvY29tcGxpY2F0aW9ucy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+SW5mbGFtbWF0aW9uIE1lZGlhdG9ycy8qYmxvb2Q8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0

ZXM+PHllYXI+MjAxNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1hciAyMTwvZGF0ZT48L3B1Yi1k

YXRlcz48L2RhdGVzPjxpc2JuPjE0NzEtMjMxOCAoRWxlY3Ryb25pYykmI3hEOzE0NzEtMjMxOCAo

TGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjQ2NTYwNTI8L2FjY2Vzc2lvbi1udW0+PHVy

bHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQv

MjQ2NTYwNTI8L3VybD48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcG1jL2FydGlj

bGVzL1BNQzM5OTQ0MzIvcGRmLzE0NzEtMjMxOC0xNC0zNi5wZGY8L3VybD48L3JlbGF0ZWQtdXJs

cz48L3VybHM+PGN1c3RvbTI+UE1DMzk5NDQzMjwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJj

ZS1udW0+MTAuMTE4Ni8xNDcxLTIzMTgtMTQtMzY8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwv

cmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYXlhPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48UmVj

TnVtPjg1NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjQy

MCw0MjE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj44NTc8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjU1MDk0MiI+ODU3PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5WYXlhLCBKLjwvYXV0aG9yPjxhdXRob3I+

U2NoaXBwZXIsIEguIE0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk

ZHJlc3M+VGhlIExhYm9yYXRvcnkgb2YgTmF0dXJhbCBNZWRpY2luYWwgQ29tcG91bmRzLCBNaWdh

bC1HYWxpbGVlIFRlY2hub2xvZ3kgQ2VudGVyLCBLaXJ5YXQtU2htb25hLCBhbmQgVGVsIEhhaSBB

Y2FkZW1pYyBDb2xsZWdlLCBJc3JhZWxEZXBhcnRtZW50IG9mIE5ldXJvbG9neSBhbmQgTmV1cm9z

dXJnZXJ5LCBNY0dpbGwgVW5pdmVyc2l0eSwgTW9udHJlYWwsIFF1ZWJlYywgQ2FuYWRhQ2VudHJl

IGZvciBOZXVyb3RyYW5zbGF0aW9uYWwgUmVzZWFyY2gsIExhZHkgRGF2aXMgSW5zdGl0dXRlIGZv

ciBNZWRpY2FsIFJlc2VhcmNoLCBTTUJEIEpld2lzaCBHZW5lcmFsIEhvc3BpdGFsLCBNb250cmVh

bCwgUXVlYmVjLCBDYW5hZGEuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+T3h5c3Rlcm9s

cywgY2hvbGVzdGVyb2wgaG9tZW9zdGFzaXMsIGFuZCBBbHpoZWltZXIgZGlzZWFzZTwvdGl0bGU+

PHNlY29uZGFyeS10aXRsZT5KIE5ldXJvY2hlbTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxw

ZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9jaGVtPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNh

bD48cGFnZXM+MTcyNy0xNzM3PC9wYWdlcz48dm9sdW1lPjEwMjwvdm9sdW1lPjxudW1iZXI+Njwv

bnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9kcnVnIHRoZXJhcHkv

Km1ldGFib2xpc20vcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0

YS1Qcm90ZWluIFByZWN1cnNvci9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8

L2tleXdvcmQ+PGtleXdvcmQ+QXBvbGlwb3Byb3RlaW5zIEUvbWV0YWJvbGlzbTwva2V5d29yZD48

a2V5d29yZD5CcmFpbi8qbWV0YWJvbGlzbS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+Q2hvbGVzdGVyb2wvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q3l0b3Byb3RlY3Rp

b24vZHJ1ZyBlZmZlY3RzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RE5BLUJpbmRpbmcg

UHJvdGVpbnMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SGVtZSBPeHlnZW5hc2UtMS9t

ZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5MaXZl

ciBYIFJlY2VwdG9yczwva2V5d29yZD48a2V5d29yZD5PcnBoYW4gTnVjbGVhciBSZWNlcHRvcnM8

L2tleXdvcmQ+PGtleXdvcmQ+UmVjZXB0b3JzLCBDeXRvcGxhc21pYyBhbmQgTnVjbGVhci8qbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5TdGVyb2xzLyptZXRhYm9saXNtPC9rZXl3b3JkPjwv

a2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5TZXA8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDIyLTMwNDIgKFByaW50KSYjeEQ7MDAyMi0z

MDQyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xNzU3MzgxOTwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8xNzU3MzgxOTwvdXJsPjx1cmw+aHR0cHM6Ly9vbmxpbmVsaWJyYXJ5LndpbGV5LmNvbS9k

b2kvcGRmLzEwLjExMTEvai4xNDcxLTQxNTkuMjAwNy4wNDY4OS54PC91cmw+PC9yZWxhdGVkLXVy

bHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTExL2ouMTQ3MS00MTU5LjIw

MDcuMDQ2ODkueDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRl

PjxBdXRob3I+TGF0aGU8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNOdW0+ODU2PC9SZWNO

dW0+PHJlY29yZD48cmVjLW51bWJlcj44NTY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5

IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRp

bWVzdGFtcD0iMTUzMjU1MDk0MiI+ODU2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5MYXRoZSwgUi48L2F1dGhvcj48YXV0aG9yPlNhcHJvbm92YSwgQS48L2F1dGhvcj48

YXV0aG9yPktvdGVsZXZ0c2V2LCBZLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48

YXV0aC1hZGRyZXNzPlN0YXRlIFVuaXZlcnNpdHkgb2YgUHVzaGNoaW5vLCBQcm9zcGVrdCBOYXVr

aSwgUHVzaGNoaW5vIDE0MjI5MCwgTW9zY293IFJlZ2lvbiwgUnVzc2lhLiBybGF0aGVAcGlldGEt

cmVzZWFyY2gub3JnLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkF0aGVyb3NjbGVyb3Np

cyBhbmQgQWx6aGVpbWVyLS1kaXNlYXNlcyB3aXRoIGEgY29tbW9uIGNhdXNlPyBJbmZsYW1tYXRp

b24sIG94eXN0ZXJvbHMsIHZhc2N1bGF0dXJlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkJNQyBH

ZXJpYXRyPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjM2PC9wYWdlcz48dm9sdW1l

PjE0PC92b2x1bWU+PGtleXdvcmRzPjxrZXl3b3JkPkFnaW5nL21ldGFib2xpc20vcGF0aG9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2Jsb29kLypldGlvbG9neS9wYXRo

b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzL2Jsb29kPC9rZXl3

b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QXRoZXJvc2NsZXJvc2lzL2Js

b29kLypldGlvbG9neS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKmJsb29kIHN1

cHBseS9tZXRhYm9saXNtL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdv

cmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy9ibG9vZDwva2V5d29yZD48a2V5d29yZD5J

bmZsYW1tYXRpb24vYmxvb2QvY29tcGxpY2F0aW9ucy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+SW5mbGFtbWF0aW9uIE1lZGlhdG9ycy8qYmxvb2Q8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0

ZXM+PHllYXI+MjAxNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1hciAyMTwvZGF0ZT48L3B1Yi1k

YXRlcz48L2RhdGVzPjxpc2JuPjE0NzEtMjMxOCAoRWxlY3Ryb25pYykmI3hEOzE0NzEtMjMxOCAo

TGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjQ2NTYwNTI8L2FjY2Vzc2lvbi1udW0+PHVy

bHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQv

MjQ2NTYwNTI8L3VybD48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcG1jL2FydGlj

bGVzL1BNQzM5OTQ0MzIvcGRmLzE0NzEtMjMxOC0xNC0zNi5wZGY8L3VybD48L3JlbGF0ZWQtdXJs

cz48L3VybHM+PGN1c3RvbTI+UE1DMzk5NDQzMjwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJj

ZS1udW0+MTAuMTE4Ni8xNDcxLTIzMTgtMTQtMzY8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwv

cmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 420,421 and to PD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJ3YXJoYTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

PFJlY051bT44NTM8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij40MjItNDI0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+ODUzPC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI1NTA4NTAiPjg1Mzwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWFyd2FyaGEsIEcuPC9hdXRob3I+

PGF1dGhvcj5SaGVuLCBULjwvYXV0aG9yPjxhdXRob3I+U2Nob21tZXIsIFQuPC9hdXRob3I+PGF1

dGhvcj5HaHJpYmksIE8uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk

ZHJlc3M+RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xvZ3ksIFVuaXZlcnNpdHkgb2YgTm9ydGggRGFr

b3RhIFNjaG9vbCBvZiBNZWRpY2luZSBhbmQgSGVhbHRoIFNjaWVuY2VzLCBHcmFuZCBGb3Jrcywg

Tm9ydGggRGFrb3RhLCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGhlIG94eXN0

ZXJvbCAyNy1oeWRyb3h5Y2hvbGVzdGVyb2wgcmVndWxhdGVzIGFscGhhLXN5bnVjbGVpbiBhbmQg

dHlyb3NpbmUgaHlkcm94eWxhc2UgZXhwcmVzc2lvbiBsZXZlbHMgaW4gaHVtYW4gbmV1cm9ibGFz

dG9tYSBjZWxscyB0aHJvdWdoIG1vZHVsYXRpb24gb2YgbGl2ZXIgWCByZWNlcHRvcnMgYW5kIGVz

dHJvZ2VuIHJlY2VwdG9ycy0tcmVsZXZhbmNlIHRvIFBhcmtpbnNvbiZhcG9zO3MgZGlzZWFzZTwv

dGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIE5ldXJvY2hlbTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0

bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9jaGVtPC9mdWxsLXRpdGxlPjwvcGVy

aW9kaWNhbD48cGFnZXM+MTExOS0zNjwvcGFnZXM+PHZvbHVtZT4xMTk8L3ZvbHVtZT48bnVtYmVy

PjU8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+Q2VsbCBMaW5lLCBUdW1vcjwva2V5d29yZD48

a2V5d29yZD5EaXNlYXNlIFByb2dyZXNzaW9uPC9rZXl3b3JkPjxrZXl3b3JkPkRvd24tUmVndWxh

dGlvbi9kcnVnIGVmZmVjdHMvcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5Fc3Ryb2dlbiBS

ZWNlcHRvciBhbHBoYS9hZ29uaXN0cy9hbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzLypiaW9z

eW50aGVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+RXN0cm9nZW4gUmVjZXB0b3IgYmV0YS9hZ29uaXN0

cy9hbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzLypiaW9zeW50aGVzaXM8L2tleXdvcmQ+PGtl

eXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5ZHJveHljaG9sZXN0ZXJvbHMvKnBoYXJt

YWNvbG9neTwva2V5d29yZD48a2V5d29yZD5MaXZlciBYIFJlY2VwdG9yczwva2V5d29yZD48a2V5

d29yZD5OZXVyb2JsYXN0b21hL2Vuenltb2xvZ3kvKm1ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPk9ycGhhbiBOdWNsZWFyIFJlY2VwdG9ycy9hZ29uaXN0cy9hbnRhZ29uaXN0

cyAmYW1wOyBpbmhpYml0b3JzLypiaW9zeW50aGVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+UGFya2lu

c29uIERpc2Vhc2UvZW56eW1vbG9neS9tZXRhYm9saXNtLypwcmV2ZW50aW9uICZhbXA7IGNvbnRy

b2w8L2tleXdvcmQ+PGtleXdvcmQ+U2lnbmFsIFRyYW5zZHVjdGlvbi9nZW5ldGljcy9waHlzaW9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPlR5cm9zaW5lIDMtTW9ub294eWdlbmFzZS8qYW50YWdvbmlz

dHMgJmFtcDsgaW5oaWJpdG9ycy9iaW9zeW50aGVzaXMvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdv

cmQ+VXAtUmVndWxhdGlvbi9kcnVnIGVmZmVjdHMvcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29y

ZD5hbHBoYS1TeW51Y2xlaW4vYmlvc3ludGhlc2lzLypnZW5ldGljczwva2V5d29yZD48L2tleXdv

cmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RGVjPC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ3MS00MTU5IChFbGVjdHJvbmljKSYjeEQ7MDAyMi0z

MDQyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMTk1MTA2NjwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8yMTk1MTA2NjwvdXJsPjx1cmw+aHR0cHM6Ly9vbmxpbmVsaWJyYXJ5LndpbGV5LmNvbS9k

b2kvcGRmLzEwLjExMTEvai4xNDcxLTQxNTkuMjAxMS4wNzQ5Ny54PC91cmw+PC9yZWxhdGVkLXVy

bHM+PC91cmxzPjxjdXN0b20yPlBNQzMyMTcxMjE8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjExMTEvai4xNDcxLTQxNTkuMjAxMS4wNzQ5Ny54PC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5Cam9ya2hlbTwvQXV0aG9yPjxZ

ZWFyPjIwMTM8L1llYXI+PFJlY051bT44NTU8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjg1

NTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUy

cHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTUwODkzIj44NTU8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJqb3JraGVtLCBJLjwvYXV0

aG9yPjxhdXRob3I+TG92Z3Jlbi1TYW5kYmxvbSwgQS48L2F1dGhvcj48YXV0aG9yPkxlb25pLCBW

LjwvYXV0aG9yPjxhdXRob3I+TWVhbmV5LCBTLjwvYXV0aG9yPjxhdXRob3I+QnJvZGluLCBMLjwv

YXV0aG9yPjxhdXRob3I+U2FsdmVzb24sIEwuPC9hdXRob3I+PGF1dGhvcj5XaW5nZSwgSy48L2F1

dGhvcj48YXV0aG9yPlBhbGhhZ2VuLCBTLjwvYXV0aG9yPjxhdXRob3I+U3Zlbm5pbmdzc29uLCBQ

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9u

IG9mIENsaW5pY2FsIENoZW1pc3RyeSwgRGVwYXJ0bWVudCBvZiBMYWJvcmF0b3J5IE1lZGljaW5l

LCBLYXJvbGluc2thIEluc3RpdHV0ZSwgU3RvY2tob2xtLCBTd2VkZW4uIEVsZWN0cm9uaWMgYWRk

cmVzczogaW5nZW1hci5iam9ya2hlbUBrYXJvbGluc2thLnNlLjwvYXV0aC1hZGRyZXNzPjx0aXRs

ZXM+PHRpdGxlPk94eXN0ZXJvbHMgYW5kIFBhcmtpbnNvbiZhcG9zO3MgZGlzZWFzZTogZXZpZGVu

Y2UgdGhhdCBsZXZlbHMgb2YgMjRTLWh5ZHJveHljaG9sZXN0ZXJvbCBpbiBjZXJlYnJvc3BpbmFs

IGZsdWlkIGNvcnJlbGF0ZXMgd2l0aCB0aGUgZHVyYXRpb24gb2YgdGhlIGRpc2Vhc2U8L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+TmV1cm9zY2kgTGV0dDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvc2NpIExldHQ8L2Z1bGwtdGl0bGU+PC9wZXJp

b2RpY2FsPjxwYWdlcz4xMDItNTwvcGFnZXM+PHZvbHVtZT41NTU8L3ZvbHVtZT48a2V5d29yZHM+

PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5DYXNlLUNvbnRyb2wgU3R1ZGllczwva2V5

d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxr

ZXl3b3JkPkh5ZHJveHljaG9sZXN0ZXJvbHMvYmxvb2QvKmNlcmVicm9zcGluYWwgZmx1aWQ8L2tl

eXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29y

ZD48a2V5d29yZD5QYXJraW5zb24gRGlzZWFzZS9ibG9vZC8qY2VyZWJyb3NwaW5hbCBmbHVpZDwv

a2V5d29yZD48a2V5d29yZD5UaW1lIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+MjRTLWh5ZHJv

eHljaG9sZXN0ZXJvbDwva2V5d29yZD48a2V5d29yZD4yNy1IeWRyb3h5Y2hvbGVzdGVyb2w8L2tl

eXdvcmQ+PGtleXdvcmQ+QmlvbWFya2Vyczwva2V5d29yZD48a2V5d29yZD5PeHlzdGVyb2xzPC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5PY3QgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xODcyLTc5NzIgKEVsZWN0

cm9uaWMpJiN4RDswMzA0LTM5NDAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI0MDM1

ODk2PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5j

YmkubmxtLm5paC5nb3YvcHVibWVkLzI0MDM1ODk2PC91cmw+PHVybD5odHRwczovL2FjLmVscy1j

ZG4uY29tL1MwMzA0Mzk0MDEzMDA4MTk3LzEtczIuMC1TMDMwNDM5NDAxMzAwODE5Ny1tYWluLnBk

Zj9fdGlkPTVkODA4NTgyLTZmMDQtNGM2NS1iN2MwLTEzOWFhY2JlMjk5MSZhbXA7YWNkbmF0PTE1

MzQ0OTQ3OTRfMzZiNDQ3NGZlZDg2ZDRiY2ZhYzNlOWZlYzI1OGVhYjk8L3VybD48L3JlbGF0ZWQt

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVsZXQuMjAx

My4wOS4wMDM8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48

QXV0aG9yPlRldW5pc3NlbjwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJlY051bT44NTI8L1Jl

Y051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjg1MjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxr

ZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIg

dGltZXN0YW1wPSIxNTMyNTUwNjk5Ij44NTI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUg

bmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9y

cz48YXV0aG9yPlRldW5pc3NlbiwgQy4gRS48L2F1dGhvcj48YXV0aG9yPkRpamtzdHJhLCBDLjwv

YXV0aG9yPjxhdXRob3I+UG9sbWFuLCBDLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTW9sZWN1bGFyIENlbGwgQmlvbG9neSBhbmQg

SW1tdW5vbG9neSwgVlUgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRlciwgQW1zdGVyZGFtLCBOZXRo

ZXJsYW5kcy4gYy50ZXVuaXNzZW5AdnVtYy5ubCAmbHQ7Yy50ZXVuaXNzZW5AdnVtYy5ubCZndDs8

L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5CaW9sb2dpY2FsIG1hcmtlcnMgaW4gQ1NGIGFu

ZCBibG9vZCBmb3IgYXhvbmFsIGRlZ2VuZXJhdGlvbiBpbiBtdWx0aXBsZSBzY2xlcm9zaXM8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+TGFuY2V0IE5ldXJvbDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0

bGVzPjxwYWdlcz4zMi00MTwvcGFnZXM+PHZvbHVtZT40PC92b2x1bWU+PG51bWJlcj4xPC9udW1i

ZXI+PGtleXdvcmRzPjxrZXl3b3JkPjE0LTMtMyBQcm90ZWlucy9ibG9vZC9jZXJlYnJvc3BpbmFs

IGZsdWlkPC9rZXl3b3JkPjxrZXl3b3JkPkFjdGlucy9ibG9vZC9jZXJlYnJvc3BpbmFsIGZsdWlk

PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1Qcm90ZWluIFByZWN1cnNvci9ibG9vZC9j

ZXJlYnJvc3BpbmFsIGZsdWlkPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWlucyBFL2Js

b29kL2NlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+QXNwYXJ0aWMgQWNpZC8q

YW5hbG9ncyAmYW1wOyBkZXJpdmF0aXZlcy9ibG9vZC9jZXJlYnJvc3BpbmFsIGZsdWlkPC9rZXl3

b3JkPjxrZXl3b3JkPkF4b25zLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QmlvbWFya2Vy

cy8qYmxvb2QvKmNlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9r

ZXl3b3JkPjxrZXl3b3JkPkh5ZHJveHljaG9sZXN0ZXJvbHMvYmxvb2QvY2VyZWJyb3NwaW5hbCBm

bHVpZDwva2V5d29yZD48a2V5d29yZD5NdWx0aXBsZSBTY2xlcm9zaXMvKmJsb29kLypjZXJlYnJv

c3BpbmFsIGZsdWlkL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD4qTmVydmUgRGVnZW5lcmF0

aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlBob3NwaG9weXJ1dmF0ZSBIeWRyYXRhc2UvYmxvb2QvY2Vy

ZWJyb3NwaW5hbCBmbHVpZDwva2V5d29yZD48a2V5d29yZD5QcmVkaWN0aXZlIFZhbHVlIG9mIFRl

c3RzPC9rZXl3b3JkPjxrZXl3b3JkPlR1YnVsaW4vYmxvb2QvY2VyZWJyb3NwaW5hbCBmbHVpZDwv

a2V5d29yZD48a2V5d29yZD50YXUgUHJvdGVpbnMvYmxvb2QvY2VyZWJyb3NwaW5hbCBmbHVpZDwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA1PC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+SmFuPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ3NC00NDIyIChQcmludCkm

I3hEOzE0NzQtNDQyMiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTU2MjA4NTU8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMTU2MjA4NTU8L3VybD48dXJsPmh0dHBzOi8vYWMuZWxzLWNkbi5jb20v

UzE0NzQ0NDIyMDQwMDk2NDAvMS1zMi4wLVMxNDc0NDQyMjA0MDA5NjQwLW1haW4ucGRmP190aWQ9

YjM5MjQxNzItNGFiZC00ZWRjLWFkM2YtMzFjNDhhMTkzNzc2JmFtcDthY2RuYXQ9MTUzNDQ5NDgy

N184ZTljODY4NDFkNmU4OTg3N2MzYzQzYWRhMTBjMzJhOTwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMTQ3NC00NDIyKDA0KTAwOTY0

LTA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJ3YXJoYTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

PFJlY051bT44NTM8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij40MjItNDI0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+ODUzPC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlh

MnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzI1NTA4NTAiPjg1Mzwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWFyd2FyaGEsIEcuPC9hdXRob3I+

PGF1dGhvcj5SaGVuLCBULjwvYXV0aG9yPjxhdXRob3I+U2Nob21tZXIsIFQuPC9hdXRob3I+PGF1

dGhvcj5HaHJpYmksIE8uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk

ZHJlc3M+RGVwYXJ0bWVudCBvZiBQaGFybWFjb2xvZ3ksIFVuaXZlcnNpdHkgb2YgTm9ydGggRGFr

b3RhIFNjaG9vbCBvZiBNZWRpY2luZSBhbmQgSGVhbHRoIFNjaWVuY2VzLCBHcmFuZCBGb3Jrcywg

Tm9ydGggRGFrb3RhLCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGhlIG94eXN0

ZXJvbCAyNy1oeWRyb3h5Y2hvbGVzdGVyb2wgcmVndWxhdGVzIGFscGhhLXN5bnVjbGVpbiBhbmQg

dHlyb3NpbmUgaHlkcm94eWxhc2UgZXhwcmVzc2lvbiBsZXZlbHMgaW4gaHVtYW4gbmV1cm9ibGFz

dG9tYSBjZWxscyB0aHJvdWdoIG1vZHVsYXRpb24gb2YgbGl2ZXIgWCByZWNlcHRvcnMgYW5kIGVz

dHJvZ2VuIHJlY2VwdG9ycy0tcmVsZXZhbmNlIHRvIFBhcmtpbnNvbiZhcG9zO3MgZGlzZWFzZTwv

dGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIE5ldXJvY2hlbTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0

bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9jaGVtPC9mdWxsLXRpdGxlPjwvcGVy

aW9kaWNhbD48cGFnZXM+MTExOS0zNjwvcGFnZXM+PHZvbHVtZT4xMTk8L3ZvbHVtZT48bnVtYmVy

PjU8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+Q2VsbCBMaW5lLCBUdW1vcjwva2V5d29yZD48

a2V5d29yZD5EaXNlYXNlIFByb2dyZXNzaW9uPC9rZXl3b3JkPjxrZXl3b3JkPkRvd24tUmVndWxh

dGlvbi9kcnVnIGVmZmVjdHMvcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5Fc3Ryb2dlbiBS

ZWNlcHRvciBhbHBoYS9hZ29uaXN0cy9hbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzLypiaW9z

eW50aGVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+RXN0cm9nZW4gUmVjZXB0b3IgYmV0YS9hZ29uaXN0

cy9hbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzLypiaW9zeW50aGVzaXM8L2tleXdvcmQ+PGtl

eXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5ZHJveHljaG9sZXN0ZXJvbHMvKnBoYXJt

YWNvbG9neTwva2V5d29yZD48a2V5d29yZD5MaXZlciBYIFJlY2VwdG9yczwva2V5d29yZD48a2V5

d29yZD5OZXVyb2JsYXN0b21hL2Vuenltb2xvZ3kvKm1ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPk9ycGhhbiBOdWNsZWFyIFJlY2VwdG9ycy9hZ29uaXN0cy9hbnRhZ29uaXN0

cyAmYW1wOyBpbmhpYml0b3JzLypiaW9zeW50aGVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+UGFya2lu

c29uIERpc2Vhc2UvZW56eW1vbG9neS9tZXRhYm9saXNtLypwcmV2ZW50aW9uICZhbXA7IGNvbnRy

b2w8L2tleXdvcmQ+PGtleXdvcmQ+U2lnbmFsIFRyYW5zZHVjdGlvbi9nZW5ldGljcy9waHlzaW9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPlR5cm9zaW5lIDMtTW9ub294eWdlbmFzZS8qYW50YWdvbmlz

dHMgJmFtcDsgaW5oaWJpdG9ycy9iaW9zeW50aGVzaXMvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdv

cmQ+VXAtUmVndWxhdGlvbi9kcnVnIGVmZmVjdHMvcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29y

ZD5hbHBoYS1TeW51Y2xlaW4vYmlvc3ludGhlc2lzLypnZW5ldGljczwva2V5d29yZD48L2tleXdv

cmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RGVjPC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ3MS00MTU5IChFbGVjdHJvbmljKSYjeEQ7MDAyMi0z

MDQyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMTk1MTA2NjwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8yMTk1MTA2NjwvdXJsPjx1cmw+aHR0cHM6Ly9vbmxpbmVsaWJyYXJ5LndpbGV5LmNvbS9k

b2kvcGRmLzEwLjExMTEvai4xNDcxLTQxNTkuMjAxMS4wNzQ5Ny54PC91cmw+PC9yZWxhdGVkLXVy

bHM+PC91cmxzPjxjdXN0b20yPlBNQzMyMTcxMjE8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjExMTEvai4xNDcxLTQxNTkuMjAxMS4wNzQ5Ny54PC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5Cam9ya2hlbTwvQXV0aG9yPjxZ

ZWFyPjIwMTM8L1llYXI+PFJlY051bT44NTU8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjg1

NTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUy

cHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTUwODkzIj44NTU8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJqb3JraGVtLCBJLjwvYXV0

aG9yPjxhdXRob3I+TG92Z3Jlbi1TYW5kYmxvbSwgQS48L2F1dGhvcj48YXV0aG9yPkxlb25pLCBW

LjwvYXV0aG9yPjxhdXRob3I+TWVhbmV5LCBTLjwvYXV0aG9yPjxhdXRob3I+QnJvZGluLCBMLjwv

YXV0aG9yPjxhdXRob3I+U2FsdmVzb24sIEwuPC9hdXRob3I+PGF1dGhvcj5XaW5nZSwgSy48L2F1

dGhvcj48YXV0aG9yPlBhbGhhZ2VuLCBTLjwvYXV0aG9yPjxhdXRob3I+U3Zlbm5pbmdzc29uLCBQ

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9u

IG9mIENsaW5pY2FsIENoZW1pc3RyeSwgRGVwYXJ0bWVudCBvZiBMYWJvcmF0b3J5IE1lZGljaW5l

LCBLYXJvbGluc2thIEluc3RpdHV0ZSwgU3RvY2tob2xtLCBTd2VkZW4uIEVsZWN0cm9uaWMgYWRk

cmVzczogaW5nZW1hci5iam9ya2hlbUBrYXJvbGluc2thLnNlLjwvYXV0aC1hZGRyZXNzPjx0aXRs

ZXM+PHRpdGxlPk94eXN0ZXJvbHMgYW5kIFBhcmtpbnNvbiZhcG9zO3MgZGlzZWFzZTogZXZpZGVu

Y2UgdGhhdCBsZXZlbHMgb2YgMjRTLWh5ZHJveHljaG9sZXN0ZXJvbCBpbiBjZXJlYnJvc3BpbmFs

IGZsdWlkIGNvcnJlbGF0ZXMgd2l0aCB0aGUgZHVyYXRpb24gb2YgdGhlIGRpc2Vhc2U8L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+TmV1cm9zY2kgTGV0dDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvc2NpIExldHQ8L2Z1bGwtdGl0bGU+PC9wZXJp

b2RpY2FsPjxwYWdlcz4xMDItNTwvcGFnZXM+PHZvbHVtZT41NTU8L3ZvbHVtZT48a2V5d29yZHM+

PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5DYXNlLUNvbnRyb2wgU3R1ZGllczwva2V5

d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxr

ZXl3b3JkPkh5ZHJveHljaG9sZXN0ZXJvbHMvYmxvb2QvKmNlcmVicm9zcGluYWwgZmx1aWQ8L2tl

eXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29y

ZD48a2V5d29yZD5QYXJraW5zb24gRGlzZWFzZS9ibG9vZC8qY2VyZWJyb3NwaW5hbCBmbHVpZDwv

a2V5d29yZD48a2V5d29yZD5UaW1lIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+MjRTLWh5ZHJv

eHljaG9sZXN0ZXJvbDwva2V5d29yZD48a2V5d29yZD4yNy1IeWRyb3h5Y2hvbGVzdGVyb2w8L2tl

eXdvcmQ+PGtleXdvcmQ+QmlvbWFya2Vyczwva2V5d29yZD48a2V5d29yZD5PeHlzdGVyb2xzPC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT5PY3QgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xODcyLTc5NzIgKEVsZWN0

cm9uaWMpJiN4RDswMzA0LTM5NDAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI0MDM1

ODk2PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5j

YmkubmxtLm5paC5nb3YvcHVibWVkLzI0MDM1ODk2PC91cmw+PHVybD5odHRwczovL2FjLmVscy1j

ZG4uY29tL1MwMzA0Mzk0MDEzMDA4MTk3LzEtczIuMC1TMDMwNDM5NDAxMzAwODE5Ny1tYWluLnBk

Zj9fdGlkPTVkODA4NTgyLTZmMDQtNGM2NS1iN2MwLTEzOWFhY2JlMjk5MSZhbXA7YWNkbmF0PTE1

MzQ0OTQ3OTRfMzZiNDQ3NGZlZDg2ZDRiY2ZhYzNlOWZlYzI1OGVhYjk8L3VybD48L3JlbGF0ZWQt

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVsZXQuMjAx

My4wOS4wMDM8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48

QXV0aG9yPlRldW5pc3NlbjwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJlY051bT44NTI8L1Jl

Y051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjg1MjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxr

ZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIg

dGltZXN0YW1wPSIxNTMyNTUwNjk5Ij44NTI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUg

bmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9y

cz48YXV0aG9yPlRldW5pc3NlbiwgQy4gRS48L2F1dGhvcj48YXV0aG9yPkRpamtzdHJhLCBDLjwv

YXV0aG9yPjxhdXRob3I+UG9sbWFuLCBDLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTW9sZWN1bGFyIENlbGwgQmlvbG9neSBhbmQg

SW1tdW5vbG9neSwgVlUgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRlciwgQW1zdGVyZGFtLCBOZXRo

ZXJsYW5kcy4gYy50ZXVuaXNzZW5AdnVtYy5ubCAmbHQ7Yy50ZXVuaXNzZW5AdnVtYy5ubCZndDs8

L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5CaW9sb2dpY2FsIG1hcmtlcnMgaW4gQ1NGIGFu

ZCBibG9vZCBmb3IgYXhvbmFsIGRlZ2VuZXJhdGlvbiBpbiBtdWx0aXBsZSBzY2xlcm9zaXM8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+TGFuY2V0IE5ldXJvbDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0

bGVzPjxwYWdlcz4zMi00MTwvcGFnZXM+PHZvbHVtZT40PC92b2x1bWU+PG51bWJlcj4xPC9udW1i

ZXI+PGtleXdvcmRzPjxrZXl3b3JkPjE0LTMtMyBQcm90ZWlucy9ibG9vZC9jZXJlYnJvc3BpbmFs

IGZsdWlkPC9rZXl3b3JkPjxrZXl3b3JkPkFjdGlucy9ibG9vZC9jZXJlYnJvc3BpbmFsIGZsdWlk

PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1Qcm90ZWluIFByZWN1cnNvci9ibG9vZC9j

ZXJlYnJvc3BpbmFsIGZsdWlkPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWlucyBFL2Js

b29kL2NlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+QXNwYXJ0aWMgQWNpZC8q

YW5hbG9ncyAmYW1wOyBkZXJpdmF0aXZlcy9ibG9vZC9jZXJlYnJvc3BpbmFsIGZsdWlkPC9rZXl3

b3JkPjxrZXl3b3JkPkF4b25zLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QmlvbWFya2Vy

cy8qYmxvb2QvKmNlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9r

ZXl3b3JkPjxrZXl3b3JkPkh5ZHJveHljaG9sZXN0ZXJvbHMvYmxvb2QvY2VyZWJyb3NwaW5hbCBm

bHVpZDwva2V5d29yZD48a2V5d29yZD5NdWx0aXBsZSBTY2xlcm9zaXMvKmJsb29kLypjZXJlYnJv

c3BpbmFsIGZsdWlkL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD4qTmVydmUgRGVnZW5lcmF0

aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlBob3NwaG9weXJ1dmF0ZSBIeWRyYXRhc2UvYmxvb2QvY2Vy

ZWJyb3NwaW5hbCBmbHVpZDwva2V5d29yZD48a2V5d29yZD5QcmVkaWN0aXZlIFZhbHVlIG9mIFRl

c3RzPC9rZXl3b3JkPjxrZXl3b3JkPlR1YnVsaW4vYmxvb2QvY2VyZWJyb3NwaW5hbCBmbHVpZDwv

a2V5d29yZD48a2V5d29yZD50YXUgUHJvdGVpbnMvYmxvb2QvY2VyZWJyb3NwaW5hbCBmbHVpZDwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA1PC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+SmFuPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ3NC00NDIyIChQcmludCkm

I3hEOzE0NzQtNDQyMiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTU2MjA4NTU8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMTU2MjA4NTU8L3VybD48dXJsPmh0dHBzOi8vYWMuZWxzLWNkbi5jb20v

UzE0NzQ0NDIyMDQwMDk2NDAvMS1zMi4wLVMxNDc0NDQyMjA0MDA5NjQwLW1haW4ucGRmP190aWQ9

YjM5MjQxNzItNGFiZC00ZWRjLWFkM2YtMzFjNDhhMTkzNzc2JmFtcDthY2RuYXQ9MTUzNDQ5NDgy

N184ZTljODY4NDFkNmU4OTg3N2MzYzQzYWRhMTBjMzJhOTwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMTQ3NC00NDIyKDA0KTAwOTY0

LTA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 422-424. It’s also associated to breast cancer PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWVrPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48UmVj

TnVtPjg1ODwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjQy

NTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjg1ODwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhw

Znd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTk3NTAyIj44NTg8L2tleT48L2ZvcmVp

Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv

bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJhZWssIEEuIEUuPC9hdXRob3I+PGF1dGhvcj5Z

dSwgWS4gQS48L2F1dGhvcj48YXV0aG9yPkhlLCBTLjwvYXV0aG9yPjxhdXRob3I+V2FyZGVsbCwg

Uy4gRS48L2F1dGhvcj48YXV0aG9yPkNoYW5nLCBDLiBZLjwvYXV0aG9yPjxhdXRob3I+S3dvbiwg

Uy48L2F1dGhvcj48YXV0aG9yPlBpbGxhaSwgUi4gVi48L2F1dGhvcj48YXV0aG9yPk1jRG93ZWxs

LCBILiBCLjwvYXV0aG9yPjxhdXRob3I+VGhvbXBzb24sIEouIFcuPC9hdXRob3I+PGF1dGhvcj5E

dWJvaXMsIEwuIEcuPC9hdXRob3I+PGF1dGhvcj5TdWxsaXZhbiwgUC4gTS48L2F1dGhvcj48YXV0

aG9yPktlbXBlciwgSi4gSy48L2F1dGhvcj48YXV0aG9yPkd1bm4sIE0uIEQuPC9hdXRob3I+PGF1

dGhvcj5NY0Rvbm5lbGwsIEQuIFAuPC9hdXRob3I+PGF1dGhvcj5OZWxzb24sIEUuIFIuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBN

b2xlY3VsYXIgYW5kIEludGVncmF0aXZlIFBoeXNpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgSWxsaW5v

aXMgYXQgVXJiYW5hLUNoYW1wYWlnbiwgNDA3UyBHb29kd2luIEF2ZW51ZSAoTUMtMTE0KSwgVXJi

YW5hLCBJTCwgNjE4MDEsIFVTQS4mI3hEO0RlcGFydG1lbnQgb2YgTWVkaWNpbmUsIERpdmlzaW9u

IG9mIENhcmRpb2xvZ3ksIER1a2UgVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUsIDM0NiBT

YW5kcyBCdWlsZGluZywgRHVyaGFtLCBOQywgMjc3MTAsIFVTQS4mI3hEO0RlcGFydG1lbnQgb2Yg

UGhhcm1hY29sb2d5IGFuZCBDYW5jZXIgQmlvbG9neSwgRHVrZSBVbml2ZXJzaXR5IFNjaG9vbCBv

ZiBNZWRpY2luZSwgQm94IDM4MTMsIER1cmhhbSwgTkMsIDI3NzEwLCBVU0EuJiN4RDtQcm90ZW9t

aWNzIGFuZCBNZXRhYm9sb21pY3MgU2hhcmVkIFJlc291cmNlcywgRHVrZSBVbml2ZXJzaXR5IFNj

aG9vbCBvZiBNZWRpY2luZSwgQjAyIExldmluZSBTY2llbmNlIFJlc2VhcmNoIENlbnRlciwgNDUw

IFNjaWVuY2UgRHJpdmUsIER1cmhhbSwgTkMsIDI3NzA4LCBVU0EuJiN4RDtEZXBhcnRtZW50IG9m

IE1lZGljaW5lLCBEdWtlIFVuaXZlcnNpdHkgU2Nob29sIG9mIE1lZGljaW5lLCBEdXJoYW0sIDI3

NzEwLCBOQywgVVNBLiYjeEQ7R2VyaWF0cmljIFJlc2VhcmNoLCBFZHVjYXRpb24gYW5kIENsaW5p

Y2FsIENlbnRlciwgRHVyaGFtIFZldGVyYW5zIEFmZmFpcnMgTWVkaWNhbCBDZW50ZXIsIDUwOCBG

dWx0b24gU3RyZWV0LCBEdXJoYW0sIE5DLCAyNzcwNSwgVVNBLiYjeEQ7RGVwYXJ0bWVudCBvZiBN

b2xlY3VsYXIgYW5kIEludGVncmF0aXZlIFBoeXNpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgSWxsaW5v

aXMgYXQgVXJiYW5hLUNoYW1wYWlnbiwgNDA3UyBHb29kd2luIEF2ZW51ZSAoTUMtMTE0KSwgVXJi

YW5hLCBJTCwgNjE4MDEsIFVTQS4gZW5lbHNAaWxsaW5vaXMuZWR1LiYjeEQ7VW5pdmVyc2l0eSBv

ZiBJbGxpbm9pcyBDYW5jZXIgQ2VudGVyLCBDaGljYWdvLCBJTCwgNjA2MTIsIFVTQS4gZW5lbHNA

aWxsaW5vaXMuZWR1LiYjeEQ7RGl2aXNpb24gb2YgTnV0cml0aW9uYWwgU2NpZW5jZXMsIFVuaXZl

cnNpdHkgb2YgSWxsaW5vaXMgYXQgVXJiYW5hLUNoYW1wYWlnbiwgVXJiYW5hLCBJTCwgNjE4MDEs

IFVTQS4gZW5lbHNAaWxsaW5vaXMuZWR1LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRo

ZSBjaG9sZXN0ZXJvbCBtZXRhYm9saXRlIDI3IGh5ZHJveHljaG9sZXN0ZXJvbCBmYWNpbGl0YXRl

cyBicmVhc3QgY2FuY2VyIG1ldGFzdGFzaXMgdGhyb3VnaCBpdHMgYWN0aW9ucyBvbiBpbW11bmUg

Y2VsbHM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0IENvbW11bjwvc2Vjb25kYXJ5LXRpdGxl

PjwvdGl0bGVzPjxwYWdlcz44NjQ8L3BhZ2VzPjx2b2x1bWU+ODwvdm9sdW1lPjxudW1iZXI+MTwv

bnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJyZWFz

dCBOZW9wbGFzbXMvKmltbXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2FyY2lub21hLyppbW11

bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgTGluZSwgVHVtb3I8L2tleXdvcmQ+PGtleXdv

cmQ+Q2hvbGVzdGVyb2wsIERpZXRhcnkvKmFkdmVyc2UgZWZmZWN0cy9tZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtl

eXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy8qYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3

b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgSW5icmVkIEM1N0JMPC9rZXl3b3JkPjxr

ZXl3b3JkPk15ZWxvaWQgQ2VsbHMvKmRydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD4qTmVv

cGxhc20gTWV0YXN0YXNpczwva2V5d29yZD48a2V5d29yZD5PYmVzaXR5L21ldGFib2xpc208L2tl

eXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRl

Pk9jdCAxMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjIwNDEtMTcyMyAoRWxlY3Ry

b25pYykmI3hEOzIwNDEtMTcyMyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjkwMjE1

MjI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNi

aS5ubG0ubmloLmdvdi9wdWJtZWQvMjkwMjE1MjI8L3VybD48dXJsPmh0dHBzOi8vd3d3Lm5jYmku

bmxtLm5paC5nb3YvcG1jL2FydGljbGVzL1BNQzU2MzY4NzkvcGRmLzQxNDY3XzIwMTdfQXJ0aWNs

ZV85MTAucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzU2MzY4Nzk8

L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMzgvczQxNDY3LTAxNy0wMDkx

MC16PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWVrPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48UmVj

TnVtPjg1ODwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjQy

NTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjg1ODwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhw

Znd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTk3NTAyIj44NTg8L2tleT48L2ZvcmVp

Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv

bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJhZWssIEEuIEUuPC9hdXRob3I+PGF1dGhvcj5Z

dSwgWS4gQS48L2F1dGhvcj48YXV0aG9yPkhlLCBTLjwvYXV0aG9yPjxhdXRob3I+V2FyZGVsbCwg

Uy4gRS48L2F1dGhvcj48YXV0aG9yPkNoYW5nLCBDLiBZLjwvYXV0aG9yPjxhdXRob3I+S3dvbiwg

Uy48L2F1dGhvcj48YXV0aG9yPlBpbGxhaSwgUi4gVi48L2F1dGhvcj48YXV0aG9yPk1jRG93ZWxs

LCBILiBCLjwvYXV0aG9yPjxhdXRob3I+VGhvbXBzb24sIEouIFcuPC9hdXRob3I+PGF1dGhvcj5E

dWJvaXMsIEwuIEcuPC9hdXRob3I+PGF1dGhvcj5TdWxsaXZhbiwgUC4gTS48L2F1dGhvcj48YXV0

aG9yPktlbXBlciwgSi4gSy48L2F1dGhvcj48YXV0aG9yPkd1bm4sIE0uIEQuPC9hdXRob3I+PGF1

dGhvcj5NY0Rvbm5lbGwsIEQuIFAuPC9hdXRob3I+PGF1dGhvcj5OZWxzb24sIEUuIFIuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBN

b2xlY3VsYXIgYW5kIEludGVncmF0aXZlIFBoeXNpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgSWxsaW5v

aXMgYXQgVXJiYW5hLUNoYW1wYWlnbiwgNDA3UyBHb29kd2luIEF2ZW51ZSAoTUMtMTE0KSwgVXJi

YW5hLCBJTCwgNjE4MDEsIFVTQS4mI3hEO0RlcGFydG1lbnQgb2YgTWVkaWNpbmUsIERpdmlzaW9u

IG9mIENhcmRpb2xvZ3ksIER1a2UgVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUsIDM0NiBT

YW5kcyBCdWlsZGluZywgRHVyaGFtLCBOQywgMjc3MTAsIFVTQS4mI3hEO0RlcGFydG1lbnQgb2Yg

UGhhcm1hY29sb2d5IGFuZCBDYW5jZXIgQmlvbG9neSwgRHVrZSBVbml2ZXJzaXR5IFNjaG9vbCBv

ZiBNZWRpY2luZSwgQm94IDM4MTMsIER1cmhhbSwgTkMsIDI3NzEwLCBVU0EuJiN4RDtQcm90ZW9t

aWNzIGFuZCBNZXRhYm9sb21pY3MgU2hhcmVkIFJlc291cmNlcywgRHVrZSBVbml2ZXJzaXR5IFNj

aG9vbCBvZiBNZWRpY2luZSwgQjAyIExldmluZSBTY2llbmNlIFJlc2VhcmNoIENlbnRlciwgNDUw

IFNjaWVuY2UgRHJpdmUsIER1cmhhbSwgTkMsIDI3NzA4LCBVU0EuJiN4RDtEZXBhcnRtZW50IG9m

IE1lZGljaW5lLCBEdWtlIFVuaXZlcnNpdHkgU2Nob29sIG9mIE1lZGljaW5lLCBEdXJoYW0sIDI3

NzEwLCBOQywgVVNBLiYjeEQ7R2VyaWF0cmljIFJlc2VhcmNoLCBFZHVjYXRpb24gYW5kIENsaW5p

Y2FsIENlbnRlciwgRHVyaGFtIFZldGVyYW5zIEFmZmFpcnMgTWVkaWNhbCBDZW50ZXIsIDUwOCBG

dWx0b24gU3RyZWV0LCBEdXJoYW0sIE5DLCAyNzcwNSwgVVNBLiYjeEQ7RGVwYXJ0bWVudCBvZiBN

b2xlY3VsYXIgYW5kIEludGVncmF0aXZlIFBoeXNpb2xvZ3ksIFVuaXZlcnNpdHkgb2YgSWxsaW5v

aXMgYXQgVXJiYW5hLUNoYW1wYWlnbiwgNDA3UyBHb29kd2luIEF2ZW51ZSAoTUMtMTE0KSwgVXJi

YW5hLCBJTCwgNjE4MDEsIFVTQS4gZW5lbHNAaWxsaW5vaXMuZWR1LiYjeEQ7VW5pdmVyc2l0eSBv

ZiBJbGxpbm9pcyBDYW5jZXIgQ2VudGVyLCBDaGljYWdvLCBJTCwgNjA2MTIsIFVTQS4gZW5lbHNA

aWxsaW5vaXMuZWR1LiYjeEQ7RGl2aXNpb24gb2YgTnV0cml0aW9uYWwgU2NpZW5jZXMsIFVuaXZl

cnNpdHkgb2YgSWxsaW5vaXMgYXQgVXJiYW5hLUNoYW1wYWlnbiwgVXJiYW5hLCBJTCwgNjE4MDEs

IFVTQS4gZW5lbHNAaWxsaW5vaXMuZWR1LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRo

ZSBjaG9sZXN0ZXJvbCBtZXRhYm9saXRlIDI3IGh5ZHJveHljaG9sZXN0ZXJvbCBmYWNpbGl0YXRl

cyBicmVhc3QgY2FuY2VyIG1ldGFzdGFzaXMgdGhyb3VnaCBpdHMgYWN0aW9ucyBvbiBpbW11bmUg

Y2VsbHM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0IENvbW11bjwvc2Vjb25kYXJ5LXRpdGxl

PjwvdGl0bGVzPjxwYWdlcz44NjQ8L3BhZ2VzPjx2b2x1bWU+ODwvdm9sdW1lPjxudW1iZXI+MTwv

bnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJyZWFz

dCBOZW9wbGFzbXMvKmltbXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2FyY2lub21hLyppbW11

bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgTGluZSwgVHVtb3I8L2tleXdvcmQ+PGtleXdv

cmQ+Q2hvbGVzdGVyb2wsIERpZXRhcnkvKmFkdmVyc2UgZWZmZWN0cy9tZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtl

eXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy8qYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3

b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgSW5icmVkIEM1N0JMPC9rZXl3b3JkPjxr

ZXl3b3JkPk15ZWxvaWQgQ2VsbHMvKmRydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD4qTmVv

cGxhc20gTWV0YXN0YXNpczwva2V5d29yZD48a2V5d29yZD5PYmVzaXR5L21ldGFib2xpc208L2tl

eXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRl

Pk9jdCAxMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjIwNDEtMTcyMyAoRWxlY3Ry

b25pYykmI3hEOzIwNDEtMTcyMyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjkwMjE1

MjI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNi

aS5ubG0ubmloLmdvdi9wdWJtZWQvMjkwMjE1MjI8L3VybD48dXJsPmh0dHBzOi8vd3d3Lm5jYmku

bmxtLm5paC5nb3YvcG1jL2FydGljbGVzL1BNQzU2MzY4NzkvcGRmLzQxNDY3XzIwMTdfQXJ0aWNs

ZV85MTAucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzU2MzY4Nzk8

L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMzgvczQxNDY3LTAxNy0wMDkx

MC16PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 425 and to a genetic disease called spastic paraplegia of the fifth type (SPG5) where a mutation causes a loss of function of CYP7B1, an enzyme that degrades 27-OH, so these patients have ten times more 27-OH than normal individuals PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaWFtPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVj

TnVtPjg1MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjQy

Niw0Mjc8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj44NTA8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjU1MDU1NCI+ODUwPC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TaWFtLCBBLjwvYXV0aG9yPjxhdXRob3I+

QnJhbmNhbGUsIEEuPC9hdXRob3I+PGF1dGhvcj5TaW1vbnMsIEMuPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+TWVkaWNpbmFsIENoZW1pc3RyeSwgV2Vsc2gg

U2Nob29sIG9mIFBoYXJtYWN5LCBDYXJkaWZmIFVuaXZlcnNpdHksIEtpbmcgRWR3YXJkIFZJSSBB

dmVudWUsIENhcmRpZmYsIENGMTAgM05CLCBVSy48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRs

ZT5Db21wYXJhdGl2ZSBtb2RlbGluZyBvZiAyNS1oeWRyb3h5Y2hvbGVzdGVyb2wtN2FscGhhLWh5

ZHJveHlsYXNlIChDWVA3QjEpOiBsaWdhbmQgYmluZGluZyBhbmQgYW5hbHlzaXMgb2YgaGVyZWRp

dGFyeSBzcGFzdGljIHBhcmFwbGVnaWEgdHlwZSA1IENZUDdCMSBtdXRhdGlvbnM8L3RpdGxlPjxz

ZWNvbmRhcnktdGl0bGU+SiBNb2wgTW9kZWw8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFn

ZXM+NDQxLTUzPC9wYWdlcz48dm9sdW1lPjE4PC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGtl

eXdvcmRzPjxrZXl3b3JkPkFtaW5vIEFjaWQgU2VxdWVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+QW5p

bWFsczwva2V5d29yZD48a2V5d29yZD5DeXRvY2hyb21lIFA0NTAgRmFtaWx5IDc8L2tleXdvcmQ+

PGtleXdvcmQ+RE5BIE11dGF0aW9uYWwgQW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5z

PC9rZXl3b3JkPjxrZXl3b3JkPkxpZ2FuZHM8L2tleXdvcmQ+PGtleXdvcmQ+Kk1vZGVscywgTW9s

ZWN1bGFyPC9rZXl3b3JkPjxrZXl3b3JkPk1vbGVjdWxhciBTZXF1ZW5jZSBEYXRhPC9rZXl3b3Jk

PjxrZXl3b3JkPipNdXRhdGlvbjwva2V5d29yZD48a2V5d29yZD5QaHlsb2dlbnk8L2tleXdvcmQ+

PGtleXdvcmQ+UHJvdGVpbiBCaW5kaW5nPC9rZXl3b3JkPjxrZXl3b3JkPlByb3RlaW4gU3RydWN0

dXJlLCBTZWNvbmRhcnk8L2tleXdvcmQ+PGtleXdvcmQ+UmVwcm9kdWNpYmlsaXR5IG9mIFJlc3Vs

dHM8L2tleXdvcmQ+PGtleXdvcmQ+U2VxdWVuY2UgQWxpZ25tZW50PC9rZXl3b3JkPjxrZXl3b3Jk

PlNlcXVlbmNlIEhvbW9sb2d5LCBBbWlubyBBY2lkPC9rZXl3b3JkPjxrZXl3b3JkPlNwYXN0aWMg

UGFyYXBsZWdpYSwgSGVyZWRpdGFyeS8qZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+U3Rlcm9p

ZCBIeWRyb3h5bGFzZXMvKmNoZW1pc3RyeS9jbGFzc2lmaWNhdGlvbi8qZ2VuZXRpY3M8L2tleXdv

cmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkZl

YjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjA5NDgtNTAyMyAoRWxlY3Ryb25pYykm

I3hEOzA5NDgtNTAyMyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjE1NDE3NDY8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMjE1NDE3NDY8L3VybD48dXJsPmh0dHBzOi8vbGluay5zcHJpbmdlci5j

b20vY29udGVudC9wZGYvMTAuMTAwNyUyRnMwMDg5NC0wMTEtMTA4NC02LnBkZjwvdXJsPjwvcmVs

YXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMDA4OTQt

MDExLTEwODQtNjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRl

PjxBdXRob3I+U2Nob2xzPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48UmVjTnVtPjU5NDwvUmVj

TnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+NTk0PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0

aW1lc3RhbXA9IjE1MzI1NTA0OTkiPjU5NDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBu

YW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3Jz

PjxhdXRob3I+U2Nob2xzLCBMLjwvYXV0aG9yPjxhdXRob3I+UmF0dGF5LCBULiBXLjwvYXV0aG9y

PjxhdXRob3I+TWFydHVzLCBQLjwvYXV0aG9yPjxhdXRob3I+TWVpc25lciwgQy48L2F1dGhvcj48

YXV0aG9yPkJhZXRzLCBKLjwvYXV0aG9yPjxhdXRob3I+RmlzY2hlciwgSS48L2F1dGhvcj48YXV0

aG9yPkphZ2xlLCBDLjwvYXV0aG9yPjxhdXRob3I+RnJhaWRha2lzLCBNLiBKLjwvYXV0aG9yPjxh

dXRob3I+TWFydGludXp6aSwgQS48L2F1dGhvcj48YXV0aG9yPlNhdXRlLCBKLiBBLjwvYXV0aG9y

PjxhdXRob3I+U2NhcmxhdG8sIE0uPC9hdXRob3I+PGF1dGhvcj5BbnRlbm9yYSwgQS48L2F1dGhv

cj48YXV0aG9yPlN0ZW5kZWwsIEMuPC9hdXRob3I+PGF1dGhvcj5Ib2ZsaW5nZXIsIFAuPC9hdXRo

b3I+PGF1dGhvcj5Mb3VyZW5jbywgQy4gTS48L2F1dGhvcj48YXV0aG9yPkFicmV1LCBMLjwvYXV0

aG9yPjxhdXRob3I+U21ldHMsIEsuPC9hdXRob3I+PGF1dGhvcj5QYXVjYXIsIE0uPC9hdXRob3I+

PGF1dGhvcj5EZWNvbmluY2ssIFQuPC9hdXRob3I+PGF1dGhvcj5CaXMsIEQuIE0uPC9hdXRob3I+

PGF1dGhvcj5XaWV0aG9mZiwgUy48L2F1dGhvcj48YXV0aG9yPkJhdWVyLCBQLjwvYXV0aG9yPjxh

dXRob3I+QXJub2xkaSwgQS48L2F1dGhvcj48YXV0aG9yPk1hcnF1ZXMsIFcuPC9hdXRob3I+PGF1

dGhvcj5KYXJkaW0sIEwuIEIuPC9hdXRob3I+PGF1dGhvcj5IYXVzZXIsIFMuPC9hdXRob3I+PGF1

dGhvcj5DcmlzY3VvbG8sIEMuPC9hdXRob3I+PGF1dGhvcj5GaWxsYSwgQS48L2F1dGhvcj48YXV0

aG9yPlp1Y2huZXIsIFMuPC9hdXRob3I+PGF1dGhvcj5CYXNzaSwgTS4gVC48L2F1dGhvcj48YXV0

aG9yPktsb3BzdG9jaywgVC48L2F1dGhvcj48YXV0aG9yPkRlIEpvbmdoZSwgUC48L2F1dGhvcj48

YXV0aG9yPkJqb3JraGVtLCBJLjwvYXV0aG9yPjxhdXRob3I+U2NodWxlLCBSLjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkNlbnRlciBmb3IgTmV1cm9sb2d5

IGFuZCBIZXJ0aWUgSW5zdGl0dXRlIGZvciBDbGluaWNhbCBCcmFpbiBSZXNlYXJjaCwgRWJlcmhh

cmQtS2FybHMtVW5pdmVyc2l0eSwgNzIwNzYgVHViaW5nZW4sIEdlcm1hbnkuJiN4RDtHZXJtYW4g

Q2VudGVyIG9mIE5ldXJvZGVnZW5lcmF0aXZlIERpc2Vhc2VzIChEWk5FKSwgNzIwNzYgVHViaW5n

ZW4sIEdlcm1hbnkuJiN4RDtJbnN0aXR1dGUgZm9yIENsaW5pY2FsIEVwaWRlbWlvbG9neSBhbmQg

QXBwbGllZCBCaW9zdGF0aXN0aWNzLCBFYmVyaGFyZC1LYXJscy1Vbml2ZXJzaXR5LCA3MjA3NiBU

dWJpbmdlbiwgR2VybWFueS4mI3hEO05ldXJvZ2VuZXRpY3MgR3JvdXAsIENlbnRlciBmb3IgTW9s

ZWN1bGFyIE5ldXJvbG9neSwgVklCLCAyNjEwIEFudHdlcnAsIEJlbGdpdW0uJiN4RDtEZXBhcnRt

ZW50IG9mIE5ldXJvbG9neSwgQW50d2VycCBVbml2ZXJzaXR5IEhvc3BpdGFsLCAyNjEwIEFudHdl

cnAsIEJlbGdpdW0uJiN4RDtMYWJvcmF0b3J5IG9mIE5ldXJvbXVzY3VsYXIgUGF0aG9sb2d5LCBJ

bnN0aXR1dGUgQm9ybi1CdW5nZSwgVW5pdmVyc2l0eSBvZiBBbnR3ZXJwLCAyNjEwIEFudHdlcnAs

IEJlbGdpdW0uJiN4RDtDZW50ZXIgZm9yIFJhcmUgRGlzZWFzZXMgYW5kIEluc3RpdHV0ZSBvZiBI

dW1hbiBHZW5ldGljcyBhbmQgQXBwbGllZCBHZW5vbWljcywgRWJlcmhhcmQtS2FybHMtVW5pdmVy

c2l0eSwgNzIwNzYgVHViaW5nZW4sIEdlcm1hbnkuJiN4RDtSYXJlIE5ldXJvbG9naWNhbCBEaXNl

YXNlcyBVbml0LCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgVW5pdmVyc2l0eSBIb3NwaXRhbCAm

YXBvcztBdHRpa29uJmFwb3M7LCBNZWRpY2FsIFNjaG9vbCBvZiB0aGUgVW5pdmVyc2l0eSBvZiBB

dGhlbnMsIDEyNDYyIEF0aGVucywgR3JlZWNlLiYjeEQ7U2NpZW50aWZpYyBJbnN0aXR1dGUgSVJD

Q1MgRS4gTWVkZWEsIENvbmVnbGlhbm8gUmVzZWFyY2ggQ2VudGVyLCAzMTAxNSBDb25lZ2xpYW5v

LCBJdGFseS4mI3hEO01lZGljYWwgR2VuZXRpY3MgU2VydmljZSwgSG9zcGl0YWwgZGUgQ2xpbmlj

YXMgZGUgUG9ydG8gQWxlZ3JlLCBQb3J0byBBbGVncmUsIEJyYXppbC4mI3hEO0dlbmV0aWNzIElk

ZW50aWZpY2F0aW9uIExhYm9yYXRvcnksIEhvc3BpdGFsIGRlIENsaW5pY2FzIGRlIFBvcnRvIEFs

ZWdyZSwgOTAwMzUgUG9ydG8gQWxlZ3JlLCBCcmF6aWwuJiN4RDtQb3N0Z3JhZHVhdGUgUHJvZ3Jh

bSBpbiBNZWRpY2luZTogTWVkaWNhbCBTY2llbmNlcywgVW5pdmVyc2lkYWRlIEZlZGVyYWwgZG8g

UmlvIEdyYW5kZSBkbyBTdWwgKFVGUkdTKSwgOTAwNDAgUG9ydG8gQWxlZ3JlLCBCcmF6aWwuJiN4

RDtOZXVyb2xvZ3kgRGVwYXJ0bWVudCBhbmQgSU5TUEUsIFNhbiBSYWZmYWVsZSBIb3NwaXRhbCwg

MjAxMzIgTWlsYW4sIEl0YWx5LiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb3NjaWVuY2VzLCBSZXBy

b2R1Y3RpdmUgYW5kIE9kb250b3N0b21hdG9sb2dpY2FsIFNjaWVuY2VzLCBGZWRlcmljbyBJSSBV

bml2ZXJzaXR5IE5hcGxlcywgODAxMzEgTmFwbGVzLCBJdGFseS4mI3hEO0RlcGFydG1lbnQgb2Yg

TmV1cm9sb2d5LCBGcmllZHJpY2ggQmF1ciBJbnN0aXR1dGUsIEx1ZHdpZy1NYXhpbWlsaWFucy1V

bml2ZXJzaXR5LCA4MDMzNiBNdW5pY2gsIEdlcm1hbnkuJiN4RDtNdW5pY2ggQ2x1c3RlciBmb3Ig

U3lzdGVtcyBOZXVyb2xvZ3kgKFN5TmVyZ3kpLCA4MTM3NyBNdW5pY2gsIEdlcm1hbnkuJiN4RDtH

ZXJtYW4gQ2VudGVyIGZvciBOZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcyAoRFpORSksIDgxMzc3

IE11bmljaCwgR2VybWFueS4mI3hEO0RlcGFydGFtZW50byBkZSBOZXVyb2xvZ2lhLCBGYWN1bGRh

ZGUgZGUgTWVkaWNpbmEgZGUgUmliZWlyYW8gUHJldG8sIFVuaXZlcnNpZGFkZSBkZSBTYW8gUGF1

bG8sIDE0MDQ5IFJpYmVpcmFvIFByZXRvLCBCcmF6aWwuJiN4RDtEZXBhcnRtZW50IG9mIEludGVy

bmFsIE1lZGljaW5lLCBVbml2ZXJzaWRhZGUgRmVkZXJhbCBkbyBSaW8gR3JhbmRlIGRvIFN1bCAo

VUZSR1MpLCA5MDA0MCBQb3J0byBBbGVncmUsIEJyYXppbC4mI3hEO0pvaG4gUC4gSHVzc21hbiBJ

bnN0aXR1dGUgZm9yIEh1bWFuIEdlbm9taWNzLCBEci4gSm9obiBULiBNYWNkb25hbGQgRm91bmRh

dGlvbiBEZXBhcnRtZW50IG9mIEh1bWFuIEdlbmV0aWNzLCBVbml2ZXJzaXR5IG9mIE1pYW1pLCAz

MzEzNiBNaWFtaSwgRmxvcmlkYSwgVVNBLiYjeEQ7RHIuIEpvaG4gVC4gTWFjZG9uYWxkIEZvdW5k

YXRpb24gRGVwYXJ0bWVudCBvZiBIdW1hbiBHZW5ldGljcywgVW5pdmVyc2l0eSBvZiBNaWFtaSwg

MzMxMzYgTWlhbWksIEZsb3JpZGEsIFVTQS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBL

YXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwgSHVkZGluZ2UgYW5kIERlcGFydG1lbnQgb2Yg

Q2xpbmljYWwgTmV1cm9zY2llbmNlLCBLYXJvbGluc2thIEluc3RpdHV0ZSwgMTQxNTIgSHVkZGlu

Z2UsIFN3ZWRlbi4mI3hEO0luc3RpdHV0ZSBvZiBOZXVyb2xvZ3ksIFF1ZWVuIFNxdWFyZSwgTG9u

ZG9uIFdDMU4gM0JHLCBVSy4mI3hEO0luc3RpdHV0ZSBvZiBNZWRpY2FsIEdlbmV0aWNzIGFuZCBB

cHBsaWVkIEdlbm9taWNzLCBFYmVyaGFyZC1LYXJscy1Vbml2ZXJzaXR5LCA3MjA3NiBUdWJpbmdl

biwgR2VybWFueS4mI3hEO0NFTlRPR0VORSBBRywgMTgwNTcgUm9zdG9jaywgR2VybWFueS4mI3hE

O0xhYm9yYXRvcnkgb2YgTW9sZWN1bGFyIEJpb2xvZ3ksIFNjaWVudGlmaWMgSW5zdGl0dXRlIElS

Q0NTIEUuIE1lZGVhLCAyMzg0MiBCb3Npc2lvIFBhcmluaSwgSXRhbHkuJiN4RDtLYXJvbGluc2th

IFVuaXZlcnNpdHkgSG9zcGl0YWwgSHVkZGluZ2UsIEthcm9saW5za2EgSW5zdGl0dXRlLCAxNDE1

MiBTdG9ja2hvbG0sIFN3ZWRlbi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5IZXJlZGl0

YXJ5IHNwYXN0aWMgcGFyYXBsZWdpYSB0eXBlIDU6IG5hdHVyYWwgaGlzdG9yeSwgYmlvbWFya2Vy

cyBhbmQgYSByYW5kb21pemVkIGNvbnRyb2xsZWQgdHJpYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0

bGU+QnJhaW48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRs

ZT5CcmFpbjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjMxMTItMzEyNzwvcGFnZXM+

PHZvbHVtZT4xNDA8L3ZvbHVtZT48bnVtYmVyPjEyPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3Jk

PkFkb2xlc2NlbnQ8L2tleXdvcmQ+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QXRv

cnZhc3RhdGluIENhbGNpdW0vKnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5CaW9t

YXJrZXJzL2Jsb29kL2NlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+Q2FzZS1D

b250cm9sIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBQcm9saWZlcmF0aW9uPC9rZXl3

b3JkPjxrZXl3b3JkPkNyb3NzLVNlY3Rpb25hbCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkN5

dG9jaHJvbWUgUDQ1MCBGYW1pbHkgNy9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5EaXNlYXNl

IFByb2dyZXNzaW9uPC9rZXl3b3JkPjxrZXl3b3JkPkRvdWJsZS1CbGluZCBNZXRob2Q8L2tleXdv

cmQ+PGtleXdvcmQ+RmFtaWx5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5

d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy9tZXRhYm9s

aXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh5ZHJveHltZXRoeWxnbHV0YXJ5bC1Db0EgUmVkdWN0YXNl

IEluaGliaXRvcnMvKnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5JbmR1Y2VkIFBs

dXJpcG90ZW50IFN0ZW0gQ2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5

d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5NdXRhdGlvbjwva2V5d29yZD48a2V5

d29yZD5OZXVyaXRlczwva2V5d29yZD48a2V5d29yZD5PeHlzdGVyb2xzL2Jsb29kL2NlcmVicm9z

cGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+UGVkaWdyZWU8L2tleXdvcmQ+PGtleXdvcmQ+

U2V2ZXJpdHkgb2YgSWxsbmVzcyBJbmRleDwva2V5d29yZD48a2V5d29yZD5TcGFzdGljIFBhcmFw

bGVnaWEsIEhlcmVkaXRhcnkvKmRydWcgdGhlcmFweS9nZW5ldGljcy9tZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPlN0ZXJvaWQgSHlkcm94eWxhc2VzL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3

b3JkPllvdW5nIEFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPlNwZzU8L2tleXdvcmQ+PGtleXdvcmQ+

YmlvbWFya2VyPC9rZXl3b3JkPjxrZXl3b3JkPmhlcmVkaXRhcnkgc3Bhc3RpYyBwYXJhcGxlZ2lh

PC9rZXl3b3JkPjxrZXl3b3JkPm94eXN0ZXJvbDwva2V5d29yZD48a2V5d29yZD5yYW5kb21pemVk

IGNvbnRyb2xsZWQgdHJpYWw8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPkRlYyAxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlz

Ym4+MTQ2MC0yMTU2IChFbGVjdHJvbmljKSYjeEQ7MDAwNi04OTUwIChMaW5raW5nKTwvaXNibj48

YWNjZXNzaW9uLW51bT4yOTEyNjIxMjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxz

Pjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yOTEyNjIxMjwvdXJsPjwv

cmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM1ODQxMDM2PC9jdXN0b20yPjxlbGVjdHJv

bmljLXJlc291cmNlLW51bT4xMC4xMDkzL2JyYWluL2F3eDI3MzwvZWxlY3Ryb25pYy1yZXNvdXJj

ZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaWFtPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVj

TnVtPjg1MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjQy

Niw0Mjc8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj44NTA8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjU1MDU1NCI+ODUwPC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TaWFtLCBBLjwvYXV0aG9yPjxhdXRob3I+

QnJhbmNhbGUsIEEuPC9hdXRob3I+PGF1dGhvcj5TaW1vbnMsIEMuPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+TWVkaWNpbmFsIENoZW1pc3RyeSwgV2Vsc2gg

U2Nob29sIG9mIFBoYXJtYWN5LCBDYXJkaWZmIFVuaXZlcnNpdHksIEtpbmcgRWR3YXJkIFZJSSBB

dmVudWUsIENhcmRpZmYsIENGMTAgM05CLCBVSy48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRs

ZT5Db21wYXJhdGl2ZSBtb2RlbGluZyBvZiAyNS1oeWRyb3h5Y2hvbGVzdGVyb2wtN2FscGhhLWh5

ZHJveHlsYXNlIChDWVA3QjEpOiBsaWdhbmQgYmluZGluZyBhbmQgYW5hbHlzaXMgb2YgaGVyZWRp

dGFyeSBzcGFzdGljIHBhcmFwbGVnaWEgdHlwZSA1IENZUDdCMSBtdXRhdGlvbnM8L3RpdGxlPjxz

ZWNvbmRhcnktdGl0bGU+SiBNb2wgTW9kZWw8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFn

ZXM+NDQxLTUzPC9wYWdlcz48dm9sdW1lPjE4PC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGtl

eXdvcmRzPjxrZXl3b3JkPkFtaW5vIEFjaWQgU2VxdWVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+QW5p

bWFsczwva2V5d29yZD48a2V5d29yZD5DeXRvY2hyb21lIFA0NTAgRmFtaWx5IDc8L2tleXdvcmQ+

PGtleXdvcmQ+RE5BIE11dGF0aW9uYWwgQW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5z

PC9rZXl3b3JkPjxrZXl3b3JkPkxpZ2FuZHM8L2tleXdvcmQ+PGtleXdvcmQ+Kk1vZGVscywgTW9s

ZWN1bGFyPC9rZXl3b3JkPjxrZXl3b3JkPk1vbGVjdWxhciBTZXF1ZW5jZSBEYXRhPC9rZXl3b3Jk

PjxrZXl3b3JkPipNdXRhdGlvbjwva2V5d29yZD48a2V5d29yZD5QaHlsb2dlbnk8L2tleXdvcmQ+

PGtleXdvcmQ+UHJvdGVpbiBCaW5kaW5nPC9rZXl3b3JkPjxrZXl3b3JkPlByb3RlaW4gU3RydWN0

dXJlLCBTZWNvbmRhcnk8L2tleXdvcmQ+PGtleXdvcmQ+UmVwcm9kdWNpYmlsaXR5IG9mIFJlc3Vs

dHM8L2tleXdvcmQ+PGtleXdvcmQ+U2VxdWVuY2UgQWxpZ25tZW50PC9rZXl3b3JkPjxrZXl3b3Jk

PlNlcXVlbmNlIEhvbW9sb2d5LCBBbWlubyBBY2lkPC9rZXl3b3JkPjxrZXl3b3JkPlNwYXN0aWMg

UGFyYXBsZWdpYSwgSGVyZWRpdGFyeS8qZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+U3Rlcm9p

ZCBIeWRyb3h5bGFzZXMvKmNoZW1pc3RyeS9jbGFzc2lmaWNhdGlvbi8qZ2VuZXRpY3M8L2tleXdv

cmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkZl

YjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjA5NDgtNTAyMyAoRWxlY3Ryb25pYykm

I3hEOzA5NDgtNTAyMyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjE1NDE3NDY8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMjE1NDE3NDY8L3VybD48dXJsPmh0dHBzOi8vbGluay5zcHJpbmdlci5j

b20vY29udGVudC9wZGYvMTAuMTAwNyUyRnMwMDg5NC0wMTEtMTA4NC02LnBkZjwvdXJsPjwvcmVs

YXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMDA4OTQt

MDExLTEwODQtNjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRl

PjxBdXRob3I+U2Nob2xzPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48UmVjTnVtPjU5NDwvUmVj

TnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+NTk0PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0

aW1lc3RhbXA9IjE1MzI1NTA0OTkiPjU5NDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBu

YW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3Jz

PjxhdXRob3I+U2Nob2xzLCBMLjwvYXV0aG9yPjxhdXRob3I+UmF0dGF5LCBULiBXLjwvYXV0aG9y

PjxhdXRob3I+TWFydHVzLCBQLjwvYXV0aG9yPjxhdXRob3I+TWVpc25lciwgQy48L2F1dGhvcj48

YXV0aG9yPkJhZXRzLCBKLjwvYXV0aG9yPjxhdXRob3I+RmlzY2hlciwgSS48L2F1dGhvcj48YXV0

aG9yPkphZ2xlLCBDLjwvYXV0aG9yPjxhdXRob3I+RnJhaWRha2lzLCBNLiBKLjwvYXV0aG9yPjxh

dXRob3I+TWFydGludXp6aSwgQS48L2F1dGhvcj48YXV0aG9yPlNhdXRlLCBKLiBBLjwvYXV0aG9y

PjxhdXRob3I+U2NhcmxhdG8sIE0uPC9hdXRob3I+PGF1dGhvcj5BbnRlbm9yYSwgQS48L2F1dGhv

cj48YXV0aG9yPlN0ZW5kZWwsIEMuPC9hdXRob3I+PGF1dGhvcj5Ib2ZsaW5nZXIsIFAuPC9hdXRo

b3I+PGF1dGhvcj5Mb3VyZW5jbywgQy4gTS48L2F1dGhvcj48YXV0aG9yPkFicmV1LCBMLjwvYXV0

aG9yPjxhdXRob3I+U21ldHMsIEsuPC9hdXRob3I+PGF1dGhvcj5QYXVjYXIsIE0uPC9hdXRob3I+

PGF1dGhvcj5EZWNvbmluY2ssIFQuPC9hdXRob3I+PGF1dGhvcj5CaXMsIEQuIE0uPC9hdXRob3I+

PGF1dGhvcj5XaWV0aG9mZiwgUy48L2F1dGhvcj48YXV0aG9yPkJhdWVyLCBQLjwvYXV0aG9yPjxh

dXRob3I+QXJub2xkaSwgQS48L2F1dGhvcj48YXV0aG9yPk1hcnF1ZXMsIFcuPC9hdXRob3I+PGF1

dGhvcj5KYXJkaW0sIEwuIEIuPC9hdXRob3I+PGF1dGhvcj5IYXVzZXIsIFMuPC9hdXRob3I+PGF1

dGhvcj5DcmlzY3VvbG8sIEMuPC9hdXRob3I+PGF1dGhvcj5GaWxsYSwgQS48L2F1dGhvcj48YXV0

aG9yPlp1Y2huZXIsIFMuPC9hdXRob3I+PGF1dGhvcj5CYXNzaSwgTS4gVC48L2F1dGhvcj48YXV0

aG9yPktsb3BzdG9jaywgVC48L2F1dGhvcj48YXV0aG9yPkRlIEpvbmdoZSwgUC48L2F1dGhvcj48

YXV0aG9yPkJqb3JraGVtLCBJLjwvYXV0aG9yPjxhdXRob3I+U2NodWxlLCBSLjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkNlbnRlciBmb3IgTmV1cm9sb2d5

IGFuZCBIZXJ0aWUgSW5zdGl0dXRlIGZvciBDbGluaWNhbCBCcmFpbiBSZXNlYXJjaCwgRWJlcmhh

cmQtS2FybHMtVW5pdmVyc2l0eSwgNzIwNzYgVHViaW5nZW4sIEdlcm1hbnkuJiN4RDtHZXJtYW4g

Q2VudGVyIG9mIE5ldXJvZGVnZW5lcmF0aXZlIERpc2Vhc2VzIChEWk5FKSwgNzIwNzYgVHViaW5n

ZW4sIEdlcm1hbnkuJiN4RDtJbnN0aXR1dGUgZm9yIENsaW5pY2FsIEVwaWRlbWlvbG9neSBhbmQg

QXBwbGllZCBCaW9zdGF0aXN0aWNzLCBFYmVyaGFyZC1LYXJscy1Vbml2ZXJzaXR5LCA3MjA3NiBU

dWJpbmdlbiwgR2VybWFueS4mI3hEO05ldXJvZ2VuZXRpY3MgR3JvdXAsIENlbnRlciBmb3IgTW9s

ZWN1bGFyIE5ldXJvbG9neSwgVklCLCAyNjEwIEFudHdlcnAsIEJlbGdpdW0uJiN4RDtEZXBhcnRt

ZW50IG9mIE5ldXJvbG9neSwgQW50d2VycCBVbml2ZXJzaXR5IEhvc3BpdGFsLCAyNjEwIEFudHdl

cnAsIEJlbGdpdW0uJiN4RDtMYWJvcmF0b3J5IG9mIE5ldXJvbXVzY3VsYXIgUGF0aG9sb2d5LCBJ

bnN0aXR1dGUgQm9ybi1CdW5nZSwgVW5pdmVyc2l0eSBvZiBBbnR3ZXJwLCAyNjEwIEFudHdlcnAs

IEJlbGdpdW0uJiN4RDtDZW50ZXIgZm9yIFJhcmUgRGlzZWFzZXMgYW5kIEluc3RpdHV0ZSBvZiBI

dW1hbiBHZW5ldGljcyBhbmQgQXBwbGllZCBHZW5vbWljcywgRWJlcmhhcmQtS2FybHMtVW5pdmVy

c2l0eSwgNzIwNzYgVHViaW5nZW4sIEdlcm1hbnkuJiN4RDtSYXJlIE5ldXJvbG9naWNhbCBEaXNl

YXNlcyBVbml0LCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgVW5pdmVyc2l0eSBIb3NwaXRhbCAm

YXBvcztBdHRpa29uJmFwb3M7LCBNZWRpY2FsIFNjaG9vbCBvZiB0aGUgVW5pdmVyc2l0eSBvZiBB

dGhlbnMsIDEyNDYyIEF0aGVucywgR3JlZWNlLiYjeEQ7U2NpZW50aWZpYyBJbnN0aXR1dGUgSVJD

Q1MgRS4gTWVkZWEsIENvbmVnbGlhbm8gUmVzZWFyY2ggQ2VudGVyLCAzMTAxNSBDb25lZ2xpYW5v

LCBJdGFseS4mI3hEO01lZGljYWwgR2VuZXRpY3MgU2VydmljZSwgSG9zcGl0YWwgZGUgQ2xpbmlj

YXMgZGUgUG9ydG8gQWxlZ3JlLCBQb3J0byBBbGVncmUsIEJyYXppbC4mI3hEO0dlbmV0aWNzIElk

ZW50aWZpY2F0aW9uIExhYm9yYXRvcnksIEhvc3BpdGFsIGRlIENsaW5pY2FzIGRlIFBvcnRvIEFs

ZWdyZSwgOTAwMzUgUG9ydG8gQWxlZ3JlLCBCcmF6aWwuJiN4RDtQb3N0Z3JhZHVhdGUgUHJvZ3Jh

bSBpbiBNZWRpY2luZTogTWVkaWNhbCBTY2llbmNlcywgVW5pdmVyc2lkYWRlIEZlZGVyYWwgZG8g

UmlvIEdyYW5kZSBkbyBTdWwgKFVGUkdTKSwgOTAwNDAgUG9ydG8gQWxlZ3JlLCBCcmF6aWwuJiN4

RDtOZXVyb2xvZ3kgRGVwYXJ0bWVudCBhbmQgSU5TUEUsIFNhbiBSYWZmYWVsZSBIb3NwaXRhbCwg

MjAxMzIgTWlsYW4sIEl0YWx5LiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb3NjaWVuY2VzLCBSZXBy

b2R1Y3RpdmUgYW5kIE9kb250b3N0b21hdG9sb2dpY2FsIFNjaWVuY2VzLCBGZWRlcmljbyBJSSBV

bml2ZXJzaXR5IE5hcGxlcywgODAxMzEgTmFwbGVzLCBJdGFseS4mI3hEO0RlcGFydG1lbnQgb2Yg

TmV1cm9sb2d5LCBGcmllZHJpY2ggQmF1ciBJbnN0aXR1dGUsIEx1ZHdpZy1NYXhpbWlsaWFucy1V

bml2ZXJzaXR5LCA4MDMzNiBNdW5pY2gsIEdlcm1hbnkuJiN4RDtNdW5pY2ggQ2x1c3RlciBmb3Ig

U3lzdGVtcyBOZXVyb2xvZ3kgKFN5TmVyZ3kpLCA4MTM3NyBNdW5pY2gsIEdlcm1hbnkuJiN4RDtH

ZXJtYW4gQ2VudGVyIGZvciBOZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcyAoRFpORSksIDgxMzc3

IE11bmljaCwgR2VybWFueS4mI3hEO0RlcGFydGFtZW50byBkZSBOZXVyb2xvZ2lhLCBGYWN1bGRh

ZGUgZGUgTWVkaWNpbmEgZGUgUmliZWlyYW8gUHJldG8sIFVuaXZlcnNpZGFkZSBkZSBTYW8gUGF1

bG8sIDE0MDQ5IFJpYmVpcmFvIFByZXRvLCBCcmF6aWwuJiN4RDtEZXBhcnRtZW50IG9mIEludGVy

bmFsIE1lZGljaW5lLCBVbml2ZXJzaWRhZGUgRmVkZXJhbCBkbyBSaW8gR3JhbmRlIGRvIFN1bCAo

VUZSR1MpLCA5MDA0MCBQb3J0byBBbGVncmUsIEJyYXppbC4mI3hEO0pvaG4gUC4gSHVzc21hbiBJ

bnN0aXR1dGUgZm9yIEh1bWFuIEdlbm9taWNzLCBEci4gSm9obiBULiBNYWNkb25hbGQgRm91bmRh

dGlvbiBEZXBhcnRtZW50IG9mIEh1bWFuIEdlbmV0aWNzLCBVbml2ZXJzaXR5IG9mIE1pYW1pLCAz

MzEzNiBNaWFtaSwgRmxvcmlkYSwgVVNBLiYjeEQ7RHIuIEpvaG4gVC4gTWFjZG9uYWxkIEZvdW5k

YXRpb24gRGVwYXJ0bWVudCBvZiBIdW1hbiBHZW5ldGljcywgVW5pdmVyc2l0eSBvZiBNaWFtaSwg

MzMxMzYgTWlhbWksIEZsb3JpZGEsIFVTQS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBL

YXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwgSHVkZGluZ2UgYW5kIERlcGFydG1lbnQgb2Yg

Q2xpbmljYWwgTmV1cm9zY2llbmNlLCBLYXJvbGluc2thIEluc3RpdHV0ZSwgMTQxNTIgSHVkZGlu

Z2UsIFN3ZWRlbi4mI3hEO0luc3RpdHV0ZSBvZiBOZXVyb2xvZ3ksIFF1ZWVuIFNxdWFyZSwgTG9u

ZG9uIFdDMU4gM0JHLCBVSy4mI3hEO0luc3RpdHV0ZSBvZiBNZWRpY2FsIEdlbmV0aWNzIGFuZCBB

cHBsaWVkIEdlbm9taWNzLCBFYmVyaGFyZC1LYXJscy1Vbml2ZXJzaXR5LCA3MjA3NiBUdWJpbmdl

biwgR2VybWFueS4mI3hEO0NFTlRPR0VORSBBRywgMTgwNTcgUm9zdG9jaywgR2VybWFueS4mI3hE

O0xhYm9yYXRvcnkgb2YgTW9sZWN1bGFyIEJpb2xvZ3ksIFNjaWVudGlmaWMgSW5zdGl0dXRlIElS

Q0NTIEUuIE1lZGVhLCAyMzg0MiBCb3Npc2lvIFBhcmluaSwgSXRhbHkuJiN4RDtLYXJvbGluc2th

IFVuaXZlcnNpdHkgSG9zcGl0YWwgSHVkZGluZ2UsIEthcm9saW5za2EgSW5zdGl0dXRlLCAxNDE1

MiBTdG9ja2hvbG0sIFN3ZWRlbi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5IZXJlZGl0

YXJ5IHNwYXN0aWMgcGFyYXBsZWdpYSB0eXBlIDU6IG5hdHVyYWwgaGlzdG9yeSwgYmlvbWFya2Vy

cyBhbmQgYSByYW5kb21pemVkIGNvbnRyb2xsZWQgdHJpYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0

bGU+QnJhaW48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRs

ZT5CcmFpbjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjMxMTItMzEyNzwvcGFnZXM+

PHZvbHVtZT4xNDA8L3ZvbHVtZT48bnVtYmVyPjEyPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3Jk

PkFkb2xlc2NlbnQ8L2tleXdvcmQ+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QXRv

cnZhc3RhdGluIENhbGNpdW0vKnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5CaW9t

YXJrZXJzL2Jsb29kL2NlcmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+Q2FzZS1D

b250cm9sIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBQcm9saWZlcmF0aW9uPC9rZXl3

b3JkPjxrZXl3b3JkPkNyb3NzLVNlY3Rpb25hbCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkN5

dG9jaHJvbWUgUDQ1MCBGYW1pbHkgNy9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5EaXNlYXNl

IFByb2dyZXNzaW9uPC9rZXl3b3JkPjxrZXl3b3JkPkRvdWJsZS1CbGluZCBNZXRob2Q8L2tleXdv

cmQ+PGtleXdvcmQ+RmFtaWx5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5

d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy9tZXRhYm9s

aXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh5ZHJveHltZXRoeWxnbHV0YXJ5bC1Db0EgUmVkdWN0YXNl

IEluaGliaXRvcnMvKnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5JbmR1Y2VkIFBs

dXJpcG90ZW50IFN0ZW0gQ2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5

d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5NdXRhdGlvbjwva2V5d29yZD48a2V5

d29yZD5OZXVyaXRlczwva2V5d29yZD48a2V5d29yZD5PeHlzdGVyb2xzL2Jsb29kL2NlcmVicm9z

cGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+UGVkaWdyZWU8L2tleXdvcmQ+PGtleXdvcmQ+

U2V2ZXJpdHkgb2YgSWxsbmVzcyBJbmRleDwva2V5d29yZD48a2V5d29yZD5TcGFzdGljIFBhcmFw

bGVnaWEsIEhlcmVkaXRhcnkvKmRydWcgdGhlcmFweS9nZW5ldGljcy9tZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPlN0ZXJvaWQgSHlkcm94eWxhc2VzL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3

b3JkPllvdW5nIEFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPlNwZzU8L2tleXdvcmQ+PGtleXdvcmQ+

YmlvbWFya2VyPC9rZXl3b3JkPjxrZXl3b3JkPmhlcmVkaXRhcnkgc3Bhc3RpYyBwYXJhcGxlZ2lh

PC9rZXl3b3JkPjxrZXl3b3JkPm94eXN0ZXJvbDwva2V5d29yZD48a2V5d29yZD5yYW5kb21pemVk

IGNvbnRyb2xsZWQgdHJpYWw8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPkRlYyAxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlz

Ym4+MTQ2MC0yMTU2IChFbGVjdHJvbmljKSYjeEQ7MDAwNi04OTUwIChMaW5raW5nKTwvaXNibj48

YWNjZXNzaW9uLW51bT4yOTEyNjIxMjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxz

Pjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yOTEyNjIxMjwvdXJsPjwv

cmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM1ODQxMDM2PC9jdXN0b20yPjxlbGVjdHJv

bmljLXJlc291cmNlLW51bT4xMC4xMDkzL2JyYWluL2F3eDI3MzwvZWxlY3Ryb25pYy1yZXNvdXJj

ZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA 426,427. Nevertheless, individuals without this mutation can also show elevated levels of 27-OH in the blood, which correlate to 27-OH levels in the CSF PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Jc21haWw8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS

ZWNOdW0+MjYzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDI4PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjYzPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzEiPjI2Mzwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SXNtYWlsLCBNLiBBLjwvYXV0aG9yPjxhdXRo

b3I+TWF0ZW9zLCBMLjwvYXV0aG9yPjxhdXRob3I+TWFpb2xpLCBTLjwvYXV0aG9yPjxhdXRob3I+

TWVyaW5vLVNlcnJhaXMsIFAuPC9hdXRob3I+PGF1dGhvcj5BbGksIFouPC9hdXRob3I+PGF1dGhv

cj5Mb2RlaXJvLCBNLjwvYXV0aG9yPjxhdXRob3I+V2VzdG1hbiwgRS48L2F1dGhvcj48YXV0aG9y

PkxlaXRlcnNkb3JmLCBFLjwvYXV0aG9yPjxhdXRob3I+R3VseWFzLCBCLjwvYXV0aG9yPjxhdXRo

b3I+T2xvZi1XYWhsdW5kLCBMLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48

YXV0aG9yPlNhdml0Y2hldmEsIEkuPC9hdXRob3I+PGF1dGhvcj5Cam9ya2hlbSwgSS48L2F1dGhv

cj48YXV0aG9yPkNlZGF6by1NaW5ndWV6LCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0cmljcywgQ2VudGVyIGZv

ciBBbHpoZWltZXIgUmVzZWFyY2gsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNj

aWVuY2VzLCBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCAxNDEgODYgU3RvY2to

b2xtLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBDbGluaWNhbCBDaGVtaXN0cnksIERlcGFydG1l

bnQgb2YgTGFib3JhdG9yeSBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFs

LCAxNDEgODYgSHVkZGluZ2UsIFN3ZWRlbi4mI3hEO0RpdmlzaW9uIG9mIENsaW5pY2FsIEdlcmlh

dHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5ldXJv

YmlvbG9neSwgQ2FyZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0dXRl

dCwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7Q2VudGVyIGZvciBSZXNlYXJjaCwgUHJl

dmVudGlvbiwgYW5kIFRyZWF0bWVudCBvZiBBdGhlcm9zY2xlcm9zaXMsIEhhZGFzc2FoIEhlYnJl

dyBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBKZXJ1c2FsZW0gOTExMjAsIElzcmFlbC4mI3hE

O0NlbnRyZSBmb3IgUHN5Y2hpYXRyeSBSZXNlYXJjaCwgRGVwYXJ0bWVudCBvZiBDbGluaWNhbCBO

ZXVyb3NjaWVuY2UsIEthcm9saW5za2EgSW5zdGl0dXRldCwgMTcxIDc3IFN0b2NraG9sbSwgU3dl

ZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBSYWRpb2xvZ3ksIEthcm9saW5za2EgVW5pdmVyc2l0eSBI

b3NwaXRhbCwgMTQxIDg2IEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBOZXVyb2dl

cmlhdHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5l

dXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0

dXRldCwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuIEFuZ2VsLkNlZGF6by1NaW5ndWV6QGtpLnNl

LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPjI3LUh5ZHJveHljaG9sZXN0ZXJvbCBpbXBh

aXJzIG5ldXJvbmFsIGdsdWNvc2UgdXB0YWtlIHRocm91Z2ggYW4gSVJBUC9HTFVUNCBzeXN0ZW0g

ZHlzcmVndWxhdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEV4cCBNZWQ8L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGFnZXM+Njk5LTcxNzwvcGFnZXM+PHZvbHVtZT4yMTQ8L3ZvbHVt

ZT48bnVtYmVyPjM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5naW90ZW5zaW4gSUkvYW5h

bG9ncyAmYW1wOyBkZXJpdmF0aXZlcy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW5p

bWFsczwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0YW5ldHJpb2wgMjYtTW9ub294eWdlbmFzZS9w

aHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sL21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+Q3lzdGlueWwgQW1pbm9wZXB0aWRhc2UvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+R2x1Y29zZS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5HbHVjb3NlIFRy

YW5zcG9ydGVyIFR5cGUgNC8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tl

eXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy8qcGhhcm1hY29sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkxpdmVyIFggUmVjZXB0b3JzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdv

cmQ+TmV1cm9ucy8qbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWFyIDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48aXNibj4xNTQwLTk1MzggKEVsZWN0cm9uaWMpJiN4RDswMDIyLTEwMDcgKExpbmtpbmcpPC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjI4MjEzNTEyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI4MjEzNTEyPC91

cmw+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3BtYy9hcnRpY2xlcy9QTUM1MzM5

NjY5L3BkZi9KRU1fMjAxNjA1MzQucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0

b20yPlBNQzUzMzk2Njk8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwODQv

amVtLjIwMTYwNTM0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Jc21haWw8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS

ZWNOdW0+MjYzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDI4PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjYzPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzEiPjI2Mzwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SXNtYWlsLCBNLiBBLjwvYXV0aG9yPjxhdXRo

b3I+TWF0ZW9zLCBMLjwvYXV0aG9yPjxhdXRob3I+TWFpb2xpLCBTLjwvYXV0aG9yPjxhdXRob3I+

TWVyaW5vLVNlcnJhaXMsIFAuPC9hdXRob3I+PGF1dGhvcj5BbGksIFouPC9hdXRob3I+PGF1dGhv

cj5Mb2RlaXJvLCBNLjwvYXV0aG9yPjxhdXRob3I+V2VzdG1hbiwgRS48L2F1dGhvcj48YXV0aG9y

PkxlaXRlcnNkb3JmLCBFLjwvYXV0aG9yPjxhdXRob3I+R3VseWFzLCBCLjwvYXV0aG9yPjxhdXRo

b3I+T2xvZi1XYWhsdW5kLCBMLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48

YXV0aG9yPlNhdml0Y2hldmEsIEkuPC9hdXRob3I+PGF1dGhvcj5Cam9ya2hlbSwgSS48L2F1dGhv

cj48YXV0aG9yPkNlZGF6by1NaW5ndWV6LCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0cmljcywgQ2VudGVyIGZv

ciBBbHpoZWltZXIgUmVzZWFyY2gsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNj

aWVuY2VzLCBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCAxNDEgODYgU3RvY2to

b2xtLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBDbGluaWNhbCBDaGVtaXN0cnksIERlcGFydG1l

bnQgb2YgTGFib3JhdG9yeSBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFs

LCAxNDEgODYgSHVkZGluZ2UsIFN3ZWRlbi4mI3hEO0RpdmlzaW9uIG9mIENsaW5pY2FsIEdlcmlh

dHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5ldXJv

YmlvbG9neSwgQ2FyZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0dXRl

dCwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7Q2VudGVyIGZvciBSZXNlYXJjaCwgUHJl

dmVudGlvbiwgYW5kIFRyZWF0bWVudCBvZiBBdGhlcm9zY2xlcm9zaXMsIEhhZGFzc2FoIEhlYnJl

dyBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBKZXJ1c2FsZW0gOTExMjAsIElzcmFlbC4mI3hE

O0NlbnRyZSBmb3IgUHN5Y2hpYXRyeSBSZXNlYXJjaCwgRGVwYXJ0bWVudCBvZiBDbGluaWNhbCBO

ZXVyb3NjaWVuY2UsIEthcm9saW5za2EgSW5zdGl0dXRldCwgMTcxIDc3IFN0b2NraG9sbSwgU3dl

ZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBSYWRpb2xvZ3ksIEthcm9saW5za2EgVW5pdmVyc2l0eSBI

b3NwaXRhbCwgMTQxIDg2IEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBOZXVyb2dl

cmlhdHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5l

dXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0

dXRldCwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuIEFuZ2VsLkNlZGF6by1NaW5ndWV6QGtpLnNl

LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPjI3LUh5ZHJveHljaG9sZXN0ZXJvbCBpbXBh

aXJzIG5ldXJvbmFsIGdsdWNvc2UgdXB0YWtlIHRocm91Z2ggYW4gSVJBUC9HTFVUNCBzeXN0ZW0g

ZHlzcmVndWxhdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEV4cCBNZWQ8L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGFnZXM+Njk5LTcxNzwvcGFnZXM+PHZvbHVtZT4yMTQ8L3ZvbHVt

ZT48bnVtYmVyPjM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5naW90ZW5zaW4gSUkvYW5h

bG9ncyAmYW1wOyBkZXJpdmF0aXZlcy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW5p

bWFsczwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0YW5ldHJpb2wgMjYtTW9ub294eWdlbmFzZS9w

aHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sL21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+Q3lzdGlueWwgQW1pbm9wZXB0aWRhc2UvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+R2x1Y29zZS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5HbHVjb3NlIFRy

YW5zcG9ydGVyIFR5cGUgNC8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tl

eXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy8qcGhhcm1hY29sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkxpdmVyIFggUmVjZXB0b3JzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdv

cmQ+TmV1cm9ucy8qbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWFyIDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48aXNibj4xNTQwLTk1MzggKEVsZWN0cm9uaWMpJiN4RDswMDIyLTEwMDcgKExpbmtpbmcpPC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjI4MjEzNTEyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI4MjEzNTEyPC91

cmw+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3BtYy9hcnRpY2xlcy9QTUM1MzM5

NjY5L3BkZi9KRU1fMjAxNjA1MzQucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0

b20yPlBNQzUzMzk2Njk8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwODQv

amVtLjIwMTYwNTM0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPn==

ADDIN EN.CITE.DATA 428. In these patients, elevated 27-OH levels correlated negatively with glucose uptake in the hippocampus, posterior cingulate and cerebellum as measured by 18F-FDG PET. The patients could be stratified in two groups: the first one would have more than 1 ng/ml 27OH in CSF and a global decrease in brain glucose uptake, while the second group with less than 1 ng/ml 27-OH in CSF with decreased glucose uptake only in the hippocampus and posterior cingulate. Preclinical models have already provided information on the mechanisms of elevated 27-OH influences glucose metabolism in the brain, contributing to cognitive decline in AD. High fat/ high cholesterol diet (HFD) in aged mice led to decreased ARC protein levels in the hippocampus as well as reduced NMDA receptor activity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXRlb3M8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS

ZWNOdW0+MzE3PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDI5PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzE3PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzYiPjMxNzwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWF0ZW9zLCBMLjwvYXV0aG9yPjxhdXRob3I+

QWt0ZXJpbiwgUy48L2F1dGhvcj48YXV0aG9yPkdpbC1CZWEsIEYuIEouPC9hdXRob3I+PGF1dGhv

cj5TcHVsYmVyLCBTLjwvYXV0aG9yPjxhdXRob3I+UmFobWFuLCBBLjwvYXV0aG9yPjxhdXRob3I+

QmpvcmtoZW0sIEkuPC9hdXRob3I+PGF1dGhvcj5TY2h1bHR6YmVyZywgTS48L2F1dGhvcj48YXV0

aG9yPkZsb3Jlcy1Nb3JhbGVzLCBBLjwvYXV0aG9yPjxhdXRob3I+Q2VkYXpvLU1pbmd1ZXosIEEu

PC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVu

dCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIEthcm9saW5za2Eg

SW5zdGl0dXRldC1BbHpoZWltZXImYXBvcztzIERpc2Vhc2UgUmVzZWFyY2ggQ2VudGVyLCBLYXJv

bGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVuLjwvYXV0aC1hZGRyZXNzPjx0aXRs

ZXM+PHRpdGxlPkFjdGl2aXR5LXJlZ3VsYXRlZCBjeXRvc2tlbGV0b24tYXNzb2NpYXRlZCBwcm90

ZWluIGluIHJvZGVudCBicmFpbiBpcyBkb3duLXJlZ3VsYXRlZCBieSBoaWdoIGZhdCBkaWV0IGlu

IHZpdm8gYW5kIGJ5IDI3LWh5ZHJveHljaG9sZXN0ZXJvbCBpbiB2aXRybzwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5CcmFpbiBQYXRob2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+

NjktODA8L3BhZ2VzPjx2b2x1bWU+MTk8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48a2V5d29y

ZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BcmdpbmluZSBWYXNvcHJlc3Np

bi9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5CcmFpbi9kcnVnIGVmZmVjdHMvKm1ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVkPC9rZXl3b3JkPjxrZXl3b3JkPkNl

cmVicmFsIENvcnRleC9kcnVnIGVmZmVjdHMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5D

eXRvc2tlbGV0YWwgUHJvdGVpbnMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+RGlldGFy

eSBGYXRzL2FkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS8qcGhhcm1hY29sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkdlbmUgRXhwcmVzc2lvbiBSZWd1bGF0aW9uL2RydWcgZWZmZWN0czwva2V5d29y

ZD48a2V5d29yZD5HdWFuaW5lIE51Y2xlb3RpZGUgRXhjaGFuZ2UgRmFjdG9ycy9nZW5ldGljczwv

a2V5d29yZD48a2V5d29yZD5IaXBwb2NhbXB1cy9jeXRvbG9neS9kcnVnIGVmZmVjdHMvbWV0YWJv

bGlzbTwva2V5d29yZD48a2V5d29yZD5IeWRyb3h5Y2hvbGVzdGVyb2xzL3BoYXJtYWNvbG9neTwv

a2V5d29yZD48a2V5d29yZD5JbW11bm9ibG90dGluZzwva2V5d29yZD48a2V5d29yZD5JbW11bm9o

aXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1p

Y2UsIEluYnJlZCBDNTdCTDwva2V5d29yZD48a2V5d29yZD5OZXJ2ZSBUaXNzdWUgUHJvdGVpbnMv

Km1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9ucy9jeXRvbG9neS9kcnVnIGVmZmVj

dHMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+T2xpZ29udWNsZW90aWRlIEFycmF5IFNl

cXVlbmNlIEFuYWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPlJOQS9nZW5ldGljcy9tZXRhYm9saXNt

PC9rZXl3b3JkPjxrZXl3b3JkPlJlY2VwdG9ycywgR2x1dGFtYXRlL21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+UmV2ZXJzZSBUcmFuc2NyaXB0YXNlIFBvbHltZXJhc2UgQ2hhaW4gUmVhY3Rp

b248L2tleXdvcmQ+PGtleXdvcmQ+c3JjLUZhbWlseSBLaW5hc2VzL21ldGFib2xpc208L2tleXdv

cmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwOTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkph

bjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE3NTAtMzYzOSAoRWxlY3Ryb25pYykm

I3hEOzEwMTUtNjMwNSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTg1MDM1NzA8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMTg1MDM1NzA8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExMTEvai4xNzUwLTM2MzkuMjAwOC4wMDE3NC54PC9lbGVj

dHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXRlb3M8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS

ZWNOdW0+MzE3PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDI5PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzE3PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzYiPjMxNzwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWF0ZW9zLCBMLjwvYXV0aG9yPjxhdXRob3I+

QWt0ZXJpbiwgUy48L2F1dGhvcj48YXV0aG9yPkdpbC1CZWEsIEYuIEouPC9hdXRob3I+PGF1dGhv

cj5TcHVsYmVyLCBTLjwvYXV0aG9yPjxhdXRob3I+UmFobWFuLCBBLjwvYXV0aG9yPjxhdXRob3I+

QmpvcmtoZW0sIEkuPC9hdXRob3I+PGF1dGhvcj5TY2h1bHR6YmVyZywgTS48L2F1dGhvcj48YXV0

aG9yPkZsb3Jlcy1Nb3JhbGVzLCBBLjwvYXV0aG9yPjxhdXRob3I+Q2VkYXpvLU1pbmd1ZXosIEEu

PC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVu

dCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIEthcm9saW5za2Eg

SW5zdGl0dXRldC1BbHpoZWltZXImYXBvcztzIERpc2Vhc2UgUmVzZWFyY2ggQ2VudGVyLCBLYXJv

bGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVuLjwvYXV0aC1hZGRyZXNzPjx0aXRs

ZXM+PHRpdGxlPkFjdGl2aXR5LXJlZ3VsYXRlZCBjeXRvc2tlbGV0b24tYXNzb2NpYXRlZCBwcm90

ZWluIGluIHJvZGVudCBicmFpbiBpcyBkb3duLXJlZ3VsYXRlZCBieSBoaWdoIGZhdCBkaWV0IGlu

IHZpdm8gYW5kIGJ5IDI3LWh5ZHJveHljaG9sZXN0ZXJvbCBpbiB2aXRybzwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5CcmFpbiBQYXRob2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+

NjktODA8L3BhZ2VzPjx2b2x1bWU+MTk8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48a2V5d29y

ZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BcmdpbmluZSBWYXNvcHJlc3Np

bi9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5CcmFpbi9kcnVnIGVmZmVjdHMvKm1ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVkPC9rZXl3b3JkPjxrZXl3b3JkPkNl

cmVicmFsIENvcnRleC9kcnVnIGVmZmVjdHMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5D

eXRvc2tlbGV0YWwgUHJvdGVpbnMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+RGlldGFy

eSBGYXRzL2FkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS8qcGhhcm1hY29sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkdlbmUgRXhwcmVzc2lvbiBSZWd1bGF0aW9uL2RydWcgZWZmZWN0czwva2V5d29y

ZD48a2V5d29yZD5HdWFuaW5lIE51Y2xlb3RpZGUgRXhjaGFuZ2UgRmFjdG9ycy9nZW5ldGljczwv

a2V5d29yZD48a2V5d29yZD5IaXBwb2NhbXB1cy9jeXRvbG9neS9kcnVnIGVmZmVjdHMvbWV0YWJv

bGlzbTwva2V5d29yZD48a2V5d29yZD5IeWRyb3h5Y2hvbGVzdGVyb2xzL3BoYXJtYWNvbG9neTwv

a2V5d29yZD48a2V5d29yZD5JbW11bm9ibG90dGluZzwva2V5d29yZD48a2V5d29yZD5JbW11bm9o

aXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1p

Y2UsIEluYnJlZCBDNTdCTDwva2V5d29yZD48a2V5d29yZD5OZXJ2ZSBUaXNzdWUgUHJvdGVpbnMv

Km1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9ucy9jeXRvbG9neS9kcnVnIGVmZmVj

dHMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+T2xpZ29udWNsZW90aWRlIEFycmF5IFNl

cXVlbmNlIEFuYWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPlJOQS9nZW5ldGljcy9tZXRhYm9saXNt

PC9rZXl3b3JkPjxrZXl3b3JkPlJlY2VwdG9ycywgR2x1dGFtYXRlL21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+UmV2ZXJzZSBUcmFuc2NyaXB0YXNlIFBvbHltZXJhc2UgQ2hhaW4gUmVhY3Rp

b248L2tleXdvcmQ+PGtleXdvcmQ+c3JjLUZhbWlseSBLaW5hc2VzL21ldGFib2xpc208L2tleXdv

cmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwOTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkph

bjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE3NTAtMzYzOSAoRWxlY3Ryb25pYykm

I3hEOzEwMTUtNjMwNSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTg1MDM1NzA8L2Fj

Y2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0u

bmloLmdvdi9wdWJtZWQvMTg1MDM1NzA8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExMTEvai4xNzUwLTM2MzkuMjAwOC4wMDE3NC54PC9lbGVj

dHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 429. As mentioned previously, cholesterol does not cross the blood-brain barrier and these studies pointed to 27-OH as a mediator of the negative effects of high-fat diets in brain function markers. Moreover, HFD leads to cognitive impairment in mice and knocking out Cyp27A1, the enzyme converting cholesterol to 27-OH, protects mice against HFD-induced cognitive deficit PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZXZlcmluPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

UmVjTnVtPjI3NjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjQzMDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI3NjwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMxNzc1MjcxIj4yNzY8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhldmVyaW4sIE0uPC9hdXRob3I+PGF1dGhv

cj5NYWlvbGksIFMuPC9hdXRob3I+PGF1dGhvcj5QaGFtLCBULjwvYXV0aG9yPjxhdXRob3I+TWF0

ZW9zLCBMLjwvYXV0aG9yPjxhdXRob3I+Q2FtcG9yZXNpLCBFLjwvYXV0aG9yPjxhdXRob3I+QWxp

LCBaLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48YXV0aG9yPkNlZGF6by1N

aW5ndWV6LCBBLjwvYXV0aG9yPjxhdXRob3I+QmpvcmtoZW0sIEkuPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGl2aXNpb24gb2YgQ2xpbmljYWwgQ2hlbWlz

dHJ5LCBEZXBhcnRtZW50IG9mIExhYm9yYXRvcnkgTWVkaWNpbmUsIEthcm9saW5za2EgSW5zdGl0

dXRlLCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIFNFIDE0MSA4NiBTdG9ja2hvbG0s

IFN3ZWRlbi4mI3hEO0thcm9saW5za2EgSW5zdGl0dXRlLCBEZXBhcnRtZW50IG9mIE5ldXJvYmlv

bG9neSBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNl

YXJjaCwgRGl2aXNpb24gb2YgTmV1cm9nZXJpYXRyaWNzLCAxNDEgNTcgU3RvY2tob2xtLCBTd2Vk

ZW4uJiN4RDtEaXZpc2lvbiBvZiBDbGluaWNhbCBDaGVtaXN0cnksIERlcGFydG1lbnQgb2YgTGFi

b3JhdG9yeSBNZWRpY2luZSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGUsIEthcm9saW5za2EgVW5pdmVy

c2l0eSBIb3NwaXRhbCwgU0UgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuLiBFbGVjdHJvbmljIGFk

ZHJlc3M6IGluZ2VtYXIuYmpvcmtoZW1Aa2Fyb2xpbnNrYS5zZS48L2F1dGgtYWRkcmVzcz48dGl0

bGVzPjx0aXRsZT4yNy1oeWRyb3h5Y2hvbGVzdGVyb2wgbWVkaWF0ZXMgbmVnYXRpdmUgZWZmZWN0

cyBvZiBkaWV0YXJ5IGNob2xlc3Rlcm9sIG9uIGNvZ25pdGlvbiBpbiBtaWNlPC90aXRsZT48c2Vj

b25kYXJ5LXRpdGxlPkJlaGF2IEJyYWluIFJlczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxw

YWdlcz4zNTYtOTwvcGFnZXM+PHZvbHVtZT4yNzg8L3ZvbHVtZT48a2V5d29yZHM+PGtleXdvcmQ+

QUlEUy1SZWxhdGVkIENvbXBsZXgvZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29y

ZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJvZHkgV2VpZ2h0L2RydWcgZWZmZWN0cy9nZW5l

dGljczwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0YW5ldHJpb2wgMjYtTW9ub294eWdlbmFzZS9k

ZWZpY2llbmN5L2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sLyphZHZlcnNl

IGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGljIEFjaWQvYWRtaW5pc3RyYXRpb24gJmFt

cDsgZG9zYWdlPC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbiBEaXNvcmRlcnMvKmV0aW9sb2d5

LypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5HZW5lIEV4cHJlc3Npb24gUmVndWxhdGlvbi9k

cnVnIGVmZmVjdHMvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9s

cy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdv

cmQ+TWF6ZSBMZWFybmluZy9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5

d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwg

S25vY2tvdXQ8L2tleXdvcmQ+PGtleXdvcmQ+Uk5BLCBNZXNzZW5nZXIvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5TcGF0aWFsIExlYXJuaW5nL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5

d29yZD4yNy1IeWRyb3h5Y2hvbGVzdGVyb2w8L2tleXdvcmQ+PGtleXdvcmQ+QWN0aXZpdHktcmVn

dWxhdGVkIGN5dG9za2VsZXRvbi1hc3NvY2lhdGVkIHByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+

Q2hvbGVzdGVyb2w8L2tleXdvcmQ+PGtleXdvcmQ+SHlwZXJjaG9sZXN0ZXJvbGVtaWE8L2tleXdv

cmQ+PGtleXdvcmQ+TW9ycmlzIHdhdGVyIG1hemU8L2tleXdvcmQ+PGtleXdvcmQ+T3h5c3Rlcm9s

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5GZWIgMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE4NzItNzU0OSAoRWxl

Y3Ryb25pYykmI3hEOzAxNjYtNDMyOCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjU0

NTM3NDQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjU0NTM3NDQ8L3VybD48dXJsPmh0dHBzOi8vYWMuZWxz

LWNkbi5jb20vUzAxNjY0MzI4MTQwMDY3NTUvMS1zMi4wLVMwMTY2NDMyODE0MDA2NzU1LW1haW4u

cGRmP190aWQ9MGFmYmIwODgtMWY1ZS00ZjBlLWI3ZmEtYWRjODQ3NzNlNWI2JmFtcDthY2RuYXQ9

MTUzNDQ5NTI3OF80MzE5MTE4MjQzMmQzMWYzMzM1M2I1NmQxOTIwN2E0YzwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmJici4yMDE0

LjEwLjAxODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90

ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZXZlcmluPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

UmVjTnVtPjI3NjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjQzMDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI3NjwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAw

cGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMxNzc1MjcxIj4yNzY8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhldmVyaW4sIE0uPC9hdXRob3I+PGF1dGhv

cj5NYWlvbGksIFMuPC9hdXRob3I+PGF1dGhvcj5QaGFtLCBULjwvYXV0aG9yPjxhdXRob3I+TWF0

ZW9zLCBMLjwvYXV0aG9yPjxhdXRob3I+Q2FtcG9yZXNpLCBFLjwvYXV0aG9yPjxhdXRob3I+QWxp

LCBaLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48YXV0aG9yPkNlZGF6by1N

aW5ndWV6LCBBLjwvYXV0aG9yPjxhdXRob3I+QmpvcmtoZW0sIEkuPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGl2aXNpb24gb2YgQ2xpbmljYWwgQ2hlbWlz

dHJ5LCBEZXBhcnRtZW50IG9mIExhYm9yYXRvcnkgTWVkaWNpbmUsIEthcm9saW5za2EgSW5zdGl0

dXRlLCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIFNFIDE0MSA4NiBTdG9ja2hvbG0s

IFN3ZWRlbi4mI3hEO0thcm9saW5za2EgSW5zdGl0dXRlLCBEZXBhcnRtZW50IG9mIE5ldXJvYmlv

bG9neSBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNl

YXJjaCwgRGl2aXNpb24gb2YgTmV1cm9nZXJpYXRyaWNzLCAxNDEgNTcgU3RvY2tob2xtLCBTd2Vk

ZW4uJiN4RDtEaXZpc2lvbiBvZiBDbGluaWNhbCBDaGVtaXN0cnksIERlcGFydG1lbnQgb2YgTGFi

b3JhdG9yeSBNZWRpY2luZSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGUsIEthcm9saW5za2EgVW5pdmVy

c2l0eSBIb3NwaXRhbCwgU0UgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuLiBFbGVjdHJvbmljIGFk

ZHJlc3M6IGluZ2VtYXIuYmpvcmtoZW1Aa2Fyb2xpbnNrYS5zZS48L2F1dGgtYWRkcmVzcz48dGl0

bGVzPjx0aXRsZT4yNy1oeWRyb3h5Y2hvbGVzdGVyb2wgbWVkaWF0ZXMgbmVnYXRpdmUgZWZmZWN0

cyBvZiBkaWV0YXJ5IGNob2xlc3Rlcm9sIG9uIGNvZ25pdGlvbiBpbiBtaWNlPC90aXRsZT48c2Vj

b25kYXJ5LXRpdGxlPkJlaGF2IEJyYWluIFJlczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxw

YWdlcz4zNTYtOTwvcGFnZXM+PHZvbHVtZT4yNzg8L3ZvbHVtZT48a2V5d29yZHM+PGtleXdvcmQ+

QUlEUy1SZWxhdGVkIENvbXBsZXgvZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29y

ZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJvZHkgV2VpZ2h0L2RydWcgZWZmZWN0cy9nZW5l

dGljczwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0YW5ldHJpb2wgMjYtTW9ub294eWdlbmFzZS9k

ZWZpY2llbmN5L2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sLyphZHZlcnNl

IGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGljIEFjaWQvYWRtaW5pc3RyYXRpb24gJmFt

cDsgZG9zYWdlPC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbiBEaXNvcmRlcnMvKmV0aW9sb2d5

LypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5HZW5lIEV4cHJlc3Npb24gUmVndWxhdGlvbi9k

cnVnIGVmZmVjdHMvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9s

cy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdv

cmQ+TWF6ZSBMZWFybmluZy9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5

d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwg

S25vY2tvdXQ8L2tleXdvcmQ+PGtleXdvcmQ+Uk5BLCBNZXNzZW5nZXIvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5TcGF0aWFsIExlYXJuaW5nL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5

d29yZD4yNy1IeWRyb3h5Y2hvbGVzdGVyb2w8L2tleXdvcmQ+PGtleXdvcmQ+QWN0aXZpdHktcmVn

dWxhdGVkIGN5dG9za2VsZXRvbi1hc3NvY2lhdGVkIHByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+

Q2hvbGVzdGVyb2w8L2tleXdvcmQ+PGtleXdvcmQ+SHlwZXJjaG9sZXN0ZXJvbGVtaWE8L2tleXdv

cmQ+PGtleXdvcmQ+TW9ycmlzIHdhdGVyIG1hemU8L2tleXdvcmQ+PGtleXdvcmQ+T3h5c3Rlcm9s

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5GZWIgMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE4NzItNzU0OSAoRWxl

Y3Ryb25pYykmI3hEOzAxNjYtNDMyOCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjU0

NTM3NDQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjU0NTM3NDQ8L3VybD48dXJsPmh0dHBzOi8vYWMuZWxz

LWNkbi5jb20vUzAxNjY0MzI4MTQwMDY3NTUvMS1zMi4wLVMwMTY2NDMyODE0MDA2NzU1LW1haW4u

cGRmP190aWQ9MGFmYmIwODgtMWY1ZS00ZjBlLWI3ZmEtYWRjODQ3NzNlNWI2JmFtcDthY2RuYXQ9

MTUzNDQ5NTI3OF80MzE5MTE4MjQzMmQzMWYzMzM1M2I1NmQxOTIwN2E0YzwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmJici4yMDE0

LjEwLjAxODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90

ZT5=

ADDIN EN.CITE.DATA 430. Alterations of the Renin-Angiotensin System in the brain in AD In an effort to identify the mechanisms by which high levels of 27-OH produce neuronal damage, we reported high levels of 27-OH increase the renin-angiotensin system activity in HFD fed mice (Fig. 8) ADDIN EN.CITE <EndNote><Cite><Author>Mateos</Author><Year>2011</Year><RecNum>798</RecNum><DisplayText><style face="superscript">431</style></DisplayText><record><rec-number>798</rec-number><foreign-keys><key app="EN" db-id="dvw2fapfts05sgerzs6x0f5ptr59xpw99a0a" timestamp="1519684281">798</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mateos, Laura</author><author>Ismail, Muhammad-Al-Mustafa</author><author>Gil-Bea, Francisco-Javier</author><author>Schüle, Rebecca</author><author>Sch?ls, Ludger</author><author>Heverin, Maura</author><author>Folkesson, Ronnie</author><author>Bj?rkhem, Ingemar</author><author>Cedazo-Mínguez, Angel</author></authors></contributors><titles><title>Side Chain-oxidized Oxysterols Regulate the Brain Renin-Angiotensin System through a Liver X Receptor-dependent Mechanism</title><secondary-title>Journal of Biological Chemistry</secondary-title></titles><periodical><full-title>Journal of Biological Chemistry</full-title></periodical><pages>25574-25585</pages><volume>286</volume><number>29</number><dates><year>2011</year><pub-dates><date>2011/05/31</date></pub-dates></dates><publisher>American Society for Biochemistry &amp; Molecular Biology (ASBMB)</publisher><isbn>0021-9258&#xD;1083-351X</isbn><urls><related-urls><url>. These results were proven translatable when found that patients with MCI and AD also present increased angiotensin (AGT) and angiotensin-converting enzyme (ACE) in the brain PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXRlb3M8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

ZWNOdW0+MzAzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDMyPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzAzPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzYiPjMwMzwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWF0ZW9zLCBMLjwvYXV0aG9yPjxhdXRob3I+

SXNtYWlsLCBNLiBBLjwvYXV0aG9yPjxhdXRob3I+R2lsLUJlYSwgRi4gSi48L2F1dGhvcj48YXV0

aG9yPkxlb25pLCBWLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48YXV0aG9y

PkJqb3JraGVtLCBJLjwvYXV0aG9yPjxhdXRob3I+Q2VkYXpvLU1pbmd1ZXosIEEuPC9hdXRob3I+

PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVy

b2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0dXRl

dC1BbHpoZWltZXImYXBvcztzIERpc2Vhc2UgUmVzZWFyY2ggQ2VudGVyLCBOT1ZVTSwgU3RvY2to

b2xtLCBTd2VkZW4uIExhdXJhLk1hdGVvcy1Nb250ZWpvQGtpLnNlPC9hdXRoLWFkZHJlc3M+PHRp

dGxlcz48dGl0bGU+VXByZWd1bGF0aW9uIG9mIGJyYWluIHJlbmluIGFuZ2lvdGVuc2luIHN5c3Rl

bSBieSAyNy1oeWRyb3h5Y2hvbGVzdGVyb2wgaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogQWx6aGVpbWVycyBEaXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIEFsemhlaW1lcnMgRGlzPC9mdWxsLXRp

dGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NjY5LTc5PC9wYWdlcz48dm9sdW1lPjI0PC92b2x1bWU+

PG51bWJlcj40PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdv

cmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2Uv

ZGlhZ25vc2lzLyptZXRhYm9saXNtLypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

QW5naW90ZW5zaW5vZ2VuL2Jpb3N5bnRoZXNpcy9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QmlvbWFya2Vycy9tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPkJyYWluIENoZW1pc3RyeS9kcnVnIGVmZmVjdHMvKnBoeXNpb2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVkPC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGl2ZSBE

eXNmdW5jdGlvbi9kaWFnbm9zaXMvKm1ldGFib2xpc20vcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkNyb3NzLVNlY3Rpb25hbCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFs

ZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xl

c3Rlcm9scy8qY2hlbWlzdHJ5LyptZXRhYm9saXNtL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5

d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3Jk

PlBlcHRpZHlsLURpcGVwdGlkYXNlIEEvYmlvc3ludGhlc2lzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+UmF0czwva2V5d29yZD48a2V5d29yZD5SYXRzLCBTcHJhZ3VlLURhd2xleTwva2V5

d29yZD48a2V5d29yZD5SZW5pbi1Bbmdpb3RlbnNpbiBTeXN0ZW0vZHJ1ZyBlZmZlY3RzLypwaHlz

aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlVwLVJlZ3VsYXRpb24vKnBoeXNpb2xvZ3k8L2tleXdv

cmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMTwveWVhcj48L2RhdGVzPjxpc2JuPjE4NzUt

ODkwOCAoRWxlY3Ryb25pYykmI3hEOzEzODctMjg3NyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lv

bi1udW0+MjEyOTcyNTQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0

dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjEyOTcyNTQ8L3VybD48L3JlbGF0ZWQt

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjMyMzMvSkFELTIwMTEtMTAx

NTEyPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXRlb3M8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

ZWNOdW0+MzAzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDMyPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzAzPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzYiPjMwMzwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWF0ZW9zLCBMLjwvYXV0aG9yPjxhdXRob3I+

SXNtYWlsLCBNLiBBLjwvYXV0aG9yPjxhdXRob3I+R2lsLUJlYSwgRi4gSi48L2F1dGhvcj48YXV0

aG9yPkxlb25pLCBWLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48YXV0aG9y

PkJqb3JraGVtLCBJLjwvYXV0aG9yPjxhdXRob3I+Q2VkYXpvLU1pbmd1ZXosIEEuPC9hdXRob3I+

PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVy

b2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0dXRl

dC1BbHpoZWltZXImYXBvcztzIERpc2Vhc2UgUmVzZWFyY2ggQ2VudGVyLCBOT1ZVTSwgU3RvY2to

b2xtLCBTd2VkZW4uIExhdXJhLk1hdGVvcy1Nb250ZWpvQGtpLnNlPC9hdXRoLWFkZHJlc3M+PHRp

dGxlcz48dGl0bGU+VXByZWd1bGF0aW9uIG9mIGJyYWluIHJlbmluIGFuZ2lvdGVuc2luIHN5c3Rl

bSBieSAyNy1oeWRyb3h5Y2hvbGVzdGVyb2wgaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogQWx6aGVpbWVycyBEaXM8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIEFsemhlaW1lcnMgRGlzPC9mdWxsLXRp

dGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NjY5LTc5PC9wYWdlcz48dm9sdW1lPjI0PC92b2x1bWU+

PG51bWJlcj40PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdv

cmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2Uv

ZGlhZ25vc2lzLyptZXRhYm9saXNtLypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

QW5naW90ZW5zaW5vZ2VuL2Jpb3N5bnRoZXNpcy9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QmlvbWFya2Vycy9tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPkJyYWluIENoZW1pc3RyeS9kcnVnIGVmZmVjdHMvKnBoeXNpb2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVkPC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGl2ZSBE

eXNmdW5jdGlvbi9kaWFnbm9zaXMvKm1ldGFib2xpc20vcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkNyb3NzLVNlY3Rpb25hbCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFs

ZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xl

c3Rlcm9scy8qY2hlbWlzdHJ5LyptZXRhYm9saXNtL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5

d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3Jk

PlBlcHRpZHlsLURpcGVwdGlkYXNlIEEvYmlvc3ludGhlc2lzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+UmF0czwva2V5d29yZD48a2V5d29yZD5SYXRzLCBTcHJhZ3VlLURhd2xleTwva2V5

d29yZD48a2V5d29yZD5SZW5pbi1Bbmdpb3RlbnNpbiBTeXN0ZW0vZHJ1ZyBlZmZlY3RzLypwaHlz

aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlVwLVJlZ3VsYXRpb24vKnBoeXNpb2xvZ3k8L2tleXdv

cmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMTwveWVhcj48L2RhdGVzPjxpc2JuPjE4NzUt

ODkwOCAoRWxlY3Ryb25pYykmI3hEOzEzODctMjg3NyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lv

bi1udW0+MjEyOTcyNTQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0

dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjEyOTcyNTQ8L3VybD48L3JlbGF0ZWQt

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjMyMzMvSkFELTIwMTEtMTAx

NTEyPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 432. Going back to the animal models to clarify the mechanisms of action of 27-OH in the brain, the Cyp27TG mice were used, a transgenic mouse model overexpressing CYP27A1 to produce 5 times more 27-OH systemically. These animals also shows cognitive impairment at 12 months old together with reduced glucose uptake in the brain PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Jc21haWw8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS

ZWNOdW0+MjYzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDI4LDQzMzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI2MzwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMxNzc1MjcxIj4yNjM8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPklzbWFpbCwgTS4gQS48L2F1dGhvcj48

YXV0aG9yPk1hdGVvcywgTC48L2F1dGhvcj48YXV0aG9yPk1haW9saSwgUy48L2F1dGhvcj48YXV0

aG9yPk1lcmluby1TZXJyYWlzLCBQLjwvYXV0aG9yPjxhdXRob3I+QWxpLCBaLjwvYXV0aG9yPjxh

dXRob3I+TG9kZWlybywgTS48L2F1dGhvcj48YXV0aG9yPldlc3RtYW4sIEUuPC9hdXRob3I+PGF1

dGhvcj5MZWl0ZXJzZG9yZiwgRS48L2F1dGhvcj48YXV0aG9yPkd1bHlhcywgQi48L2F1dGhvcj48

YXV0aG9yPk9sb2YtV2FobHVuZCwgTC48L2F1dGhvcj48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRo

b3I+PGF1dGhvcj5TYXZpdGNoZXZhLCBJLjwvYXV0aG9yPjxhdXRob3I+QmpvcmtoZW0sIEkuPC9h

dXRob3I+PGF1dGhvcj5DZWRhem8tTWluZ3VleiwgQS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EaXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIENlbnRl

ciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2Fy

ZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0dXRldCwgMTQxIDg2IFN0

b2NraG9sbSwgU3dlZGVuLiYjeEQ7RGl2aXNpb24gb2YgQ2xpbmljYWwgQ2hlbWlzdHJ5LCBEZXBh

cnRtZW50IG9mIExhYm9yYXRvcnkgTWVkaWNpbmUsIEthcm9saW5za2EgVW5pdmVyc2l0eSBIb3Nw

aXRhbCwgMTQxIDg2IEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBDbGluaWNhbCBH

ZXJpYXRyaWNzLCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGVwYXJ0bWVudCBvZiBO

ZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMsIGFuZCBTb2NpZXR5LCBLYXJvbGluc2thIEluc3Rp

dHV0ZXQsIDE0MSA4NiBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0NlbnRlciBmb3IgUmVzZWFyY2gs

IFByZXZlbnRpb24sIGFuZCBUcmVhdG1lbnQgb2YgQXRoZXJvc2NsZXJvc2lzLCBIYWRhc3NhaCBI

ZWJyZXcgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRlciwgSmVydXNhbGVtIDkxMTIwLCBJc3JhZWwu

JiN4RDtDZW50cmUgZm9yIFBzeWNoaWF0cnkgUmVzZWFyY2gsIERlcGFydG1lbnQgb2YgQ2xpbmlj

YWwgTmV1cm9zY2llbmNlLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIDE3MSA3NyBTdG9ja2hvbG0s

IFN3ZWRlbi4mI3hEO0RlcGFydG1lbnQgb2YgUmFkaW9sb2d5LCBLYXJvbGluc2thIFVuaXZlcnNp

dHkgSG9zcGl0YWwsIDE0MSA4NiBIdWRkaW5nZSwgU3dlZGVuLiYjeEQ7RGl2aXNpb24gb2YgTmV1

cm9nZXJpYXRyaWNzLCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGVwYXJ0bWVudCBv

ZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMsIGFuZCBTb2NpZXR5LCBLYXJvbGluc2thIElu

c3RpdHV0ZXQsIDE0MSA4NiBTdG9ja2hvbG0sIFN3ZWRlbiBBbmdlbC5DZWRhem8tTWluZ3VlekBr

aS5zZS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT4yNy1IeWRyb3h5Y2hvbGVzdGVyb2wg

aW1wYWlycyBuZXVyb25hbCBnbHVjb3NlIHVwdGFrZSB0aHJvdWdoIGFuIElSQVAvR0xVVDQgc3lz

dGVtIGR5c3JlZ3VsYXRpb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBFeHAgTWVkPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjY5OS03MTc8L3BhZ2VzPjx2b2x1bWU+MjE0PC92

b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFuZ2lvdGVuc2luIElJ

L2FuYWxvZ3MgJmFtcDsgZGVyaXZhdGl2ZXMvcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGVzdGFuZXRyaW9sIDI2LU1vbm9veHlnZW5h

c2UvcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0ZXJvbC9tZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPkN5c3RpbnlsIEFtaW5vcGVwdGlkYXNlLypwaHlzaW9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPkdsdWNvc2UvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y29z

ZSBUcmFuc3BvcnRlciBUeXBlIDQvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5z

PC9rZXl3b3JkPjxrZXl3b3JkPkh5ZHJveHljaG9sZXN0ZXJvbHMvKnBoYXJtYWNvbG9neTwva2V5

d29yZD48a2V5d29yZD5MaXZlciBYIFJlY2VwdG9ycy9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgSW5icmVkIEM1N0JMPC9rZXl3b3JkPjxr

ZXl3b3JkPk5ldXJvbnMvKm1ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1hciA2PC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PGlzYm4+MTU0MC05NTM4IChFbGVjdHJvbmljKSYjeEQ7MDAyMi0xMDA3IChMaW5raW5n

KTwvaXNibj48YWNjZXNzaW9uLW51bT4yODIxMzUxMjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVs

YXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yODIxMzUx

MjwvdXJsPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wbWMvYXJ0aWNsZXMvUE1D

NTMzOTY2OS9wZGYvSkVNXzIwMTYwNTM0LnBkZjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48

Y3VzdG9tMj5QTUM1MzM5NjY5PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4x

MDg0L2plbS4yMDE2MDUzNDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRl

PjxDaXRlPjxBdXRob3I+TWVpcjwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+PFJlY051bT40NTk8

L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjQ1OTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz

PjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVh

diIgdGltZXN0YW1wPSIxNTMyNTQ5OTQ3Ij40NTk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5

cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0

aG9ycz48YXV0aG9yPk1laXIsIEsuPC9hdXRob3I+PGF1dGhvcj5LaXRzYmVyZywgRC48L2F1dGhv

cj48YXV0aG9yPkFsa2FsYXksIEkuPC9hdXRob3I+PGF1dGhvcj5TemFmZXIsIEYuPC9hdXRob3I+

PGF1dGhvcj5Sb3NlbiwgSC48L2F1dGhvcj48YXV0aG9yPlNocGl0emVuLCBTLjwvYXV0aG9yPjxh

dXRob3I+QXZpLCBMLiBCLjwvYXV0aG9yPjxhdXRob3I+U3RhZWxzLCBCLjwvYXV0aG9yPjxhdXRo

b3I+RmlldmV0LCBDLjwvYXV0aG9yPjxhdXRob3I+TWVpbmVyLCBWLjwvYXV0aG9yPjxhdXRob3I+

QmpvcmtoZW0sIEkuPC9hdXRob3I+PGF1dGhvcj5MZWl0ZXJzZG9yZiwgRS48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIFBhdGhvbG9n

eSwgSGFkYXNzYWggVW5pdmVyc2l0eSBIb3NwaXRhbCwgOTExMjAgSmVydXNhbGVtLCBJc3JhZWwu

LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkh1bWFuIHN0ZXJvbCAyNy1oeWRyb3h5bGFz

ZSAoQ1lQMjcpIG92ZXJleHByZXNzb3IgdHJhbnNnZW5pYyBtb3VzZSBtb2RlbC4gRXZpZGVuY2Ug

YWdhaW5zdCAyNy1oeWRyb3h5Y2hvbGVzdGVyb2wgYXMgYSBjcml0aWNhbCByZWd1bGF0b3Igb2Yg

Y2hvbGVzdGVyb2wgaG9tZW9zdGFzaXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBCaW9sIENo

ZW08L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIEJp

b2wgQ2hlbTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjM0MDM2LTQxPC9wYWdlcz48

dm9sdW1lPjI3Nzwvdm9sdW1lPjxudW1iZXI+Mzc8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+

QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CaWxlL2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29y

ZD5CaWxlIEFjaWRzIGFuZCBTYWx0cy9hbmFseXNpczwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0

YW5ldHJpb2wgMjYtTW9ub294eWdlbmFzZTwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0ZXJvbC8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5EaWV0YXJ5IEZhdHMvYWRtaW5pc3RyYXRpb24g

JmFtcDsgZG9zYWdlPC9rZXl3b3JkPjxrZXl3b3JkPkZlY2VzL2NoZW1pc3RyeTwva2V5d29yZD48

a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SG9tZW9zdGFzaXM8L2tleXdvcmQ+PGtl

eXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkxpcGlkcy9ibG9vZDwva2V5d29yZD48a2V5

d29yZD5MaXBvcHJvdGVpbnMvYmxvb2Q8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48

a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgSW5icmVk

IENCQTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFuc2dlbmljPC9rZXl3b3JkPjxrZXl3b3Jk

PlN0ZXJvaWQgSHlkcm94eWxhc2VzL2dlbmV0aWNzLypwaHlzaW9sb2d5PC9rZXl3b3JkPjwva2V5

d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDI8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMTM8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDIxLTkyNTggKFByaW50KSYjeEQ7MDAyMS05

MjU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xMjExOTI4NTwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8xMjExOTI4NTwvdXJsPjx1cmw+aHR0cDovL3d3dy5qYmMub3JnL2NvbnRlbnQvMjc3LzM3

LzM0MDM2LmZ1bGwucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4xMDc0L2piYy5NMjAxMTIyMjAwPC9lbGVjdHJvbmljLXJlc291cmNlLW51

bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Jc21haWw8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS

ZWNOdW0+MjYzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDI4LDQzMzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI2MzwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMxNzc1MjcxIj4yNjM8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPklzbWFpbCwgTS4gQS48L2F1dGhvcj48

YXV0aG9yPk1hdGVvcywgTC48L2F1dGhvcj48YXV0aG9yPk1haW9saSwgUy48L2F1dGhvcj48YXV0

aG9yPk1lcmluby1TZXJyYWlzLCBQLjwvYXV0aG9yPjxhdXRob3I+QWxpLCBaLjwvYXV0aG9yPjxh

dXRob3I+TG9kZWlybywgTS48L2F1dGhvcj48YXV0aG9yPldlc3RtYW4sIEUuPC9hdXRob3I+PGF1

dGhvcj5MZWl0ZXJzZG9yZiwgRS48L2F1dGhvcj48YXV0aG9yPkd1bHlhcywgQi48L2F1dGhvcj48

YXV0aG9yPk9sb2YtV2FobHVuZCwgTC48L2F1dGhvcj48YXV0aG9yPldpbmJsYWQsIEIuPC9hdXRo

b3I+PGF1dGhvcj5TYXZpdGNoZXZhLCBJLjwvYXV0aG9yPjxhdXRob3I+QmpvcmtoZW0sIEkuPC9h

dXRob3I+PGF1dGhvcj5DZWRhem8tTWluZ3VleiwgQS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EaXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIENlbnRl

ciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2Fy

ZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0dXRldCwgMTQxIDg2IFN0

b2NraG9sbSwgU3dlZGVuLiYjeEQ7RGl2aXNpb24gb2YgQ2xpbmljYWwgQ2hlbWlzdHJ5LCBEZXBh

cnRtZW50IG9mIExhYm9yYXRvcnkgTWVkaWNpbmUsIEthcm9saW5za2EgVW5pdmVyc2l0eSBIb3Nw

aXRhbCwgMTQxIDg2IEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBDbGluaWNhbCBH

ZXJpYXRyaWNzLCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGVwYXJ0bWVudCBvZiBO

ZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMsIGFuZCBTb2NpZXR5LCBLYXJvbGluc2thIEluc3Rp

dHV0ZXQsIDE0MSA4NiBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0NlbnRlciBmb3IgUmVzZWFyY2gs

IFByZXZlbnRpb24sIGFuZCBUcmVhdG1lbnQgb2YgQXRoZXJvc2NsZXJvc2lzLCBIYWRhc3NhaCBI

ZWJyZXcgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRlciwgSmVydXNhbGVtIDkxMTIwLCBJc3JhZWwu

JiN4RDtDZW50cmUgZm9yIFBzeWNoaWF0cnkgUmVzZWFyY2gsIERlcGFydG1lbnQgb2YgQ2xpbmlj

YWwgTmV1cm9zY2llbmNlLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIDE3MSA3NyBTdG9ja2hvbG0s

IFN3ZWRlbi4mI3hEO0RlcGFydG1lbnQgb2YgUmFkaW9sb2d5LCBLYXJvbGluc2thIFVuaXZlcnNp

dHkgSG9zcGl0YWwsIDE0MSA4NiBIdWRkaW5nZSwgU3dlZGVuLiYjeEQ7RGl2aXNpb24gb2YgTmV1

cm9nZXJpYXRyaWNzLCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGVwYXJ0bWVudCBv

ZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMsIGFuZCBTb2NpZXR5LCBLYXJvbGluc2thIElu

c3RpdHV0ZXQsIDE0MSA4NiBTdG9ja2hvbG0sIFN3ZWRlbiBBbmdlbC5DZWRhem8tTWluZ3VlekBr

aS5zZS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT4yNy1IeWRyb3h5Y2hvbGVzdGVyb2wg

aW1wYWlycyBuZXVyb25hbCBnbHVjb3NlIHVwdGFrZSB0aHJvdWdoIGFuIElSQVAvR0xVVDQgc3lz

dGVtIGR5c3JlZ3VsYXRpb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBFeHAgTWVkPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjY5OS03MTc8L3BhZ2VzPjx2b2x1bWU+MjE0PC92

b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFuZ2lvdGVuc2luIElJ

L2FuYWxvZ3MgJmFtcDsgZGVyaXZhdGl2ZXMvcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGVzdGFuZXRyaW9sIDI2LU1vbm9veHlnZW5h

c2UvcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0ZXJvbC9tZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPkN5c3RpbnlsIEFtaW5vcGVwdGlkYXNlLypwaHlzaW9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPkdsdWNvc2UvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+R2x1Y29z

ZSBUcmFuc3BvcnRlciBUeXBlIDQvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5z

PC9rZXl3b3JkPjxrZXl3b3JkPkh5ZHJveHljaG9sZXN0ZXJvbHMvKnBoYXJtYWNvbG9neTwva2V5

d29yZD48a2V5d29yZD5MaXZlciBYIFJlY2VwdG9ycy9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgSW5icmVkIEM1N0JMPC9rZXl3b3JkPjxr

ZXl3b3JkPk5ldXJvbnMvKm1ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1hciA2PC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PGlzYm4+MTU0MC05NTM4IChFbGVjdHJvbmljKSYjeEQ7MDAyMi0xMDA3IChMaW5raW5n

KTwvaXNibj48YWNjZXNzaW9uLW51bT4yODIxMzUxMjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVs

YXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yODIxMzUx

MjwvdXJsPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wbWMvYXJ0aWNsZXMvUE1D

NTMzOTY2OS9wZGYvSkVNXzIwMTYwNTM0LnBkZjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48

Y3VzdG9tMj5QTUM1MzM5NjY5PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4x

MDg0L2plbS4yMDE2MDUzNDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRl

PjxDaXRlPjxBdXRob3I+TWVpcjwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+PFJlY051bT40NTk8

L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjQ1OTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz

PjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVh

diIgdGltZXN0YW1wPSIxNTMyNTQ5OTQ3Ij40NTk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5

cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0

aG9ycz48YXV0aG9yPk1laXIsIEsuPC9hdXRob3I+PGF1dGhvcj5LaXRzYmVyZywgRC48L2F1dGhv

cj48YXV0aG9yPkFsa2FsYXksIEkuPC9hdXRob3I+PGF1dGhvcj5TemFmZXIsIEYuPC9hdXRob3I+

PGF1dGhvcj5Sb3NlbiwgSC48L2F1dGhvcj48YXV0aG9yPlNocGl0emVuLCBTLjwvYXV0aG9yPjxh

dXRob3I+QXZpLCBMLiBCLjwvYXV0aG9yPjxhdXRob3I+U3RhZWxzLCBCLjwvYXV0aG9yPjxhdXRo

b3I+RmlldmV0LCBDLjwvYXV0aG9yPjxhdXRob3I+TWVpbmVyLCBWLjwvYXV0aG9yPjxhdXRob3I+

QmpvcmtoZW0sIEkuPC9hdXRob3I+PGF1dGhvcj5MZWl0ZXJzZG9yZiwgRS48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIFBhdGhvbG9n

eSwgSGFkYXNzYWggVW5pdmVyc2l0eSBIb3NwaXRhbCwgOTExMjAgSmVydXNhbGVtLCBJc3JhZWwu

LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkh1bWFuIHN0ZXJvbCAyNy1oeWRyb3h5bGFz

ZSAoQ1lQMjcpIG92ZXJleHByZXNzb3IgdHJhbnNnZW5pYyBtb3VzZSBtb2RlbC4gRXZpZGVuY2Ug

YWdhaW5zdCAyNy1oeWRyb3h5Y2hvbGVzdGVyb2wgYXMgYSBjcml0aWNhbCByZWd1bGF0b3Igb2Yg

Y2hvbGVzdGVyb2wgaG9tZW9zdGFzaXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBCaW9sIENo

ZW08L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIEJp

b2wgQ2hlbTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjM0MDM2LTQxPC9wYWdlcz48

dm9sdW1lPjI3Nzwvdm9sdW1lPjxudW1iZXI+Mzc8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+

QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CaWxlL2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29y

ZD5CaWxlIEFjaWRzIGFuZCBTYWx0cy9hbmFseXNpczwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0

YW5ldHJpb2wgMjYtTW9ub294eWdlbmFzZTwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0ZXJvbC8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5EaWV0YXJ5IEZhdHMvYWRtaW5pc3RyYXRpb24g

JmFtcDsgZG9zYWdlPC9rZXl3b3JkPjxrZXl3b3JkPkZlY2VzL2NoZW1pc3RyeTwva2V5d29yZD48

a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SG9tZW9zdGFzaXM8L2tleXdvcmQ+PGtl

eXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkxpcGlkcy9ibG9vZDwva2V5d29yZD48a2V5

d29yZD5MaXBvcHJvdGVpbnMvYmxvb2Q8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48

a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgSW5icmVk

IENCQTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBUcmFuc2dlbmljPC9rZXl3b3JkPjxrZXl3b3Jk

PlN0ZXJvaWQgSHlkcm94eWxhc2VzL2dlbmV0aWNzLypwaHlzaW9sb2d5PC9rZXl3b3JkPjwva2V5

d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDI8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMTM8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDIxLTkyNTggKFByaW50KSYjeEQ7MDAyMS05

MjU4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xMjExOTI4NTwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8xMjExOTI4NTwvdXJsPjx1cmw+aHR0cDovL3d3dy5qYmMub3JnL2NvbnRlbnQvMjc3LzM3

LzM0MDM2LmZ1bGwucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4xMDc0L2piYy5NMjAxMTIyMjAwPC9lbGVjdHJvbmljLXJlc291cmNlLW51

bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 428,433. The mechanisms leading to reduced glucose uptake in these mice is mediated by an overactivation of the RAS system, leading to an imbalance between the angiotensin isoforms AngIII and IV PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Jc21haWw8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS

ZWNOdW0+MjYzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDI4PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjYzPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzEiPjI2Mzwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SXNtYWlsLCBNLiBBLjwvYXV0aG9yPjxhdXRo

b3I+TWF0ZW9zLCBMLjwvYXV0aG9yPjxhdXRob3I+TWFpb2xpLCBTLjwvYXV0aG9yPjxhdXRob3I+

TWVyaW5vLVNlcnJhaXMsIFAuPC9hdXRob3I+PGF1dGhvcj5BbGksIFouPC9hdXRob3I+PGF1dGhv

cj5Mb2RlaXJvLCBNLjwvYXV0aG9yPjxhdXRob3I+V2VzdG1hbiwgRS48L2F1dGhvcj48YXV0aG9y

PkxlaXRlcnNkb3JmLCBFLjwvYXV0aG9yPjxhdXRob3I+R3VseWFzLCBCLjwvYXV0aG9yPjxhdXRo

b3I+T2xvZi1XYWhsdW5kLCBMLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48

YXV0aG9yPlNhdml0Y2hldmEsIEkuPC9hdXRob3I+PGF1dGhvcj5Cam9ya2hlbSwgSS48L2F1dGhv

cj48YXV0aG9yPkNlZGF6by1NaW5ndWV6LCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0cmljcywgQ2VudGVyIGZv

ciBBbHpoZWltZXIgUmVzZWFyY2gsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNj

aWVuY2VzLCBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCAxNDEgODYgU3RvY2to

b2xtLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBDbGluaWNhbCBDaGVtaXN0cnksIERlcGFydG1l

bnQgb2YgTGFib3JhdG9yeSBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFs

LCAxNDEgODYgSHVkZGluZ2UsIFN3ZWRlbi4mI3hEO0RpdmlzaW9uIG9mIENsaW5pY2FsIEdlcmlh

dHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5ldXJv

YmlvbG9neSwgQ2FyZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0dXRl

dCwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7Q2VudGVyIGZvciBSZXNlYXJjaCwgUHJl

dmVudGlvbiwgYW5kIFRyZWF0bWVudCBvZiBBdGhlcm9zY2xlcm9zaXMsIEhhZGFzc2FoIEhlYnJl

dyBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBKZXJ1c2FsZW0gOTExMjAsIElzcmFlbC4mI3hE

O0NlbnRyZSBmb3IgUHN5Y2hpYXRyeSBSZXNlYXJjaCwgRGVwYXJ0bWVudCBvZiBDbGluaWNhbCBO

ZXVyb3NjaWVuY2UsIEthcm9saW5za2EgSW5zdGl0dXRldCwgMTcxIDc3IFN0b2NraG9sbSwgU3dl

ZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBSYWRpb2xvZ3ksIEthcm9saW5za2EgVW5pdmVyc2l0eSBI

b3NwaXRhbCwgMTQxIDg2IEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBOZXVyb2dl

cmlhdHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5l

dXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0

dXRldCwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuIEFuZ2VsLkNlZGF6by1NaW5ndWV6QGtpLnNl

LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPjI3LUh5ZHJveHljaG9sZXN0ZXJvbCBpbXBh

aXJzIG5ldXJvbmFsIGdsdWNvc2UgdXB0YWtlIHRocm91Z2ggYW4gSVJBUC9HTFVUNCBzeXN0ZW0g

ZHlzcmVndWxhdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEV4cCBNZWQ8L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGFnZXM+Njk5LTcxNzwvcGFnZXM+PHZvbHVtZT4yMTQ8L3ZvbHVt

ZT48bnVtYmVyPjM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5naW90ZW5zaW4gSUkvYW5h

bG9ncyAmYW1wOyBkZXJpdmF0aXZlcy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW5p

bWFsczwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0YW5ldHJpb2wgMjYtTW9ub294eWdlbmFzZS9w

aHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sL21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+Q3lzdGlueWwgQW1pbm9wZXB0aWRhc2UvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+R2x1Y29zZS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5HbHVjb3NlIFRy

YW5zcG9ydGVyIFR5cGUgNC8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tl

eXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy8qcGhhcm1hY29sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkxpdmVyIFggUmVjZXB0b3JzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdv

cmQ+TmV1cm9ucy8qbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWFyIDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48aXNibj4xNTQwLTk1MzggKEVsZWN0cm9uaWMpJiN4RDswMDIyLTEwMDcgKExpbmtpbmcpPC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjI4MjEzNTEyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI4MjEzNTEyPC91

cmw+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3BtYy9hcnRpY2xlcy9QTUM1MzM5

NjY5L3BkZi9KRU1fMjAxNjA1MzQucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0

b20yPlBNQzUzMzk2Njk8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwODQv

amVtLjIwMTYwNTM0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Jc21haWw8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS

ZWNOdW0+MjYzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDI4PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjYzPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzEiPjI2Mzwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SXNtYWlsLCBNLiBBLjwvYXV0aG9yPjxhdXRo

b3I+TWF0ZW9zLCBMLjwvYXV0aG9yPjxhdXRob3I+TWFpb2xpLCBTLjwvYXV0aG9yPjxhdXRob3I+

TWVyaW5vLVNlcnJhaXMsIFAuPC9hdXRob3I+PGF1dGhvcj5BbGksIFouPC9hdXRob3I+PGF1dGhv

cj5Mb2RlaXJvLCBNLjwvYXV0aG9yPjxhdXRob3I+V2VzdG1hbiwgRS48L2F1dGhvcj48YXV0aG9y

PkxlaXRlcnNkb3JmLCBFLjwvYXV0aG9yPjxhdXRob3I+R3VseWFzLCBCLjwvYXV0aG9yPjxhdXRo

b3I+T2xvZi1XYWhsdW5kLCBMLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48

YXV0aG9yPlNhdml0Y2hldmEsIEkuPC9hdXRob3I+PGF1dGhvcj5Cam9ya2hlbSwgSS48L2F1dGhv

cj48YXV0aG9yPkNlZGF6by1NaW5ndWV6LCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0cmljcywgQ2VudGVyIGZv

ciBBbHpoZWltZXIgUmVzZWFyY2gsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNj

aWVuY2VzLCBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCAxNDEgODYgU3RvY2to

b2xtLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBDbGluaWNhbCBDaGVtaXN0cnksIERlcGFydG1l

bnQgb2YgTGFib3JhdG9yeSBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFs

LCAxNDEgODYgSHVkZGluZ2UsIFN3ZWRlbi4mI3hEO0RpdmlzaW9uIG9mIENsaW5pY2FsIEdlcmlh

dHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5ldXJv

YmlvbG9neSwgQ2FyZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0dXRl

dCwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7Q2VudGVyIGZvciBSZXNlYXJjaCwgUHJl

dmVudGlvbiwgYW5kIFRyZWF0bWVudCBvZiBBdGhlcm9zY2xlcm9zaXMsIEhhZGFzc2FoIEhlYnJl

dyBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBKZXJ1c2FsZW0gOTExMjAsIElzcmFlbC4mI3hE

O0NlbnRyZSBmb3IgUHN5Y2hpYXRyeSBSZXNlYXJjaCwgRGVwYXJ0bWVudCBvZiBDbGluaWNhbCBO

ZXVyb3NjaWVuY2UsIEthcm9saW5za2EgSW5zdGl0dXRldCwgMTcxIDc3IFN0b2NraG9sbSwgU3dl

ZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBSYWRpb2xvZ3ksIEthcm9saW5za2EgVW5pdmVyc2l0eSBI

b3NwaXRhbCwgMTQxIDg2IEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBOZXVyb2dl

cmlhdHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5l

dXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0

dXRldCwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuIEFuZ2VsLkNlZGF6by1NaW5ndWV6QGtpLnNl

LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPjI3LUh5ZHJveHljaG9sZXN0ZXJvbCBpbXBh

aXJzIG5ldXJvbmFsIGdsdWNvc2UgdXB0YWtlIHRocm91Z2ggYW4gSVJBUC9HTFVUNCBzeXN0ZW0g

ZHlzcmVndWxhdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEV4cCBNZWQ8L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGFnZXM+Njk5LTcxNzwvcGFnZXM+PHZvbHVtZT4yMTQ8L3ZvbHVt

ZT48bnVtYmVyPjM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5naW90ZW5zaW4gSUkvYW5h

bG9ncyAmYW1wOyBkZXJpdmF0aXZlcy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW5p

bWFsczwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0YW5ldHJpb2wgMjYtTW9ub294eWdlbmFzZS9w

aHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sL21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+Q3lzdGlueWwgQW1pbm9wZXB0aWRhc2UvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+R2x1Y29zZS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5HbHVjb3NlIFRy

YW5zcG9ydGVyIFR5cGUgNC8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tl

eXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy8qcGhhcm1hY29sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkxpdmVyIFggUmVjZXB0b3JzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdv

cmQ+TmV1cm9ucy8qbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWFyIDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48aXNibj4xNTQwLTk1MzggKEVsZWN0cm9uaWMpJiN4RDswMDIyLTEwMDcgKExpbmtpbmcpPC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjI4MjEzNTEyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI4MjEzNTEyPC91

cmw+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3BtYy9hcnRpY2xlcy9QTUM1MzM5

NjY5L3BkZi9KRU1fMjAxNjA1MzQucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0

b20yPlBNQzUzMzk2Njk8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwODQv

amVtLjIwMTYwNTM0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPn==

ADDIN EN.CITE.DATA 428. The balance between these forms is also modified by the catabolism of AngIV by aminopeptidases, which are modulated importantly by 27-OH, particularly aminopeptidase-A (AP-A) and aminopeptidase-N (AP-N). In CYP27TG brains, elevated 27-OH increases APN, which cleaves AngIV thus decreasing its levels. AngIV under physiological conditions downregulates the abundance of insulin-regulated aminopeptidase (IRAP) in the brain PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGJpc3RvbjwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+

PFJlY051bT4xMjAxPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+NDM0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTIwMTwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMzMzA0NDg1Ij4xMjAxPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5BbGJpc3RvbiwgQS4gTC48L2F1dGhv

cj48YXV0aG9yPk1jRG93YWxsLCBTLiBHLjwvYXV0aG9yPjxhdXRob3I+TWF0c2Fjb3MsIEQuPC9h

dXRob3I+PGF1dGhvcj5TaW0sIFAuPC9hdXRob3I+PGF1dGhvcj5DbHVuZSwgRS48L2F1dGhvcj48

YXV0aG9yPk11c3RhZmEsIFQuPC9hdXRob3I+PGF1dGhvcj5MZWUsIEouPC9hdXRob3I+PGF1dGhv

cj5NZW5kZWxzb2huLCBGLiBBLjwvYXV0aG9yPjxhdXRob3I+U2ltcHNvbiwgUi4gSi48L2F1dGhv

cj48YXV0aG9yPkNvbm5vbGx5LCBMLiBNLjwvYXV0aG9yPjxhdXRob3I+Q2hhaSwgUy4gWS48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Ib3dhcmQgRmxvcmV5

IEluc3RpdHV0ZSBvZiBFeHBlcmltZW50YWwgUGh5c2lvbG9neSBhbmQgTWVkaWNpbmUsIFVuaXZl

cnNpdHkgb2YgTWVsYm91cm5lLCBWaWN0b3JpYSAzMDEwLCBBdXN0cmFsaWEuPC9hdXRoLWFkZHJl

c3M+PHRpdGxlcz48dGl0bGU+RXZpZGVuY2UgdGhhdCB0aGUgYW5naW90ZW5zaW4gSVYgKEFUKDQp

KSByZWNlcHRvciBpcyB0aGUgZW56eW1lIGluc3VsaW4tcmVndWxhdGVkIGFtaW5vcGVwdGlkYXNl

PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogQmlvbCBDaGVtPC9zZWNvbmRhcnktdGl0bGU+PC90

aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBCaW9sIENoZW08L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxwYWdlcz40ODYyMy02PC9wYWdlcz48dm9sdW1lPjI3Njwvdm9sdW1lPjxudW1i

ZXI+NTI8L251bWJlcj48ZWRpdGlvbj4yMDAxLzExLzE1PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5

d29yZD5BbWlub3BlcHRpZGFzZXMvYW50YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9ycy9nZW5ldGlj

cy9pc29sYXRpb24gJmFtcDs8L2tleXdvcmQ+PGtleXdvcmQ+cHVyaWZpY2F0aW9uLyptZXRhYm9s

aXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFuZ2lvdGVuc2luIElJLyphbmFsb2dzICZhbXA7IGRlcml2

YXRpdmVzL2NoZW1pc3RyeS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNp

biBSZWNlcHRvciBBbnRhZ29uaXN0czwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3Jk

PjxrZXl3b3JkPkF1dG9yYWRpb2dyYXBoeTwva2V5d29yZD48a2V5d29yZD5CcmFpbi9jeXRvbG9n

eS9lbnp5bW9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBMaW5lPC9rZXl3

b3JkPjxrZXl3b3JkPkN5c3RpbnlsIEFtaW5vcGVwdGlkYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkhl

bW9nbG9iaW5zL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxr

ZXl3b3JkPkltbXVub2hpc3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkluIFNpdHUgSHli

cmlkaXphdGlvbjwva2V5d29yZD48a2V5d29yZD5Jb2RpbmUgUmFkaW9pc290b3Blcy9jaGVtaXN0

cnkvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1p

Y2UsIEluYnJlZCBDNTdCTDwva2V5d29yZD48a2V5d29yZD5QZXB0aWRlIEZyYWdtZW50cy9tZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlJhZGlvbGlnYW5kIEFzc2F5PC9rZXl3b3JkPjxrZXl3

b3JkPlJlY2VwdG9ycywgQW5naW90ZW5zaW4vZ2VuZXRpY3MvaXNvbGF0aW9uICZhbXA7IHB1cmlm

aWNhdGlvbi8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5SZWNvbWJpbmFudCBGdXNpb24g

UHJvdGVpbnMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5UcmFuc2ZlY3Rpb248L2tleXdv

cmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkRl

YyAyODwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMjEtOTI1OCAoUHJpbnQpJiN4

RDswMDIxLTkyNTggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjExNzA3NDI3PC9hY2Nl

c3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5u

aWguZ292L3B1Ym1lZC8xMTcwNzQyNzwvdXJsPjx1cmw+aHR0cDovL3d3dy5qYmMub3JnL2NvbnRl

bnQvMjc2LzUyLzQ4NjIzLmZ1bGwucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVj

dHJvbmljLXJlc291cmNlLW51bT4xMC4xMDc0L2piYy5DMTAwNTEyMjAwPC9lbGVjdHJvbmljLXJl

c291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGJpc3RvbjwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+

PFJlY051bT4xMjAxPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+NDM0PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTIwMTwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2

ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMzMzA0NDg1Ij4xMjAxPC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5BbGJpc3RvbiwgQS4gTC48L2F1dGhv

cj48YXV0aG9yPk1jRG93YWxsLCBTLiBHLjwvYXV0aG9yPjxhdXRob3I+TWF0c2Fjb3MsIEQuPC9h

dXRob3I+PGF1dGhvcj5TaW0sIFAuPC9hdXRob3I+PGF1dGhvcj5DbHVuZSwgRS48L2F1dGhvcj48

YXV0aG9yPk11c3RhZmEsIFQuPC9hdXRob3I+PGF1dGhvcj5MZWUsIEouPC9hdXRob3I+PGF1dGhv

cj5NZW5kZWxzb2huLCBGLiBBLjwvYXV0aG9yPjxhdXRob3I+U2ltcHNvbiwgUi4gSi48L2F1dGhv

cj48YXV0aG9yPkNvbm5vbGx5LCBMLiBNLjwvYXV0aG9yPjxhdXRob3I+Q2hhaSwgUy4gWS48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Ib3dhcmQgRmxvcmV5

IEluc3RpdHV0ZSBvZiBFeHBlcmltZW50YWwgUGh5c2lvbG9neSBhbmQgTWVkaWNpbmUsIFVuaXZl

cnNpdHkgb2YgTWVsYm91cm5lLCBWaWN0b3JpYSAzMDEwLCBBdXN0cmFsaWEuPC9hdXRoLWFkZHJl

c3M+PHRpdGxlcz48dGl0bGU+RXZpZGVuY2UgdGhhdCB0aGUgYW5naW90ZW5zaW4gSVYgKEFUKDQp

KSByZWNlcHRvciBpcyB0aGUgZW56eW1lIGluc3VsaW4tcmVndWxhdGVkIGFtaW5vcGVwdGlkYXNl

PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogQmlvbCBDaGVtPC9zZWNvbmRhcnktdGl0bGU+PC90

aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBCaW9sIENoZW08L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxwYWdlcz40ODYyMy02PC9wYWdlcz48dm9sdW1lPjI3Njwvdm9sdW1lPjxudW1i

ZXI+NTI8L251bWJlcj48ZWRpdGlvbj4yMDAxLzExLzE1PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5

d29yZD5BbWlub3BlcHRpZGFzZXMvYW50YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9ycy9nZW5ldGlj

cy9pc29sYXRpb24gJmFtcDs8L2tleXdvcmQ+PGtleXdvcmQ+cHVyaWZpY2F0aW9uLyptZXRhYm9s

aXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFuZ2lvdGVuc2luIElJLyphbmFsb2dzICZhbXA7IGRlcml2

YXRpdmVzL2NoZW1pc3RyeS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5Bbmdpb3RlbnNp

biBSZWNlcHRvciBBbnRhZ29uaXN0czwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3Jk

PjxrZXl3b3JkPkF1dG9yYWRpb2dyYXBoeTwva2V5d29yZD48a2V5d29yZD5CcmFpbi9jeXRvbG9n

eS9lbnp5bW9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBMaW5lPC9rZXl3

b3JkPjxrZXl3b3JkPkN5c3RpbnlsIEFtaW5vcGVwdGlkYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkhl

bW9nbG9iaW5zL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxr

ZXl3b3JkPkltbXVub2hpc3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkluIFNpdHUgSHli

cmlkaXphdGlvbjwva2V5d29yZD48a2V5d29yZD5Jb2RpbmUgUmFkaW9pc290b3Blcy9jaGVtaXN0

cnkvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1p

Y2UsIEluYnJlZCBDNTdCTDwva2V5d29yZD48a2V5d29yZD5QZXB0aWRlIEZyYWdtZW50cy9tZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlJhZGlvbGlnYW5kIEFzc2F5PC9rZXl3b3JkPjxrZXl3

b3JkPlJlY2VwdG9ycywgQW5naW90ZW5zaW4vZ2VuZXRpY3MvaXNvbGF0aW9uICZhbXA7IHB1cmlm

aWNhdGlvbi8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5SZWNvbWJpbmFudCBGdXNpb24g

UHJvdGVpbnMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5UcmFuc2ZlY3Rpb248L2tleXdv

cmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkRl

YyAyODwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMjEtOTI1OCAoUHJpbnQpJiN4

RDswMDIxLTkyNTggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjExNzA3NDI3PC9hY2Nl

c3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5u

aWguZ292L3B1Ym1lZC8xMTcwNzQyNzwvdXJsPjx1cmw+aHR0cDovL3d3dy5qYmMub3JnL2NvbnRl

bnQvMjc2LzUyLzQ4NjIzLmZ1bGwucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVj

dHJvbmljLXJlc291cmNlLW51bT4xMC4xMDc0L2piYy5DMTAwNTEyMjAwPC9lbGVjdHJvbmljLXJl

c291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 434, but under high 27-OH levels, AP-N degrades AngIV allowing increased IRAP activity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Jc21haWw8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS

ZWNOdW0+MjYzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDI4PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjYzPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzEiPjI2Mzwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SXNtYWlsLCBNLiBBLjwvYXV0aG9yPjxhdXRo

b3I+TWF0ZW9zLCBMLjwvYXV0aG9yPjxhdXRob3I+TWFpb2xpLCBTLjwvYXV0aG9yPjxhdXRob3I+

TWVyaW5vLVNlcnJhaXMsIFAuPC9hdXRob3I+PGF1dGhvcj5BbGksIFouPC9hdXRob3I+PGF1dGhv

cj5Mb2RlaXJvLCBNLjwvYXV0aG9yPjxhdXRob3I+V2VzdG1hbiwgRS48L2F1dGhvcj48YXV0aG9y

PkxlaXRlcnNkb3JmLCBFLjwvYXV0aG9yPjxhdXRob3I+R3VseWFzLCBCLjwvYXV0aG9yPjxhdXRo

b3I+T2xvZi1XYWhsdW5kLCBMLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48

YXV0aG9yPlNhdml0Y2hldmEsIEkuPC9hdXRob3I+PGF1dGhvcj5Cam9ya2hlbSwgSS48L2F1dGhv

cj48YXV0aG9yPkNlZGF6by1NaW5ndWV6LCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0cmljcywgQ2VudGVyIGZv

ciBBbHpoZWltZXIgUmVzZWFyY2gsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNj

aWVuY2VzLCBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCAxNDEgODYgU3RvY2to

b2xtLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBDbGluaWNhbCBDaGVtaXN0cnksIERlcGFydG1l

bnQgb2YgTGFib3JhdG9yeSBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFs

LCAxNDEgODYgSHVkZGluZ2UsIFN3ZWRlbi4mI3hEO0RpdmlzaW9uIG9mIENsaW5pY2FsIEdlcmlh

dHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5ldXJv

YmlvbG9neSwgQ2FyZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0dXRl

dCwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7Q2VudGVyIGZvciBSZXNlYXJjaCwgUHJl

dmVudGlvbiwgYW5kIFRyZWF0bWVudCBvZiBBdGhlcm9zY2xlcm9zaXMsIEhhZGFzc2FoIEhlYnJl

dyBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBKZXJ1c2FsZW0gOTExMjAsIElzcmFlbC4mI3hE

O0NlbnRyZSBmb3IgUHN5Y2hpYXRyeSBSZXNlYXJjaCwgRGVwYXJ0bWVudCBvZiBDbGluaWNhbCBO

ZXVyb3NjaWVuY2UsIEthcm9saW5za2EgSW5zdGl0dXRldCwgMTcxIDc3IFN0b2NraG9sbSwgU3dl

ZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBSYWRpb2xvZ3ksIEthcm9saW5za2EgVW5pdmVyc2l0eSBI

b3NwaXRhbCwgMTQxIDg2IEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBOZXVyb2dl

cmlhdHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5l

dXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0

dXRldCwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuIEFuZ2VsLkNlZGF6by1NaW5ndWV6QGtpLnNl

LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPjI3LUh5ZHJveHljaG9sZXN0ZXJvbCBpbXBh

aXJzIG5ldXJvbmFsIGdsdWNvc2UgdXB0YWtlIHRocm91Z2ggYW4gSVJBUC9HTFVUNCBzeXN0ZW0g

ZHlzcmVndWxhdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEV4cCBNZWQ8L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGFnZXM+Njk5LTcxNzwvcGFnZXM+PHZvbHVtZT4yMTQ8L3ZvbHVt

ZT48bnVtYmVyPjM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5naW90ZW5zaW4gSUkvYW5h

bG9ncyAmYW1wOyBkZXJpdmF0aXZlcy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW5p

bWFsczwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0YW5ldHJpb2wgMjYtTW9ub294eWdlbmFzZS9w

aHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sL21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+Q3lzdGlueWwgQW1pbm9wZXB0aWRhc2UvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+R2x1Y29zZS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5HbHVjb3NlIFRy

YW5zcG9ydGVyIFR5cGUgNC8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tl

eXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy8qcGhhcm1hY29sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkxpdmVyIFggUmVjZXB0b3JzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdv

cmQ+TmV1cm9ucy8qbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWFyIDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48aXNibj4xNTQwLTk1MzggKEVsZWN0cm9uaWMpJiN4RDswMDIyLTEwMDcgKExpbmtpbmcpPC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjI4MjEzNTEyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI4MjEzNTEyPC91

cmw+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3BtYy9hcnRpY2xlcy9QTUM1MzM5

NjY5L3BkZi9KRU1fMjAxNjA1MzQucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0

b20yPlBNQzUzMzk2Njk8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwODQv

amVtLjIwMTYwNTM0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Jc21haWw8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS

ZWNOdW0+MjYzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDI4PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjYzPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzEiPjI2Mzwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SXNtYWlsLCBNLiBBLjwvYXV0aG9yPjxhdXRo

b3I+TWF0ZW9zLCBMLjwvYXV0aG9yPjxhdXRob3I+TWFpb2xpLCBTLjwvYXV0aG9yPjxhdXRob3I+

TWVyaW5vLVNlcnJhaXMsIFAuPC9hdXRob3I+PGF1dGhvcj5BbGksIFouPC9hdXRob3I+PGF1dGhv

cj5Mb2RlaXJvLCBNLjwvYXV0aG9yPjxhdXRob3I+V2VzdG1hbiwgRS48L2F1dGhvcj48YXV0aG9y

PkxlaXRlcnNkb3JmLCBFLjwvYXV0aG9yPjxhdXRob3I+R3VseWFzLCBCLjwvYXV0aG9yPjxhdXRo

b3I+T2xvZi1XYWhsdW5kLCBMLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48

YXV0aG9yPlNhdml0Y2hldmEsIEkuPC9hdXRob3I+PGF1dGhvcj5Cam9ya2hlbSwgSS48L2F1dGhv

cj48YXV0aG9yPkNlZGF6by1NaW5ndWV6LCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0cmljcywgQ2VudGVyIGZv

ciBBbHpoZWltZXIgUmVzZWFyY2gsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNj

aWVuY2VzLCBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCAxNDEgODYgU3RvY2to

b2xtLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBDbGluaWNhbCBDaGVtaXN0cnksIERlcGFydG1l

bnQgb2YgTGFib3JhdG9yeSBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFs

LCAxNDEgODYgSHVkZGluZ2UsIFN3ZWRlbi4mI3hEO0RpdmlzaW9uIG9mIENsaW5pY2FsIEdlcmlh

dHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5ldXJv

YmlvbG9neSwgQ2FyZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0dXRl

dCwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7Q2VudGVyIGZvciBSZXNlYXJjaCwgUHJl

dmVudGlvbiwgYW5kIFRyZWF0bWVudCBvZiBBdGhlcm9zY2xlcm9zaXMsIEhhZGFzc2FoIEhlYnJl

dyBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBKZXJ1c2FsZW0gOTExMjAsIElzcmFlbC4mI3hE

O0NlbnRyZSBmb3IgUHN5Y2hpYXRyeSBSZXNlYXJjaCwgRGVwYXJ0bWVudCBvZiBDbGluaWNhbCBO

ZXVyb3NjaWVuY2UsIEthcm9saW5za2EgSW5zdGl0dXRldCwgMTcxIDc3IFN0b2NraG9sbSwgU3dl

ZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBSYWRpb2xvZ3ksIEthcm9saW5za2EgVW5pdmVyc2l0eSBI

b3NwaXRhbCwgMTQxIDg2IEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBOZXVyb2dl

cmlhdHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5l

dXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0

dXRldCwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuIEFuZ2VsLkNlZGF6by1NaW5ndWV6QGtpLnNl

LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPjI3LUh5ZHJveHljaG9sZXN0ZXJvbCBpbXBh

aXJzIG5ldXJvbmFsIGdsdWNvc2UgdXB0YWtlIHRocm91Z2ggYW4gSVJBUC9HTFVUNCBzeXN0ZW0g

ZHlzcmVndWxhdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEV4cCBNZWQ8L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGFnZXM+Njk5LTcxNzwvcGFnZXM+PHZvbHVtZT4yMTQ8L3ZvbHVt

ZT48bnVtYmVyPjM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5naW90ZW5zaW4gSUkvYW5h

bG9ncyAmYW1wOyBkZXJpdmF0aXZlcy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW5p

bWFsczwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0YW5ldHJpb2wgMjYtTW9ub294eWdlbmFzZS9w

aHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sL21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+Q3lzdGlueWwgQW1pbm9wZXB0aWRhc2UvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+R2x1Y29zZS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5HbHVjb3NlIFRy

YW5zcG9ydGVyIFR5cGUgNC8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tl

eXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy8qcGhhcm1hY29sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkxpdmVyIFggUmVjZXB0b3JzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdv

cmQ+TmV1cm9ucy8qbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWFyIDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48aXNibj4xNTQwLTk1MzggKEVsZWN0cm9uaWMpJiN4RDswMDIyLTEwMDcgKExpbmtpbmcpPC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjI4MjEzNTEyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI4MjEzNTEyPC91

cmw+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3BtYy9hcnRpY2xlcy9QTUM1MzM5

NjY5L3BkZi9KRU1fMjAxNjA1MzQucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0

b20yPlBNQzUzMzk2Njk8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwODQv

amVtLjIwMTYwNTM0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPn==

ADDIN EN.CITE.DATA 428. Elevated 27-OH levels not only increase IRAP activity but also decrease the levels of the glucose transporter GLUT4, which is regulated negatively by AngIII. In CYP27TG brains, Ang III is elevated due to increased AP-A activity (converting AngII to AngIII), which in turn downregulates GLUT4 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Jc21haWw8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS

ZWNOdW0+MjYzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDI4PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjYzPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzEiPjI2Mzwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SXNtYWlsLCBNLiBBLjwvYXV0aG9yPjxhdXRo

b3I+TWF0ZW9zLCBMLjwvYXV0aG9yPjxhdXRob3I+TWFpb2xpLCBTLjwvYXV0aG9yPjxhdXRob3I+

TWVyaW5vLVNlcnJhaXMsIFAuPC9hdXRob3I+PGF1dGhvcj5BbGksIFouPC9hdXRob3I+PGF1dGhv

cj5Mb2RlaXJvLCBNLjwvYXV0aG9yPjxhdXRob3I+V2VzdG1hbiwgRS48L2F1dGhvcj48YXV0aG9y

PkxlaXRlcnNkb3JmLCBFLjwvYXV0aG9yPjxhdXRob3I+R3VseWFzLCBCLjwvYXV0aG9yPjxhdXRo

b3I+T2xvZi1XYWhsdW5kLCBMLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48

YXV0aG9yPlNhdml0Y2hldmEsIEkuPC9hdXRob3I+PGF1dGhvcj5Cam9ya2hlbSwgSS48L2F1dGhv

cj48YXV0aG9yPkNlZGF6by1NaW5ndWV6LCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0cmljcywgQ2VudGVyIGZv

ciBBbHpoZWltZXIgUmVzZWFyY2gsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNj

aWVuY2VzLCBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCAxNDEgODYgU3RvY2to

b2xtLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBDbGluaWNhbCBDaGVtaXN0cnksIERlcGFydG1l

bnQgb2YgTGFib3JhdG9yeSBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFs

LCAxNDEgODYgSHVkZGluZ2UsIFN3ZWRlbi4mI3hEO0RpdmlzaW9uIG9mIENsaW5pY2FsIEdlcmlh

dHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5ldXJv

YmlvbG9neSwgQ2FyZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0dXRl

dCwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7Q2VudGVyIGZvciBSZXNlYXJjaCwgUHJl

dmVudGlvbiwgYW5kIFRyZWF0bWVudCBvZiBBdGhlcm9zY2xlcm9zaXMsIEhhZGFzc2FoIEhlYnJl

dyBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBKZXJ1c2FsZW0gOTExMjAsIElzcmFlbC4mI3hE

O0NlbnRyZSBmb3IgUHN5Y2hpYXRyeSBSZXNlYXJjaCwgRGVwYXJ0bWVudCBvZiBDbGluaWNhbCBO

ZXVyb3NjaWVuY2UsIEthcm9saW5za2EgSW5zdGl0dXRldCwgMTcxIDc3IFN0b2NraG9sbSwgU3dl

ZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBSYWRpb2xvZ3ksIEthcm9saW5za2EgVW5pdmVyc2l0eSBI

b3NwaXRhbCwgMTQxIDg2IEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBOZXVyb2dl

cmlhdHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5l

dXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0

dXRldCwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuIEFuZ2VsLkNlZGF6by1NaW5ndWV6QGtpLnNl

LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPjI3LUh5ZHJveHljaG9sZXN0ZXJvbCBpbXBh

aXJzIG5ldXJvbmFsIGdsdWNvc2UgdXB0YWtlIHRocm91Z2ggYW4gSVJBUC9HTFVUNCBzeXN0ZW0g

ZHlzcmVndWxhdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEV4cCBNZWQ8L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGFnZXM+Njk5LTcxNzwvcGFnZXM+PHZvbHVtZT4yMTQ8L3ZvbHVt

ZT48bnVtYmVyPjM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5naW90ZW5zaW4gSUkvYW5h

bG9ncyAmYW1wOyBkZXJpdmF0aXZlcy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW5p

bWFsczwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0YW5ldHJpb2wgMjYtTW9ub294eWdlbmFzZS9w

aHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sL21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+Q3lzdGlueWwgQW1pbm9wZXB0aWRhc2UvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+R2x1Y29zZS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5HbHVjb3NlIFRy

YW5zcG9ydGVyIFR5cGUgNC8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tl

eXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy8qcGhhcm1hY29sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkxpdmVyIFggUmVjZXB0b3JzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdv

cmQ+TmV1cm9ucy8qbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWFyIDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48aXNibj4xNTQwLTk1MzggKEVsZWN0cm9uaWMpJiN4RDswMDIyLTEwMDcgKExpbmtpbmcpPC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjI4MjEzNTEyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI4MjEzNTEyPC91

cmw+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3BtYy9hcnRpY2xlcy9QTUM1MzM5

NjY5L3BkZi9KRU1fMjAxNjA1MzQucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0

b20yPlBNQzUzMzk2Njk8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwODQv

amVtLjIwMTYwNTM0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Jc21haWw8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS

ZWNOdW0+MjYzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDI4PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjYzPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzEiPjI2Mzwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SXNtYWlsLCBNLiBBLjwvYXV0aG9yPjxhdXRo

b3I+TWF0ZW9zLCBMLjwvYXV0aG9yPjxhdXRob3I+TWFpb2xpLCBTLjwvYXV0aG9yPjxhdXRob3I+

TWVyaW5vLVNlcnJhaXMsIFAuPC9hdXRob3I+PGF1dGhvcj5BbGksIFouPC9hdXRob3I+PGF1dGhv

cj5Mb2RlaXJvLCBNLjwvYXV0aG9yPjxhdXRob3I+V2VzdG1hbiwgRS48L2F1dGhvcj48YXV0aG9y

PkxlaXRlcnNkb3JmLCBFLjwvYXV0aG9yPjxhdXRob3I+R3VseWFzLCBCLjwvYXV0aG9yPjxhdXRo

b3I+T2xvZi1XYWhsdW5kLCBMLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48

YXV0aG9yPlNhdml0Y2hldmEsIEkuPC9hdXRob3I+PGF1dGhvcj5Cam9ya2hlbSwgSS48L2F1dGhv

cj48YXV0aG9yPkNlZGF6by1NaW5ndWV6LCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0cmljcywgQ2VudGVyIGZv

ciBBbHpoZWltZXIgUmVzZWFyY2gsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNj

aWVuY2VzLCBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCAxNDEgODYgU3RvY2to

b2xtLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBDbGluaWNhbCBDaGVtaXN0cnksIERlcGFydG1l

bnQgb2YgTGFib3JhdG9yeSBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFs

LCAxNDEgODYgSHVkZGluZ2UsIFN3ZWRlbi4mI3hEO0RpdmlzaW9uIG9mIENsaW5pY2FsIEdlcmlh

dHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5ldXJv

YmlvbG9neSwgQ2FyZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0dXRl

dCwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7Q2VudGVyIGZvciBSZXNlYXJjaCwgUHJl

dmVudGlvbiwgYW5kIFRyZWF0bWVudCBvZiBBdGhlcm9zY2xlcm9zaXMsIEhhZGFzc2FoIEhlYnJl

dyBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBKZXJ1c2FsZW0gOTExMjAsIElzcmFlbC4mI3hE

O0NlbnRyZSBmb3IgUHN5Y2hpYXRyeSBSZXNlYXJjaCwgRGVwYXJ0bWVudCBvZiBDbGluaWNhbCBO

ZXVyb3NjaWVuY2UsIEthcm9saW5za2EgSW5zdGl0dXRldCwgMTcxIDc3IFN0b2NraG9sbSwgU3dl

ZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBSYWRpb2xvZ3ksIEthcm9saW5za2EgVW5pdmVyc2l0eSBI

b3NwaXRhbCwgMTQxIDg2IEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBOZXVyb2dl

cmlhdHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5l

dXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0

dXRldCwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuIEFuZ2VsLkNlZGF6by1NaW5ndWV6QGtpLnNl

LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPjI3LUh5ZHJveHljaG9sZXN0ZXJvbCBpbXBh

aXJzIG5ldXJvbmFsIGdsdWNvc2UgdXB0YWtlIHRocm91Z2ggYW4gSVJBUC9HTFVUNCBzeXN0ZW0g

ZHlzcmVndWxhdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEV4cCBNZWQ8L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGFnZXM+Njk5LTcxNzwvcGFnZXM+PHZvbHVtZT4yMTQ8L3ZvbHVt

ZT48bnVtYmVyPjM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5naW90ZW5zaW4gSUkvYW5h

bG9ncyAmYW1wOyBkZXJpdmF0aXZlcy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW5p

bWFsczwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0YW5ldHJpb2wgMjYtTW9ub294eWdlbmFzZS9w

aHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sL21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+Q3lzdGlueWwgQW1pbm9wZXB0aWRhc2UvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+R2x1Y29zZS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5HbHVjb3NlIFRy

YW5zcG9ydGVyIFR5cGUgNC8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tl

eXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy8qcGhhcm1hY29sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkxpdmVyIFggUmVjZXB0b3JzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdv

cmQ+TmV1cm9ucy8qbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWFyIDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48aXNibj4xNTQwLTk1MzggKEVsZWN0cm9uaWMpJiN4RDswMDIyLTEwMDcgKExpbmtpbmcpPC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjI4MjEzNTEyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI4MjEzNTEyPC91

cmw+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3BtYy9hcnRpY2xlcy9QTUM1MzM5

NjY5L3BkZi9KRU1fMjAxNjA1MzQucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0

b20yPlBNQzUzMzk2Njk8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwODQv

amVtLjIwMTYwNTM0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPn==

ADDIN EN.CITE.DATA 428. Together with increase IRAP activity, GLUT4 downregulation leads to reduced glucose uptake by neurons (Fig. 8). These mechanisms have been confirmed in vitro by knock-down experiments and they explain the alterations observed in patients with altered RAS markers in the CSF. Yet, more research is needed to clarify if alterations in the brain RAS system in humans could also influence glucose uptake in the brain by alteration on the blood flow in the neurovascular unit discussed elsewhere in this review. Figure 8. Metabolic effects of elevated 27-OH in the brain. Elevated cholesterol in the periphery cannot cross the BBB. CYP27A1 converts peripheral cholesterol to 27-OH, which is able to cross the BBB into the brain and inside cells. In neurons, increased levels of 27-OH dysregulate the renin-angiotensin system (RAS), by acting directly or indirectly over the glucose transporter GLUT4 and the insulin-regulated adaptor protein (IRAP). This leads to a decreased glucose uptake and reduces the metabolic activity of neurons, contributing to cognitive decline. Moreover, insulin aggregation also decreases glucose uptake. Insulin aggregation reduces dramatically its signaling and these effects are not fully understood. A link between RAS system and insulin aggregation also remains unknown, but it could involve IRAP signaling, Ang-IV derived peptides (produced by AP-N and AP-A activity), or through reduction of blood flow in brain vessels. Insulin aggregation in AD The reduced glucose uptake mediated by high 27-OH levels might pose a link between cholesterol and glucose metabolism alterations as important players in the development of AD. We recently reported that insulin aggregates and accumulates in neurons with hyperphosphorylated Tau from humans PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb2RyaWd1ZXotUm9kcmlndWV6PC9BdXRob3I+PFllYXI+

MjAxNzwvWWVhcj48UmVjTnVtPjI2MTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0i

c3VwZXJzY3JpcHQiPjI4ODwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVy

PjI2MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTBy

eDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMxNzc1MjcxIj4y

NjE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x

NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlJvZHJpZ3Vlei1Sb2Ry

aWd1ZXosIFAuPC9hdXRob3I+PGF1dGhvcj5TYW5kZWJyaW5nLU1hdHRvbiwgQS48L2F1dGhvcj48

YXV0aG9yPk1lcmluby1TZXJyYWlzLCBQLjwvYXV0aG9yPjxhdXRob3I+UGFycmFkby1GZXJuYW5k

ZXosIEMuPC9hdXRob3I+PGF1dGhvcj5SYWJhbm8sIEEuPC9hdXRob3I+PGF1dGhvcj5XaW5ibGFk

LCBCLjwvYXV0aG9yPjxhdXRob3I+QXZpbGEsIEouPC9hdXRob3I+PGF1dGhvcj5GZXJyZXIsIEku

PC9hdXRob3I+PGF1dGhvcj5DZWRhem8tTWluZ3VleiwgQS48L2F1dGhvcj48L2F1dGhvcnM+PC9j

b250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5LYXJvbGluc2thIEluc3RpdHV0ZXQsIENlbnRlciBm

b3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSBDYXJlIFNj

aWVuY2VzIGFuZCBTb2NpZXR5LCBEaXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIFN0b2NraG9s

bSwgU3dlZGVuLiYjeEQ7TmV0d29ya2luZyBSZXNlYXJjaCBDZW50ZXIgb24gTmV1cm9kZWdlbmVy

YXRpdmUgRGlzZWFzZXMgKENJQkVSTkVEKSwgSW5zdGl0dXRvIGRlIFNhbHVkIENhcmxvcyBJSUks

IFNwYWluLiYjeEQ7RnVuZGFjaW9uIENJRU4sIE1hZHJpZCwgU3BhaW4uJiN4RDtDZW50cm8gZGUg

QmlvbG9naWEgTW9sZWN1bGFyIFNldmVybyBPY2hvYSAoQ1NJQy1VQU0pLCBNYWRyaWQsIFNwYWlu

LiYjeEQ7SW5zdGl0dXQgZGUgTmV1cm9wYXRvbG9naWEsIFNlcnZlaSBBbmF0b21pYSBQYXRvbG9n

aWNhLCBJRElCRUxMLUhvc3BpdGFsIFVuaXZlcnNpdGFyaSBkZSBCZWxsdml0Z2UsIFVuaXZlcnNp

dGF0IGRlIEJhcmNlbG9uYSwgSG9zcGl0YWxldCBkZSBMbG9icmVnYXQsIEJhcmNlbG9uYSwgU3Bh

aW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGF1IGh5cGVycGhvc3Bob3J5bGF0aW9u

IGluZHVjZXMgb2xpZ29tZXJpYyBpbnN1bGluIGFjY3VtdWxhdGlvbiBhbmQgaW5zdWxpbiByZXNp

c3RhbmNlIGluIG5ldXJvbnM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QnJhaW48L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5CcmFpbjwvZnVsbC10aXRs

ZT48L3BlcmlvZGljYWw+PHBhZ2VzPjMyNjktMzI4NTwvcGFnZXM+PHZvbHVtZT4xNDA8L3ZvbHVt

ZT48bnVtYmVyPjEyPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vh

c2UvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKm1ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5

d29yZD5JbnN1bGluLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPipJbnN1bGluIFJlc2lz

dGFuY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdl

ZDwva2V5d29yZD48a2V5d29yZD5OZXVyb25zLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

PlBob3NwaG9yeWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5TdXByYW51Y2xlYXIgUGFsc3ksIFBy

b2dyZXNzaXZlL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5zLyptZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29y

ZD48a2V5d29yZD5pbnN1bGluPC9rZXl3b3JkPjxrZXl3b3JkPm5ldXJvZmlicmlsbGFyeSB0YW5n

bGVzPC9rZXl3b3JkPjxrZXl3b3JkPm9saWdvbWVyczwva2V5d29yZD48a2V5d29yZD50YXU8L2tl

eXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRl

PkRlYyAxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ2MC0yMTU2IChFbGVjdHJv

bmljKSYjeEQ7MDAwNi04OTUwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yOTA1Mzc4

NjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3B1Ym1lZC8yOTA1Mzc4NjwvdXJsPjx1cmw+aHR0cHM6Ly93YXRlcm1hcmsu

c2lsdmVyY2hhaXIuY29tL2F3eDI1Ni5wZGY/dG9rZW49QVFFQ0FIaTIwOEJFNDlPb2FuOWtraFdf

RXJjeTdEbTNaTF85Q2YzcWZLQWM0ODV5c2dBQUFjY3dnZ0hEQmdrcWhraUc5dzBCQndhZ2dnRzBN

SUlCc0FJQkFEQ0NBYWtHQ1NxR1NJYjNEUUVIQVRBZUJnbGdoa2dCWlFNRUFTNHdFUVFNTHFKVXVO

OG5wT2RCSmdDREFnRVFnSUlCZW1LcEM5cEppbGRubjlNbmpVM2pZT21CLURWYnlOeHA3T3JlcGhQ

WWJUMktHRG5BcG5jOGxHd0ROU1loNUh3TmVsNnVWaHhSM3NneUJQeFlnNVR1VE9DOHZLZzd3Tngw

OTlpYmpmWl9FV3kzc3Rlend0VzRjSWpJa2N1ZE9zNXE3U3E5eWlQa3ZaRXhzUTZxMHkxc05GVlkx

bkh1WDFSdE5JbG55QkVSMDlFZG44LUtHWnJlN2E3WjdkeHZRcEI1a0ZsNmx3TGZacURBNzJTcXhV

cFF2N0lYNFVZVTFSLWo5ZFpUdGxGMDFpQ0lyb3lURllUVnVrSTN4eWNCOG1tYUtqVWp2QWRnUzJf

R25NYWJTcVVaUWR5NDNnSk5Jc2VZQlpJUWVuTEhvSzBGbFZhc1hscDZTVE9BcHlOOElHeUUwN0Fi

OHZySnVYOU1DYnA3QU1QY3dNUzRpY2x5OF9uNmJpUDJUS0h4cnZHYnE3UGpDQmFYcUJKMTdmS3JO

QlN2RWtYM1NMRFlZVzhZN1poVFhyVHRGZFUxdUkwT2NfRGQ3TzBMcTVtNnBZd3VKeklLYTlhLWFn

M29PNTNsT282bm9HLTJ1NTVWWjQtREFQVzhtNkhMM2J1VDg5cnp5M0RnT0JQMFU4WnY2dWMwbl9q

cy1nS3pHbkhud1E8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjEwOTMvYnJhaW4vYXd4MjU2PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3Jl

Y29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb2RyaWd1ZXotUm9kcmlndWV6PC9BdXRob3I+PFllYXI+

MjAxNzwvWWVhcj48UmVjTnVtPjI2MTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0i

c3VwZXJzY3JpcHQiPjI4ODwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVy

PjI2MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTBy

eDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMxNzc1MjcxIj4y

NjE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x

NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlJvZHJpZ3Vlei1Sb2Ry

aWd1ZXosIFAuPC9hdXRob3I+PGF1dGhvcj5TYW5kZWJyaW5nLU1hdHRvbiwgQS48L2F1dGhvcj48

YXV0aG9yPk1lcmluby1TZXJyYWlzLCBQLjwvYXV0aG9yPjxhdXRob3I+UGFycmFkby1GZXJuYW5k

ZXosIEMuPC9hdXRob3I+PGF1dGhvcj5SYWJhbm8sIEEuPC9hdXRob3I+PGF1dGhvcj5XaW5ibGFk

LCBCLjwvYXV0aG9yPjxhdXRob3I+QXZpbGEsIEouPC9hdXRob3I+PGF1dGhvcj5GZXJyZXIsIEku

PC9hdXRob3I+PGF1dGhvcj5DZWRhem8tTWluZ3VleiwgQS48L2F1dGhvcj48L2F1dGhvcnM+PC9j

b250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5LYXJvbGluc2thIEluc3RpdHV0ZXQsIENlbnRlciBm

b3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSBDYXJlIFNj

aWVuY2VzIGFuZCBTb2NpZXR5LCBEaXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIFN0b2NraG9s

bSwgU3dlZGVuLiYjeEQ7TmV0d29ya2luZyBSZXNlYXJjaCBDZW50ZXIgb24gTmV1cm9kZWdlbmVy

YXRpdmUgRGlzZWFzZXMgKENJQkVSTkVEKSwgSW5zdGl0dXRvIGRlIFNhbHVkIENhcmxvcyBJSUks

IFNwYWluLiYjeEQ7RnVuZGFjaW9uIENJRU4sIE1hZHJpZCwgU3BhaW4uJiN4RDtDZW50cm8gZGUg

QmlvbG9naWEgTW9sZWN1bGFyIFNldmVybyBPY2hvYSAoQ1NJQy1VQU0pLCBNYWRyaWQsIFNwYWlu

LiYjeEQ7SW5zdGl0dXQgZGUgTmV1cm9wYXRvbG9naWEsIFNlcnZlaSBBbmF0b21pYSBQYXRvbG9n

aWNhLCBJRElCRUxMLUhvc3BpdGFsIFVuaXZlcnNpdGFyaSBkZSBCZWxsdml0Z2UsIFVuaXZlcnNp

dGF0IGRlIEJhcmNlbG9uYSwgSG9zcGl0YWxldCBkZSBMbG9icmVnYXQsIEJhcmNlbG9uYSwgU3Bh

aW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGF1IGh5cGVycGhvc3Bob3J5bGF0aW9u

IGluZHVjZXMgb2xpZ29tZXJpYyBpbnN1bGluIGFjY3VtdWxhdGlvbiBhbmQgaW5zdWxpbiByZXNp

c3RhbmNlIGluIG5ldXJvbnM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QnJhaW48L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5CcmFpbjwvZnVsbC10aXRs

ZT48L3BlcmlvZGljYWw+PHBhZ2VzPjMyNjktMzI4NTwvcGFnZXM+PHZvbHVtZT4xNDA8L3ZvbHVt

ZT48bnVtYmVyPjEyPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vh

c2UvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKm1ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5

d29yZD5JbnN1bGluLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPipJbnN1bGluIFJlc2lz

dGFuY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdl

ZDwva2V5d29yZD48a2V5d29yZD5OZXVyb25zLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

PlBob3NwaG9yeWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5TdXByYW51Y2xlYXIgUGFsc3ksIFBy

b2dyZXNzaXZlL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5zLyptZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwva2V5d29y

ZD48a2V5d29yZD5pbnN1bGluPC9rZXl3b3JkPjxrZXl3b3JkPm5ldXJvZmlicmlsbGFyeSB0YW5n

bGVzPC9rZXl3b3JkPjxrZXl3b3JkPm9saWdvbWVyczwva2V5d29yZD48a2V5d29yZD50YXU8L2tl

eXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRl

PkRlYyAxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ2MC0yMTU2IChFbGVjdHJv

bmljKSYjeEQ7MDAwNi04OTUwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yOTA1Mzc4

NjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3B1Ym1lZC8yOTA1Mzc4NjwvdXJsPjx1cmw+aHR0cHM6Ly93YXRlcm1hcmsu

c2lsdmVyY2hhaXIuY29tL2F3eDI1Ni5wZGY/dG9rZW49QVFFQ0FIaTIwOEJFNDlPb2FuOWtraFdf

RXJjeTdEbTNaTF85Q2YzcWZLQWM0ODV5c2dBQUFjY3dnZ0hEQmdrcWhraUc5dzBCQndhZ2dnRzBN

SUlCc0FJQkFEQ0NBYWtHQ1NxR1NJYjNEUUVIQVRBZUJnbGdoa2dCWlFNRUFTNHdFUVFNTHFKVXVO

OG5wT2RCSmdDREFnRVFnSUlCZW1LcEM5cEppbGRubjlNbmpVM2pZT21CLURWYnlOeHA3T3JlcGhQ

WWJUMktHRG5BcG5jOGxHd0ROU1loNUh3TmVsNnVWaHhSM3NneUJQeFlnNVR1VE9DOHZLZzd3Tngw

OTlpYmpmWl9FV3kzc3Rlend0VzRjSWpJa2N1ZE9zNXE3U3E5eWlQa3ZaRXhzUTZxMHkxc05GVlkx

bkh1WDFSdE5JbG55QkVSMDlFZG44LUtHWnJlN2E3WjdkeHZRcEI1a0ZsNmx3TGZacURBNzJTcXhV

cFF2N0lYNFVZVTFSLWo5ZFpUdGxGMDFpQ0lyb3lURllUVnVrSTN4eWNCOG1tYUtqVWp2QWRnUzJf

R25NYWJTcVVaUWR5NDNnSk5Jc2VZQlpJUWVuTEhvSzBGbFZhc1hscDZTVE9BcHlOOElHeUUwN0Fi

OHZySnVYOU1DYnA3QU1QY3dNUzRpY2x5OF9uNmJpUDJUS0h4cnZHYnE3UGpDQmFYcUJKMTdmS3JO

QlN2RWtYM1NMRFlZVzhZN1poVFhyVHRGZFUxdUkwT2NfRGQ3TzBMcTVtNnBZd3VKeklLYTlhLWFn

M29PNTNsT282bm9HLTJ1NTVWWjQtREFQVzhtNkhMM2J1VDg5cnp5M0RnT0JQMFU4WnY2dWMwbl9q

cy1nS3pHbkhud1E8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjEwOTMvYnJhaW4vYXd4MjU2PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3Jl

Y29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 288. The finding was not only exclusive of AD but also of other tauopathies, having insulin resistance as a common denominator for most cases. Moreover, neurons with aggregated insulin show decreased insulin receptor levels and neuroblastoma cells overexpressing Tau show decreased GLUT4 expression levels (Fig. 8). This is in line with other papers suggesting similar relationships between insulin resistance and Tau PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJjaW5pYWs8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFy

PjxSZWNOdW0+MTIwNDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjEzNyw0MzU8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMjA0

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzMzMDU2NDIiPjEyMDQ8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1hcmNpbmlhaywgRS48L2F1

dGhvcj48YXV0aG9yPkxlYm91Y2hlciwgQS48L2F1dGhvcj48YXV0aG9yPkNhcm9uLCBFLjwvYXV0

aG9yPjxhdXRob3I+QWhtZWQsIFQuPC9hdXRob3I+PGF1dGhvcj5UYWlsbGV1eCwgQS48L2F1dGhv

cj48YXV0aG9yPkR1bW9udCwgSi48L2F1dGhvcj48YXV0aG9yPklzc2FkLCBULjwvYXV0aG9yPjxh

dXRob3I+R2VyaGFyZHQsIEUuPC9hdXRob3I+PGF1dGhvcj5QYWdlc3ksIFAuPC9hdXRob3I+PGF1

dGhvcj5WaWxlbm8sIE0uPC9hdXRob3I+PGF1dGhvcj5Cb3Vybm9udmlsbGUsIEMuPC9hdXRob3I+

PGF1dGhvcj5IYW1kYW5lLCBNLjwvYXV0aG9yPjxhdXRob3I+QmFudHVidW5naSwgSy48L2F1dGhv

cj48YXV0aG9yPkxhbmNlbCwgUy48L2F1dGhvcj48YXV0aG9yPkRlbWV5ZXIsIEQuPC9hdXRob3I+

PGF1dGhvcj5FZGRhcmthb3VpLCBTLjwvYXV0aG9yPjxhdXRob3I+VmFsbGV6LCBFLjwvYXV0aG9y

PjxhdXRob3I+VmllYXUsIEQuPC9hdXRob3I+PGF1dGhvcj5IdW1leiwgUy48L2F1dGhvcj48YXV0

aG9yPkZhaXZyZSwgRS48L2F1dGhvcj48YXV0aG9yPkdyZW5pZXItQm9sZXksIEIuPC9hdXRob3I+

PGF1dGhvcj5PdXRlaXJvLCBULiBGLjwvYXV0aG9yPjxhdXRob3I+U3RhZWxzLCBCLjwvYXV0aG9y

PjxhdXRob3I+QW1vdXllbCwgUC48L2F1dGhvcj48YXV0aG9yPkJhbHNjaHVuLCBELjwvYXV0aG9y

PjxhdXRob3I+QnVlZSwgTC48L2F1dGhvcj48YXV0aG9yPkJsdW0sIEQuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+VW5pdmVyc2l0ZSBkZSBMaWxsZSwgSW5z

dGl0dXQgTmF0aW9uYWwgZGUgbGEgU2FudGUgZXQgZGUgbGEgUmVjaGVyY2hlIE1lZGljYWxlIChJ

TlNFUk0pLCBDSFUgTGlsbGUsIFVNUi1TIDExNzIgSlBBcmMsIExpbGxlLCBGcmFuY2UuJiN4RDtM

YWJFeCBESVNUQUxaIChEZXZlbG9wbWVudCBvZiBJbm5vdmF0aXZlIFN0cmF0ZWdpZXMgZm9yIGEg

VHJhbnNkaXNjaXBsaW5hcnkgYXBwcm9hY2ggdG8gQUxaaGVpbWVyJmFwb3M7cyBkaXNlYXNlKSwg

TGlsbGUsIEZyYW5jZS4mI3hEO0xhYm9yYXRvcnkgb2YgQmlvbG9naWNhbCBQc3ljaG9sb2d5LCBG

YWN1bHR5IG9mIFBzeWNob2xvZ3kgYW5kIEVkdWNhdGlvbmFsIFNjaWVuY2VzLCBLVSBMZXV2ZW4s

IExldXZlbiwgQmVsZ2l1bS4mI3hEO05ldXJvbG9naWNhbCBEaXNvcmRlcnMgUmVzZWFyY2ggQ2Vu

dGVyLCBRYXRhciBCaW9tZWRpY2FsIFJlc2VhcmNoIEluc3RpdHV0ZSwgSGFtYWQgQmluIEtoYWxp

ZmEgVW5pdmVyc2l0eSwgRG9oYSwgUWF0YXIuJiN4RDtVbml2ZXJzaXRlIGRlIExpbGxlLCBJTlNF

Uk0sIENIVSBMaWxsZSwgSW5zdGl0dXQgUGFzdGV1ciBkZSBMaWxsZSwgVTEwMTFFR0lELCBMaWxs

ZSwgRnJhbmNlLiYjeEQ7VW5pdmVyc2l0ZSBkZSBMaWxsZSwgSU5TRVJNLCBDSFUgTGlsbGUsIElu

c3RpdHV0IFBhc3RldXIgZGUgTGlsbGUsIFUxMTY3IFJJRC1BR0UgRmFjdGV1cnMgZGUgUmlzcXVl

IGV0IERldGVybWluYW50cyBNb2xlY3VsYWlyZXMgZGVzIE1hbGFkaWVzIExpZWVzIGF1IFZpZWls

bGlzc2VtZW50LCBMaWxsZSwgRnJhbmNlLiYjeEQ7SU5TRVJNIFUxMDE2LCBDTlJTIFVNUjgxMDQs

IFVuaXZlcnNpdGUgUGFyaXMgRGVzY2FydGVzIFNvcmJvbm5lIFBhcmlzIENpdGUsIEluc3RpdHV0

IENvY2hpbiwgUGFyaXMsIEZyYW5jZS4mI3hEO0RlcGFydG1lbnQgb2YgRXhwZXJpbWVudGFsIE5l

dXJvZGVnZW5lcmF0aW9uLCBDZW50ZXIgZm9yIE5hbm9zY2FsZSBNaWNyb3Njb3B5IGFuZCBNb2xl

Y3VsYXIgUGh5c2lvbG9neSBvZiB0aGUgQnJhaW4sIFVuaXZlcnNpdHkgTWVkaWNhbCBDZW50ZXIg

R29ldHRpbmdlbiwgR29ldHRpbmdlbiwgR2VybWFueS4mI3hEO1VuaXZlcnNpdGUgZGUgTGlsbGUs

IEluc3RpdHV0IE5hdGlvbmFsIGRlIGxhIFNhbnRlIGV0IGRlIGxhIFJlY2hlcmNoZSBNZWRpY2Fs

ZSAoSU5TRVJNKSwgQ0hVIExpbGxlLCBVTVItUyAxMTcyIEpQQXJjLCBMaWxsZSwgRnJhbmNlIGRh

dmlkLmJsdW1AaW5zZXJtLmZyLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRhdSBkZWxl

dGlvbiBwcm9tb3RlcyBicmFpbiBpbnN1bGluIHJlc2lzdGFuY2U8L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+SiBFeHAgTWVkPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjIyNTctMjI2

OTwvcGFnZXM+PHZvbHVtZT4yMTQ8L3ZvbHVtZT48bnVtYmVyPjg8L251bWJlcj48ZWRpdGlvbj4y

MDE3LzA2LzI4PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxr

ZXl3b3JkPkJyYWluLyptZXRhYm9saXNtL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q29n

bml0aXZlIER5c2Z1bmN0aW9uL2V0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkhhcGxvdHlwZXM8

L2tleXdvcmQ+PGtleXdvcmQ+SGlwcG9jYW1wdXMvcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29y

ZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxpbi9waHlzaW9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPipJbnN1bGluIFJlc2lzdGFuY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29y

ZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIEluYnJlZCBDNTdCTDwva2V5

d29yZD48a2V5d29yZD5NaWNlLCBLbm9ja291dDwva2V5d29yZD48a2V5d29yZD50YXUgUHJvdGVp

bnMvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwveWVh

cj48cHViLWRhdGVzPjxkYXRlPkF1ZyA3PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+

MTU0MC05NTM4IChFbGVjdHJvbmljKSYjeEQ7MDAyMi0xMDA3IChMaW5raW5nKTwvaXNibj48YWNj

ZXNzaW9uLW51bT4yODY1MjMwMzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1

cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjg2NTIzMDM8L3VybD48dXJs

Pmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcG1jL2FydGljbGVzL1BNQzU1NTE1NzAvcGRm

L0pFTV8yMDE2MTczMS5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1D

NTU1MTU3MDwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA4NC9qZW0uMjAx

NjE3MzE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPlNwb2xjb3ZhPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48UmVjTnVtPjEyMDk8L1JlY051

bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEyMDk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5

IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRp

bWVzdGFtcD0iMTUzMzMwNTkzMyI+MTIwOTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBu

YW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3Jz

PjxhdXRob3I+U3BvbGNvdmEsIEEuPC9hdXRob3I+PGF1dGhvcj5NaWt1bGFza292YSwgQi48L2F1

dGhvcj48YXV0aG9yPktyc2tvdmEsIEsuPC9hdXRob3I+PGF1dGhvcj5HYWpkb3NlY2hvdmEsIEwu

PC9hdXRob3I+PGF1dGhvcj5ab3JhZCwgUy48L2F1dGhvcj48YXV0aG9yPk9sc3phbmVja2ksIFIu

PC9hdXRob3I+PGF1dGhvcj5TdXNraSwgTS48L2F1dGhvcj48YXV0aG9yPkJ1amFrLUdpenlja2Es

IEIuPC9hdXRob3I+PGF1dGhvcj5aZWxlem5hLCBCLjwvYXV0aG9yPjxhdXRob3I+TWFsZXRpbnNr

YSwgTC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5JbnN0

aXR1dGUgb2YgT3JnYW5pYyBDaGVtaXN0cnkgYW5kIEJpb2NoZW1pc3RyeSwgUHJhZ3VlLCAxNjYg

MTAsIEN6ZWNoIFJlcHVibGljLiBtYWxldGluQHVvY2hiLmNhcy5jei48L2F1dGgtYWRkcmVzcz48

dGl0bGVzPjx0aXRsZT5EZWZpY2llbnQgaGlwcG9jYW1wYWwgaW5zdWxpbiBzaWduYWxpbmcgYW5k

IGF1Z21lbnRlZCBUYXUgcGhvc3Bob3J5bGF0aW9uIGlzIHJlbGF0ZWQgdG8gb2Jlc2l0eS0gYW5k

IGFnZS1pbmR1Y2VkIHBlcmlwaGVyYWwgaW5zdWxpbiByZXNpc3RhbmNlOiBhIHN0dWR5IGluIFp1

Y2tlciByYXRzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkJNQyBOZXVyb3NjaTwvc2Vjb25kYXJ5

LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMTE8L3BhZ2VzPjx2b2x1bWU+MTU8L3ZvbHVtZT48ZWRp

dGlvbj4yMDE0LzA5LzI3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2luZy8qcGh5c2lv

bG9neTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJsb3R0aW5n

LCBXZXN0ZXJuPC9rZXl3b3JkPjxrZXl3b3JkPkdsdWNvc2UgVG9sZXJhbmNlIFRlc3Q8L2tleXdv

cmQ+PGtleXdvcmQ+R2x5Y29nZW4gU3ludGhhc2UgS2luYXNlIDMvbWV0YWJvbGlzbTwva2V5d29y

ZD48a2V5d29yZD5HbHljb2dlbiBTeW50aGFzZSBLaW5hc2UgMyBiZXRhPC9rZXl3b3JkPjxrZXl3

b3JkPkhpcHBvY2FtcHVzLypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bi8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5JbnN1bGluIFJlc2lzdGFuY2UvKnBoeXNp

b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5PYmVzaXR5Lypw

aHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UGhvc3Bob3J5bGF0aW9uPC9rZXl3b3Jk

PjxrZXl3b3JkPlByb3RvLU9uY29nZW5lIFByb3RlaW5zIGMtYWt0L21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+UmF0cywgWnVja2VyPC9rZXl3b3JkPjxrZXl3b3JkPlNpZ25hbCBUcmFuc2R1

Y3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5zL2dlbmV0aWNzLyptZXRhYm9saXNt

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDcxLTIyMDIgKEVs

ZWN0cm9uaWMpJiN4RDsxNDcxLTIyMDIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1

MjU3NTU5PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3

dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNTI1NzU1OTwvdXJsPjx1cmw+aHR0cHM6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wbWMvYXJ0aWNsZXMvUE1DNDI2MTYwOS9wZGYvMTI4NjhfMjAxM19B

cnRpY2xlXzM3OTkucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQy

NjE2MDk8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExODYvMTQ3MS0yMjAy

LTE1LTExMTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90

ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJjaW5pYWs8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFy

PjxSZWNOdW0+MTIwNDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjEzNyw0MzU8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMjA0

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzMzMDU2NDIiPjEyMDQ8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1hcmNpbmlhaywgRS48L2F1

dGhvcj48YXV0aG9yPkxlYm91Y2hlciwgQS48L2F1dGhvcj48YXV0aG9yPkNhcm9uLCBFLjwvYXV0

aG9yPjxhdXRob3I+QWhtZWQsIFQuPC9hdXRob3I+PGF1dGhvcj5UYWlsbGV1eCwgQS48L2F1dGhv

cj48YXV0aG9yPkR1bW9udCwgSi48L2F1dGhvcj48YXV0aG9yPklzc2FkLCBULjwvYXV0aG9yPjxh

dXRob3I+R2VyaGFyZHQsIEUuPC9hdXRob3I+PGF1dGhvcj5QYWdlc3ksIFAuPC9hdXRob3I+PGF1

dGhvcj5WaWxlbm8sIE0uPC9hdXRob3I+PGF1dGhvcj5Cb3Vybm9udmlsbGUsIEMuPC9hdXRob3I+

PGF1dGhvcj5IYW1kYW5lLCBNLjwvYXV0aG9yPjxhdXRob3I+QmFudHVidW5naSwgSy48L2F1dGhv

cj48YXV0aG9yPkxhbmNlbCwgUy48L2F1dGhvcj48YXV0aG9yPkRlbWV5ZXIsIEQuPC9hdXRob3I+

PGF1dGhvcj5FZGRhcmthb3VpLCBTLjwvYXV0aG9yPjxhdXRob3I+VmFsbGV6LCBFLjwvYXV0aG9y

PjxhdXRob3I+VmllYXUsIEQuPC9hdXRob3I+PGF1dGhvcj5IdW1leiwgUy48L2F1dGhvcj48YXV0

aG9yPkZhaXZyZSwgRS48L2F1dGhvcj48YXV0aG9yPkdyZW5pZXItQm9sZXksIEIuPC9hdXRob3I+

PGF1dGhvcj5PdXRlaXJvLCBULiBGLjwvYXV0aG9yPjxhdXRob3I+U3RhZWxzLCBCLjwvYXV0aG9y

PjxhdXRob3I+QW1vdXllbCwgUC48L2F1dGhvcj48YXV0aG9yPkJhbHNjaHVuLCBELjwvYXV0aG9y

PjxhdXRob3I+QnVlZSwgTC48L2F1dGhvcj48YXV0aG9yPkJsdW0sIEQuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+VW5pdmVyc2l0ZSBkZSBMaWxsZSwgSW5z

dGl0dXQgTmF0aW9uYWwgZGUgbGEgU2FudGUgZXQgZGUgbGEgUmVjaGVyY2hlIE1lZGljYWxlIChJ

TlNFUk0pLCBDSFUgTGlsbGUsIFVNUi1TIDExNzIgSlBBcmMsIExpbGxlLCBGcmFuY2UuJiN4RDtM

YWJFeCBESVNUQUxaIChEZXZlbG9wbWVudCBvZiBJbm5vdmF0aXZlIFN0cmF0ZWdpZXMgZm9yIGEg

VHJhbnNkaXNjaXBsaW5hcnkgYXBwcm9hY2ggdG8gQUxaaGVpbWVyJmFwb3M7cyBkaXNlYXNlKSwg

TGlsbGUsIEZyYW5jZS4mI3hEO0xhYm9yYXRvcnkgb2YgQmlvbG9naWNhbCBQc3ljaG9sb2d5LCBG

YWN1bHR5IG9mIFBzeWNob2xvZ3kgYW5kIEVkdWNhdGlvbmFsIFNjaWVuY2VzLCBLVSBMZXV2ZW4s

IExldXZlbiwgQmVsZ2l1bS4mI3hEO05ldXJvbG9naWNhbCBEaXNvcmRlcnMgUmVzZWFyY2ggQ2Vu

dGVyLCBRYXRhciBCaW9tZWRpY2FsIFJlc2VhcmNoIEluc3RpdHV0ZSwgSGFtYWQgQmluIEtoYWxp

ZmEgVW5pdmVyc2l0eSwgRG9oYSwgUWF0YXIuJiN4RDtVbml2ZXJzaXRlIGRlIExpbGxlLCBJTlNF

Uk0sIENIVSBMaWxsZSwgSW5zdGl0dXQgUGFzdGV1ciBkZSBMaWxsZSwgVTEwMTFFR0lELCBMaWxs

ZSwgRnJhbmNlLiYjeEQ7VW5pdmVyc2l0ZSBkZSBMaWxsZSwgSU5TRVJNLCBDSFUgTGlsbGUsIElu

c3RpdHV0IFBhc3RldXIgZGUgTGlsbGUsIFUxMTY3IFJJRC1BR0UgRmFjdGV1cnMgZGUgUmlzcXVl

IGV0IERldGVybWluYW50cyBNb2xlY3VsYWlyZXMgZGVzIE1hbGFkaWVzIExpZWVzIGF1IFZpZWls

bGlzc2VtZW50LCBMaWxsZSwgRnJhbmNlLiYjeEQ7SU5TRVJNIFUxMDE2LCBDTlJTIFVNUjgxMDQs

IFVuaXZlcnNpdGUgUGFyaXMgRGVzY2FydGVzIFNvcmJvbm5lIFBhcmlzIENpdGUsIEluc3RpdHV0

IENvY2hpbiwgUGFyaXMsIEZyYW5jZS4mI3hEO0RlcGFydG1lbnQgb2YgRXhwZXJpbWVudGFsIE5l

dXJvZGVnZW5lcmF0aW9uLCBDZW50ZXIgZm9yIE5hbm9zY2FsZSBNaWNyb3Njb3B5IGFuZCBNb2xl

Y3VsYXIgUGh5c2lvbG9neSBvZiB0aGUgQnJhaW4sIFVuaXZlcnNpdHkgTWVkaWNhbCBDZW50ZXIg

R29ldHRpbmdlbiwgR29ldHRpbmdlbiwgR2VybWFueS4mI3hEO1VuaXZlcnNpdGUgZGUgTGlsbGUs

IEluc3RpdHV0IE5hdGlvbmFsIGRlIGxhIFNhbnRlIGV0IGRlIGxhIFJlY2hlcmNoZSBNZWRpY2Fs

ZSAoSU5TRVJNKSwgQ0hVIExpbGxlLCBVTVItUyAxMTcyIEpQQXJjLCBMaWxsZSwgRnJhbmNlIGRh

dmlkLmJsdW1AaW5zZXJtLmZyLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRhdSBkZWxl

dGlvbiBwcm9tb3RlcyBicmFpbiBpbnN1bGluIHJlc2lzdGFuY2U8L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+SiBFeHAgTWVkPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjIyNTctMjI2

OTwvcGFnZXM+PHZvbHVtZT4yMTQ8L3ZvbHVtZT48bnVtYmVyPjg8L251bWJlcj48ZWRpdGlvbj4y

MDE3LzA2LzI4PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxr

ZXl3b3JkPkJyYWluLyptZXRhYm9saXNtL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q29n

bml0aXZlIER5c2Z1bmN0aW9uL2V0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkhhcGxvdHlwZXM8

L2tleXdvcmQ+PGtleXdvcmQ+SGlwcG9jYW1wdXMvcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29y

ZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxpbi9waHlzaW9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPipJbnN1bGluIFJlc2lzdGFuY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29y

ZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIEluYnJlZCBDNTdCTDwva2V5

d29yZD48a2V5d29yZD5NaWNlLCBLbm9ja291dDwva2V5d29yZD48a2V5d29yZD50YXUgUHJvdGVp

bnMvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwveWVh

cj48cHViLWRhdGVzPjxkYXRlPkF1ZyA3PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+

MTU0MC05NTM4IChFbGVjdHJvbmljKSYjeEQ7MDAyMi0xMDA3IChMaW5raW5nKTwvaXNibj48YWNj

ZXNzaW9uLW51bT4yODY1MjMwMzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1

cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjg2NTIzMDM8L3VybD48dXJs

Pmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcG1jL2FydGljbGVzL1BNQzU1NTE1NzAvcGRm

L0pFTV8yMDE2MTczMS5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1D

NTU1MTU3MDwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA4NC9qZW0uMjAx

NjE3MzE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPlNwb2xjb3ZhPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48UmVjTnVtPjEyMDk8L1JlY051

bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEyMDk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5

IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRp

bWVzdGFtcD0iMTUzMzMwNTkzMyI+MTIwOTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBu

YW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3Jz

PjxhdXRob3I+U3BvbGNvdmEsIEEuPC9hdXRob3I+PGF1dGhvcj5NaWt1bGFza292YSwgQi48L2F1

dGhvcj48YXV0aG9yPktyc2tvdmEsIEsuPC9hdXRob3I+PGF1dGhvcj5HYWpkb3NlY2hvdmEsIEwu

PC9hdXRob3I+PGF1dGhvcj5ab3JhZCwgUy48L2F1dGhvcj48YXV0aG9yPk9sc3phbmVja2ksIFIu

PC9hdXRob3I+PGF1dGhvcj5TdXNraSwgTS48L2F1dGhvcj48YXV0aG9yPkJ1amFrLUdpenlja2Es

IEIuPC9hdXRob3I+PGF1dGhvcj5aZWxlem5hLCBCLjwvYXV0aG9yPjxhdXRob3I+TWFsZXRpbnNr

YSwgTC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5JbnN0

aXR1dGUgb2YgT3JnYW5pYyBDaGVtaXN0cnkgYW5kIEJpb2NoZW1pc3RyeSwgUHJhZ3VlLCAxNjYg

MTAsIEN6ZWNoIFJlcHVibGljLiBtYWxldGluQHVvY2hiLmNhcy5jei48L2F1dGgtYWRkcmVzcz48

dGl0bGVzPjx0aXRsZT5EZWZpY2llbnQgaGlwcG9jYW1wYWwgaW5zdWxpbiBzaWduYWxpbmcgYW5k

IGF1Z21lbnRlZCBUYXUgcGhvc3Bob3J5bGF0aW9uIGlzIHJlbGF0ZWQgdG8gb2Jlc2l0eS0gYW5k

IGFnZS1pbmR1Y2VkIHBlcmlwaGVyYWwgaW5zdWxpbiByZXNpc3RhbmNlOiBhIHN0dWR5IGluIFp1

Y2tlciByYXRzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkJNQyBOZXVyb3NjaTwvc2Vjb25kYXJ5

LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xMTE8L3BhZ2VzPjx2b2x1bWU+MTU8L3ZvbHVtZT48ZWRp

dGlvbj4yMDE0LzA5LzI3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2luZy8qcGh5c2lv

bG9neTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJsb3R0aW5n

LCBXZXN0ZXJuPC9rZXl3b3JkPjxrZXl3b3JkPkdsdWNvc2UgVG9sZXJhbmNlIFRlc3Q8L2tleXdv

cmQ+PGtleXdvcmQ+R2x5Y29nZW4gU3ludGhhc2UgS2luYXNlIDMvbWV0YWJvbGlzbTwva2V5d29y

ZD48a2V5d29yZD5HbHljb2dlbiBTeW50aGFzZSBLaW5hc2UgMyBiZXRhPC9rZXl3b3JkPjxrZXl3

b3JkPkhpcHBvY2FtcHVzLypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SW5zdWxp

bi8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5JbnN1bGluIFJlc2lzdGFuY2UvKnBoeXNp

b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5PYmVzaXR5Lypw

aHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UGhvc3Bob3J5bGF0aW9uPC9rZXl3b3Jk

PjxrZXl3b3JkPlByb3RvLU9uY29nZW5lIFByb3RlaW5zIGMtYWt0L21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+UmF0cywgWnVja2VyPC9rZXl3b3JkPjxrZXl3b3JkPlNpZ25hbCBUcmFuc2R1

Y3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5zL2dlbmV0aWNzLyptZXRhYm9saXNt

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5TZXAgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDcxLTIyMDIgKEVs

ZWN0cm9uaWMpJiN4RDsxNDcxLTIyMDIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1

MjU3NTU5PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3

dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNTI1NzU1OTwvdXJsPjx1cmw+aHR0cHM6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wbWMvYXJ0aWNsZXMvUE1DNDI2MTYwOS9wZGYvMTI4NjhfMjAxM19B

cnRpY2xlXzM3OTkucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQy

NjE2MDk8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExODYvMTQ3MS0yMjAy

LTE1LTExMTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90

ZT5=

ADDIN EN.CITE.DATA 137,435. While some reports exist linking high cholesterol with hyperphosphorylated Tau PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJ3YXJoYTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

PFJlY051bT44NTM8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij40MjIsNDM2LDQzNzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjg1

MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUy

cHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTUwODUwIj44NTM8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1hcndhcmhhLCBHLjwvYXV0

aG9yPjxhdXRob3I+UmhlbiwgVC48L2F1dGhvcj48YXV0aG9yPlNjaG9tbWVyLCBULjwvYXV0aG9y

PjxhdXRob3I+R2hyaWJpLCBPLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0

aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgUGhhcm1hY29sb2d5LCBVbml2ZXJzaXR5IG9mIE5vcnRo

IERha290YSBTY2hvb2wgb2YgTWVkaWNpbmUgYW5kIEhlYWx0aCBTY2llbmNlcywgR3JhbmQgRm9y

a3MsIE5vcnRoIERha290YSwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSBv

eHlzdGVyb2wgMjctaHlkcm94eWNob2xlc3Rlcm9sIHJlZ3VsYXRlcyBhbHBoYS1zeW51Y2xlaW4g

YW5kIHR5cm9zaW5lIGh5ZHJveHlsYXNlIGV4cHJlc3Npb24gbGV2ZWxzIGluIGh1bWFuIG5ldXJv

Ymxhc3RvbWEgY2VsbHMgdGhyb3VnaCBtb2R1bGF0aW9uIG9mIGxpdmVyIFggcmVjZXB0b3JzIGFu

ZCBlc3Ryb2dlbiByZWNlcHRvcnMtLXJlbGV2YW5jZSB0byBQYXJraW5zb24mYXBvcztzIGRpc2Vh

c2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBOZXVyb2NoZW08L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIE5ldXJvY2hlbTwvZnVsbC10aXRsZT48

L3BlcmlvZGljYWw+PHBhZ2VzPjExMTktMzY8L3BhZ2VzPjx2b2x1bWU+MTE5PC92b2x1bWU+PG51

bWJlcj41PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkNlbGwgTGluZSwgVHVtb3I8L2tleXdv

cmQ+PGtleXdvcmQ+RGlzZWFzZSBQcm9ncmVzc2lvbjwva2V5d29yZD48a2V5d29yZD5Eb3duLVJl

Z3VsYXRpb24vZHJ1ZyBlZmZlY3RzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RXN0cm9n

ZW4gUmVjZXB0b3IgYWxwaGEvYWdvbmlzdHMvYW50YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9ycy8q

Ymlvc3ludGhlc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkVzdHJvZ2VuIFJlY2VwdG9yIGJldGEvYWdv

bmlzdHMvYW50YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9ycy8qYmlvc3ludGhlc2lzPC9rZXl3b3Jk

PjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IeWRyb3h5Y2hvbGVzdGVyb2xzLypw

aGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TGl2ZXIgWCBSZWNlcHRvcnM8L2tleXdvcmQ+

PGtleXdvcmQ+TmV1cm9ibGFzdG9tYS9lbnp5bW9sb2d5LyptZXRhYm9saXNtL3BhdGhvbG9neTwv

a2V5d29yZD48a2V5d29yZD5PcnBoYW4gTnVjbGVhciBSZWNlcHRvcnMvYWdvbmlzdHMvYW50YWdv

bmlzdHMgJmFtcDsgaW5oaWJpdG9ycy8qYmlvc3ludGhlc2lzPC9rZXl3b3JkPjxrZXl3b3JkPlBh

cmtpbnNvbiBEaXNlYXNlL2Vuenltb2xvZ3kvbWV0YWJvbGlzbS8qcHJldmVudGlvbiAmYW1wOyBj

b250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPlNpZ25hbCBUcmFuc2R1Y3Rpb24vZ2VuZXRpY3MvcGh5

c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5UeXJvc2luZSAzLU1vbm9veHlnZW5hc2UvKmFudGFn

b25pc3RzICZhbXA7IGluaGliaXRvcnMvYmlvc3ludGhlc2lzL2dlbmV0aWNzPC9rZXl3b3JkPjxr

ZXl3b3JkPlVwLVJlZ3VsYXRpb24vZHJ1ZyBlZmZlY3RzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+YWxwaGEtU3ludWNsZWluL2Jpb3N5bnRoZXNpcy8qZ2VuZXRpY3M8L2tleXdvcmQ+PC9r

ZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkRlYzwvZGF0

ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0NzEtNDE1OSAoRWxlY3Ryb25pYykmI3hEOzAw

MjItMzA0MiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjE5NTEwNjY8L2FjY2Vzc2lv

bi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdv

di9wdWJtZWQvMjE5NTEwNjY8L3VybD48dXJsPmh0dHBzOi8vb25saW5lbGlicmFyeS53aWxleS5j

b20vZG9pL3BkZi8xMC4xMTExL2ouMTQ3MS00MTU5LjIwMTEuMDc0OTcueDwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUMzMjE3MTIxPC9jdXN0b20yPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4xMTExL2ouMTQ3MS00MTU5LjIwMTEuMDc0OTcueDwvZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TWFyd2FyaGE8L0F1dGhv

cj48WWVhcj4yMDEwPC9ZZWFyPjxSZWNOdW0+MTIwMTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1i

ZXI+MTIwMTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3

YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMzMjQyNjM4

Ij4xMjAxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs

ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5NYXJ3YXJoYSwg

Ry48L2F1dGhvcj48YXV0aG9yPkRhc2FyaSwgQi48L2F1dGhvcj48YXV0aG9yPlByYXNhbnRoaSwg

Si4gUi48L2F1dGhvcj48YXV0aG9yPlNjaG9tbWVyLCBKLjwvYXV0aG9yPjxhdXRob3I+R2hyaWJp

LCBPLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFy

dG1lbnQgb2YgUGhhcm1hY29sb2d5LCBQaHlzaW9sb2d5IGFuZCBUaGVyYXBldXRpY3MsIFVuaXZl

cnNpdHkgb2YgTm9ydGggRGFrb3RhIFNjaG9vbCBvZiBNZWRpY2luZSBhbmQgSGVhbHRoIFNjaWVu

Y2VzLCBHcmFuZCBGb3JrcywgTkQsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5M

ZXB0aW4gcmVkdWNlcyB0aGUgYWNjdW11bGF0aW9uIG9mIEFiZXRhIGFuZCBwaG9zcGhvcnlsYXRl

ZCB0YXUgaW5kdWNlZCBieSAyNy1oeWRyb3h5Y2hvbGVzdGVyb2wgaW4gcmFiYml0IG9yZ2Fub3R5

cGljIHNsaWNlczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEFsemhlaW1lcnMgRGlzPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBBbHpoZWltZXJz

IERpczwvZnVsbC10aXRsZT48YWJici0xPkpvdXJuYWwgb2YgQWx6aGVpbWVyJmFwb3M7cyBkaXNl

YXNlIDogSkFEPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMDA3LTE5PC9wYWdlcz48dm9s

dW1lPjE5PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhl

aW1lciBEaXNlYXNlL21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxv

aWQgUHJlY3Vyc29yIFByb3RlaW4gU2VjcmV0YXNlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3

b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy8qYW50YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9yczwv

a2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkFzcGFydGljIEFjaWQg

RW5kb3BlcHRpZGFzZXMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5CbG90dGluZywgV2Vz

dGVybjwva2V5d29yZD48a2V5d29yZD5Fbnp5bWUtTGlua2VkIEltbXVub3NvcmJlbnQgQXNzYXk8

L2tleXdvcmQ+PGtleXdvcmQ+R2x5Y29nZW4gU3ludGhhc2UgS2luYXNlIDMvbWV0YWJvbGlzbTwv

a2V5d29yZD48a2V5d29yZD5HbHljb2dlbiBTeW50aGFzZSBLaW5hc2UgMyBiZXRhPC9rZXl3b3Jk

PjxrZXl3b3JkPkhpcHBvY2FtcHVzL21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPkh5ZHJveHljaG9sZXN0ZXJvbHMvKnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5M

ZXB0aW4vKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29y

ZD5PcmdhbiBDdWx0dXJlIFRlY2huaXF1ZXM8L2tleXdvcmQ+PGtleXdvcmQ+UGhvc3Bob3J5bGF0

aW9uL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UmFiYml0czwva2V5d29yZD48a2V5d29y

ZD50YXUgUHJvdGVpbnMvKmRydWcgZWZmZWN0czwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4yMDEwPC95ZWFyPjwvZGF0ZXM+PGlzYm4+MTg3NS04OTA4IChFbGVjdHJvbmljKSYjeEQ7

MTM4Ny0yODc3IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMDE1NzI1NTwvYWNjZXNz

aW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWgu

Z292L3B1Ym1lZC8yMDE1NzI1NTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5Q

TUMyOTI0Mjg0PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4zMjMzL0pBRC0y

MDEwLTEyOTg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48

QXV0aG9yPlJhaG1hbjwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJlY051bT4zMjc8L1JlY051

bT48cmVjb3JkPjxyZWMtbnVtYmVyPjMyNzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg

YXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGlt

ZXN0YW1wPSIxNTMxNzc1Mjc4Ij4zMjc8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt

ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48

YXV0aG9yPlJhaG1hbiwgQS48L2F1dGhvcj48YXV0aG9yPkFrdGVyaW4sIFMuPC9hdXRob3I+PGF1

dGhvcj5GbG9yZXMtTW9yYWxlcywgQS48L2F1dGhvcj48YXV0aG9yPkNyaXNieSwgTS48L2F1dGhv

cj48YXV0aG9yPktpdmlwZWx0bywgTS48L2F1dGhvcj48YXV0aG9yPlNjaHVsdHpiZXJnLCBNLjwv

YXV0aG9yPjxhdXRob3I+Q2VkYXpvLU1pbmd1ZXosIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+S2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBOZXVyb3RlYyBE

ZXBhcnRtZW50LCBEaXZpc2lvbiBvZiBFeHBlcmltZW50YWwgR2VyaWF0cmljcywgTm92dW0sIEth

cm9saW5za2EgVW5pdmVyc2l0eSBIb3NwaXRhbCwgU0UtMTQxODYgSHVkZGluZ2UsIFN3ZWRlbi48

L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5IaWdoIGNob2xlc3Rlcm9sIGRpZXQgaW5kdWNl

cyB0YXUgaHlwZXJwaG9zcGhvcnlsYXRpb24gaW4gYXBvbGlwb3Byb3RlaW4gRSBkZWZpY2llbnQg

bWljZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5GRUJTIExldHQ8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+NjQxMS02PC9wYWdlcz48dm9sdW1lPjU3OTwvdm9sdW1lPjxudW1iZXI+

Mjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5B

cG9saXBvcHJvdGVpbnMgRS8qZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgQ29y

dGV4L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGVzdGVyb2wvKmFkbWluaXN0cmF0

aW9uICZhbXA7IGRvc2FnZTwva2V5d29yZD48a2V5d29yZD5EaWV0PC9rZXl3b3JkPjxrZXl3b3Jk

Pk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgS25vY2tvdXQ8L2tleXdvcmQ+PGtleXdvcmQ+

UGhvc3Bob3JpYyBNb25vZXN0ZXIgSHlkcm9sYXNlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3

b3JkPlBob3NwaG9yeWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5Qcm90ZWluLVNlcmluZS1UaHJl

b25pbmUgS2luYXNlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlRhdW9wYXRoaWVzL2dl

bmV0aWNzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlVwLVJlZ3VsYXRpb248L2tleXdv

cmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5zLyptZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+

PGRhdGVzPjx5ZWFyPjIwMDU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5Ob3YgMjE8L2RhdGU+PC9w

dWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDE0LTU3OTMgKFByaW50KSYjeEQ7MDAxNC01NzkzIChM

aW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xNjI4ODc1MDwvYWNjZXNzaW9uLW51bT48dXJs

cz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8x

NjI4ODc1MDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+MTAuMTAxNi9qLmZlYnNsZXQuMjAwNS4xMC4wMjQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJ3YXJoYTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

PFJlY051bT44NTM8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij40MjIsNDM2LDQzNzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjg1

MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUy

cHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyNTUwODUwIj44NTM8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1hcndhcmhhLCBHLjwvYXV0

aG9yPjxhdXRob3I+UmhlbiwgVC48L2F1dGhvcj48YXV0aG9yPlNjaG9tbWVyLCBULjwvYXV0aG9y

PjxhdXRob3I+R2hyaWJpLCBPLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0

aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgUGhhcm1hY29sb2d5LCBVbml2ZXJzaXR5IG9mIE5vcnRo

IERha290YSBTY2hvb2wgb2YgTWVkaWNpbmUgYW5kIEhlYWx0aCBTY2llbmNlcywgR3JhbmQgRm9y

a3MsIE5vcnRoIERha290YSwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSBv

eHlzdGVyb2wgMjctaHlkcm94eWNob2xlc3Rlcm9sIHJlZ3VsYXRlcyBhbHBoYS1zeW51Y2xlaW4g

YW5kIHR5cm9zaW5lIGh5ZHJveHlsYXNlIGV4cHJlc3Npb24gbGV2ZWxzIGluIGh1bWFuIG5ldXJv

Ymxhc3RvbWEgY2VsbHMgdGhyb3VnaCBtb2R1bGF0aW9uIG9mIGxpdmVyIFggcmVjZXB0b3JzIGFu

ZCBlc3Ryb2dlbiByZWNlcHRvcnMtLXJlbGV2YW5jZSB0byBQYXJraW5zb24mYXBvcztzIGRpc2Vh

c2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBOZXVyb2NoZW08L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIE5ldXJvY2hlbTwvZnVsbC10aXRsZT48

L3BlcmlvZGljYWw+PHBhZ2VzPjExMTktMzY8L3BhZ2VzPjx2b2x1bWU+MTE5PC92b2x1bWU+PG51

bWJlcj41PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkNlbGwgTGluZSwgVHVtb3I8L2tleXdv

cmQ+PGtleXdvcmQ+RGlzZWFzZSBQcm9ncmVzc2lvbjwva2V5d29yZD48a2V5d29yZD5Eb3duLVJl

Z3VsYXRpb24vZHJ1ZyBlZmZlY3RzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RXN0cm9n

ZW4gUmVjZXB0b3IgYWxwaGEvYWdvbmlzdHMvYW50YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9ycy8q

Ymlvc3ludGhlc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkVzdHJvZ2VuIFJlY2VwdG9yIGJldGEvYWdv

bmlzdHMvYW50YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9ycy8qYmlvc3ludGhlc2lzPC9rZXl3b3Jk

PjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IeWRyb3h5Y2hvbGVzdGVyb2xzLypw

aGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TGl2ZXIgWCBSZWNlcHRvcnM8L2tleXdvcmQ+

PGtleXdvcmQ+TmV1cm9ibGFzdG9tYS9lbnp5bW9sb2d5LyptZXRhYm9saXNtL3BhdGhvbG9neTwv

a2V5d29yZD48a2V5d29yZD5PcnBoYW4gTnVjbGVhciBSZWNlcHRvcnMvYWdvbmlzdHMvYW50YWdv

bmlzdHMgJmFtcDsgaW5oaWJpdG9ycy8qYmlvc3ludGhlc2lzPC9rZXl3b3JkPjxrZXl3b3JkPlBh

cmtpbnNvbiBEaXNlYXNlL2Vuenltb2xvZ3kvbWV0YWJvbGlzbS8qcHJldmVudGlvbiAmYW1wOyBj

b250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPlNpZ25hbCBUcmFuc2R1Y3Rpb24vZ2VuZXRpY3MvcGh5

c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5UeXJvc2luZSAzLU1vbm9veHlnZW5hc2UvKmFudGFn

b25pc3RzICZhbXA7IGluaGliaXRvcnMvYmlvc3ludGhlc2lzL2dlbmV0aWNzPC9rZXl3b3JkPjxr

ZXl3b3JkPlVwLVJlZ3VsYXRpb24vZHJ1ZyBlZmZlY3RzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+YWxwaGEtU3ludWNsZWluL2Jpb3N5bnRoZXNpcy8qZ2VuZXRpY3M8L2tleXdvcmQ+PC9r

ZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkRlYzwvZGF0

ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0NzEtNDE1OSAoRWxlY3Ryb25pYykmI3hEOzAw

MjItMzA0MiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjE5NTEwNjY8L2FjY2Vzc2lv

bi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdv

di9wdWJtZWQvMjE5NTEwNjY8L3VybD48dXJsPmh0dHBzOi8vb25saW5lbGlicmFyeS53aWxleS5j

b20vZG9pL3BkZi8xMC4xMTExL2ouMTQ3MS00MTU5LjIwMTEuMDc0OTcueDwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUMzMjE3MTIxPC9jdXN0b20yPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4xMTExL2ouMTQ3MS00MTU5LjIwMTEuMDc0OTcueDwvZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TWFyd2FyaGE8L0F1dGhv

cj48WWVhcj4yMDEwPC9ZZWFyPjxSZWNOdW0+MTIwMTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1i

ZXI+MTIwMTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3

YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMzMjQyNjM4

Ij4xMjAxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs

ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5NYXJ3YXJoYSwg

Ry48L2F1dGhvcj48YXV0aG9yPkRhc2FyaSwgQi48L2F1dGhvcj48YXV0aG9yPlByYXNhbnRoaSwg

Si4gUi48L2F1dGhvcj48YXV0aG9yPlNjaG9tbWVyLCBKLjwvYXV0aG9yPjxhdXRob3I+R2hyaWJp

LCBPLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFy

dG1lbnQgb2YgUGhhcm1hY29sb2d5LCBQaHlzaW9sb2d5IGFuZCBUaGVyYXBldXRpY3MsIFVuaXZl

cnNpdHkgb2YgTm9ydGggRGFrb3RhIFNjaG9vbCBvZiBNZWRpY2luZSBhbmQgSGVhbHRoIFNjaWVu

Y2VzLCBHcmFuZCBGb3JrcywgTkQsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5M

ZXB0aW4gcmVkdWNlcyB0aGUgYWNjdW11bGF0aW9uIG9mIEFiZXRhIGFuZCBwaG9zcGhvcnlsYXRl

ZCB0YXUgaW5kdWNlZCBieSAyNy1oeWRyb3h5Y2hvbGVzdGVyb2wgaW4gcmFiYml0IG9yZ2Fub3R5

cGljIHNsaWNlczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEFsemhlaW1lcnMgRGlzPC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBBbHpoZWltZXJz

IERpczwvZnVsbC10aXRsZT48YWJici0xPkpvdXJuYWwgb2YgQWx6aGVpbWVyJmFwb3M7cyBkaXNl

YXNlIDogSkFEPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMDA3LTE5PC9wYWdlcz48dm9s

dW1lPjE5PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhl

aW1lciBEaXNlYXNlL21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxv

aWQgUHJlY3Vyc29yIFByb3RlaW4gU2VjcmV0YXNlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3

b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy8qYW50YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9yczwv

a2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkFzcGFydGljIEFjaWQg

RW5kb3BlcHRpZGFzZXMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5CbG90dGluZywgV2Vz

dGVybjwva2V5d29yZD48a2V5d29yZD5Fbnp5bWUtTGlua2VkIEltbXVub3NvcmJlbnQgQXNzYXk8

L2tleXdvcmQ+PGtleXdvcmQ+R2x5Y29nZW4gU3ludGhhc2UgS2luYXNlIDMvbWV0YWJvbGlzbTwv

a2V5d29yZD48a2V5d29yZD5HbHljb2dlbiBTeW50aGFzZSBLaW5hc2UgMyBiZXRhPC9rZXl3b3Jk

PjxrZXl3b3JkPkhpcHBvY2FtcHVzL21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPkh5ZHJveHljaG9sZXN0ZXJvbHMvKnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5M

ZXB0aW4vKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29y

ZD5PcmdhbiBDdWx0dXJlIFRlY2huaXF1ZXM8L2tleXdvcmQ+PGtleXdvcmQ+UGhvc3Bob3J5bGF0

aW9uL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UmFiYml0czwva2V5d29yZD48a2V5d29y

ZD50YXUgUHJvdGVpbnMvKmRydWcgZWZmZWN0czwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4yMDEwPC95ZWFyPjwvZGF0ZXM+PGlzYm4+MTg3NS04OTA4IChFbGVjdHJvbmljKSYjeEQ7

MTM4Ny0yODc3IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMDE1NzI1NTwvYWNjZXNz

aW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWgu

Z292L3B1Ym1lZC8yMDE1NzI1NTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5Q

TUMyOTI0Mjg0PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4zMjMzL0pBRC0y

MDEwLTEyOTg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48

QXV0aG9yPlJhaG1hbjwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJlY051bT4zMjc8L1JlY051

bT48cmVjb3JkPjxyZWMtbnVtYmVyPjMyNzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg

YXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGlt

ZXN0YW1wPSIxNTMxNzc1Mjc4Ij4zMjc8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt

ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48

YXV0aG9yPlJhaG1hbiwgQS48L2F1dGhvcj48YXV0aG9yPkFrdGVyaW4sIFMuPC9hdXRob3I+PGF1

dGhvcj5GbG9yZXMtTW9yYWxlcywgQS48L2F1dGhvcj48YXV0aG9yPkNyaXNieSwgTS48L2F1dGhv

cj48YXV0aG9yPktpdmlwZWx0bywgTS48L2F1dGhvcj48YXV0aG9yPlNjaHVsdHpiZXJnLCBNLjwv

YXV0aG9yPjxhdXRob3I+Q2VkYXpvLU1pbmd1ZXosIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+S2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBOZXVyb3RlYyBE

ZXBhcnRtZW50LCBEaXZpc2lvbiBvZiBFeHBlcmltZW50YWwgR2VyaWF0cmljcywgTm92dW0sIEth

cm9saW5za2EgVW5pdmVyc2l0eSBIb3NwaXRhbCwgU0UtMTQxODYgSHVkZGluZ2UsIFN3ZWRlbi48

L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5IaWdoIGNob2xlc3Rlcm9sIGRpZXQgaW5kdWNl

cyB0YXUgaHlwZXJwaG9zcGhvcnlsYXRpb24gaW4gYXBvbGlwb3Byb3RlaW4gRSBkZWZpY2llbnQg

bWljZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5GRUJTIExldHQ8L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGFnZXM+NjQxMS02PC9wYWdlcz48dm9sdW1lPjU3OTwvdm9sdW1lPjxudW1iZXI+

Mjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5B

cG9saXBvcHJvdGVpbnMgRS8qZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgQ29y

dGV4L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGVzdGVyb2wvKmFkbWluaXN0cmF0

aW9uICZhbXA7IGRvc2FnZTwva2V5d29yZD48a2V5d29yZD5EaWV0PC9rZXl3b3JkPjxrZXl3b3Jk

Pk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgS25vY2tvdXQ8L2tleXdvcmQ+PGtleXdvcmQ+

UGhvc3Bob3JpYyBNb25vZXN0ZXIgSHlkcm9sYXNlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3

b3JkPlBob3NwaG9yeWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5Qcm90ZWluLVNlcmluZS1UaHJl

b25pbmUgS2luYXNlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlRhdW9wYXRoaWVzL2dl

bmV0aWNzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlVwLVJlZ3VsYXRpb248L2tleXdv

cmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5zLyptZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+

PGRhdGVzPjx5ZWFyPjIwMDU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5Ob3YgMjE8L2RhdGU+PC9w

dWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDE0LTU3OTMgKFByaW50KSYjeEQ7MDAxNC01NzkzIChM

aW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xNjI4ODc1MDwvYWNjZXNzaW9uLW51bT48dXJs

cz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8x

NjI4ODc1MDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+MTAuMTAxNi9qLmZlYnNsZXQuMjAwNS4xMC4wMjQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 422,436,437, the mechanistic link between glucose and cholesterol metabolism underlining neurodegeneration needs further research. Yet it is highly possible that such a link exists and plays a major role not only in AD but also in other tauopathies and in PD. This underlines the importance of redirecting research efforts to classify AD patients according to specific biochemical pathway imbalances they might present in order to better design clinical trials for treating or modifying AD progression. Further research should focus on topics of insulin metabolism, cholesterol and lipid dynamics in the brain and their relationship with parallel pathologies such as diabetes that could lead to earlier hallmarks of AD manifestation, new targets for drug development and new therapeutic strategies to treat neurodegenerative diseases.DISCUSSION AND PERSPECTIVES Currently, in the clinic, the diagnosis of AD is based on symptomatology and, to some extent, on biomarkers. Memory tests help the neurologist or geriatrician to first identify dementia and then screen for Aβ via CSF tests, using PET imaging or both. The symptom-based classification leads to the staging of AD, as we know it, with MCI in the early phases and AD with its different stages later on PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TcGVybGluZzwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

PFJlY051bT4zNzM8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij40MDc8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zNzM8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjU0OTMzNCI+MzczPC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TcGVybGluZywgUi4gQS48L2F1dGhvcj48

YXV0aG9yPkFpc2VuLCBQLiBTLjwvYXV0aG9yPjxhdXRob3I+QmVja2V0dCwgTC4gQS48L2F1dGhv

cj48YXV0aG9yPkJlbm5ldHQsIEQuIEEuPC9hdXRob3I+PGF1dGhvcj5DcmFmdCwgUy48L2F1dGhv

cj48YXV0aG9yPkZhZ2FuLCBBLiBNLjwvYXV0aG9yPjxhdXRob3I+SXdhdHN1Ym8sIFQuPC9hdXRo

b3I+PGF1dGhvcj5KYWNrLCBDLiBSLiwgSnIuPC9hdXRob3I+PGF1dGhvcj5LYXllLCBKLjwvYXV0

aG9yPjxhdXRob3I+TW9udGluZSwgVC4gSi48L2F1dGhvcj48YXV0aG9yPlBhcmssIEQuIEMuPC9h

dXRob3I+PGF1dGhvcj5SZWltYW4sIEUuIE0uPC9hdXRob3I+PGF1dGhvcj5Sb3dlLCBDLiBDLjwv

YXV0aG9yPjxhdXRob3I+U2llbWVycywgRS48L2F1dGhvcj48YXV0aG9yPlN0ZXJuLCBZLjwvYXV0

aG9yPjxhdXRob3I+WWFmZmUsIEsuPC9hdXRob3I+PGF1dGhvcj5DYXJyaWxsbywgTS4gQy48L2F1

dGhvcj48YXV0aG9yPlRoaWVzLCBCLjwvYXV0aG9yPjxhdXRob3I+TW9ycmlzb24tQm9nb3JhZCwg

TS48L2F1dGhvcj48YXV0aG9yPldhZ3N0ZXIsIE0uIFYuPC9hdXRob3I+PGF1dGhvcj5QaGVscHMs

IEMuIEguPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+Q2Vu

dGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2ggYW5kIFRyZWF0bWVudCwgRGVwYXJ0bWVudCBvZiBO

ZXVyb2xvZ3ksIEJyaWdoYW0gYW5kIFdvbWVuJmFwb3M7cyBIb3NwaXRhbCwgSGFydmFyZCBNZWRp

Y2FsIFNjaG9vbCwgQm9zdG9uLCBNQSwgVVNBLiByZWlzYUByaWNzLmJ3aC5oYXJ2YXJkLmVkdTwv

YXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRvd2FyZCBkZWZpbmluZyB0aGUgcHJlY2xpbmlj

YWwgc3RhZ2VzIG9mIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogcmVjb21tZW5kYXRpb25zIGZy

b20gdGhlIE5hdGlvbmFsIEluc3RpdHV0ZSBvbiBBZ2luZy1BbHpoZWltZXImYXBvcztzIEFzc29j

aWF0aW9uIHdvcmtncm91cHMgb24gZGlhZ25vc3RpYyBndWlkZWxpbmVzIGZvciBBbHpoZWltZXIm

YXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWx6aGVpbWVycyBEZW1lbnQ8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MjgwLTkyPC9wYWdlcz48dm9sdW1lPjc8

L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERp

c2Vhc2UvKmRpYWdub3Npcy9waHlzaW9wYXRob2xvZ3kvcHN5Y2hvbG9neTwva2V5d29yZD48a2V5

d29yZD5CaW9tYXJrZXJzL2FuYWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbiBEaXNv

cmRlcnMvKmRpYWdub3Npcy9waHlzaW9wYXRob2xvZ3kvcHN5Y2hvbG9neTwva2V5d29yZD48a2V5

d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TmF0aW9uYWwgSW5zdGl0dXRlIG9uIEFnaW5n

IChVLlMuKS8qc3RhbmRhcmRzPC9rZXl3b3JkPjxrZXl3b3JkPlByYWN0aWNlIEd1aWRlbGluZXMg

YXMgVG9waWMvKnN0YW5kYXJkczwva2V5d29yZD48a2V5d29yZD5Vbml0ZWQgU3RhdGVzPC9rZXl3

b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5N

YXk8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTUyLTUyNzkgKEVsZWN0cm9uaWMp

JiN4RDsxNTUyLTUyNjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIxNTE0MjQ4PC9h

Y2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxt

Lm5paC5nb3YvcHVibWVkLzIxNTE0MjQ4PC91cmw+PHVybD5odHRwczovL2FjLmVscy1jZG4uY29t

L1MxNTUyNTI2MDExMDAwOTk5LzEtczIuMC1TMTU1MjUyNjAxMTAwMDk5OS1tYWluLnBkZj9fdGlk

PWFjYzA5MjJjLTM1NjEtNGIzYy04MmVjLTAwNTkwZTNhZjZkMiZhbXA7YWNkbmF0PTE1MzQ0OTQ4

MjBfMGUyNTdiN2E0ZTM3ZDczNjc0NDNkMWRlYzUwOTRmYTE8L3VybD48L3JlbGF0ZWQtdXJscz48

L3VybHM+PGN1c3RvbTI+UE1DMzIyMDk0NjwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+MTAuMTAxNi9qLmphbHouMjAxMS4wMy4wMDM8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwv

cmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TcGVybGluZzwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

PFJlY051bT4zNzM8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij40MDc8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zNzM8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjU0OTMzNCI+MzczPC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TcGVybGluZywgUi4gQS48L2F1dGhvcj48

YXV0aG9yPkFpc2VuLCBQLiBTLjwvYXV0aG9yPjxhdXRob3I+QmVja2V0dCwgTC4gQS48L2F1dGhv

cj48YXV0aG9yPkJlbm5ldHQsIEQuIEEuPC9hdXRob3I+PGF1dGhvcj5DcmFmdCwgUy48L2F1dGhv

cj48YXV0aG9yPkZhZ2FuLCBBLiBNLjwvYXV0aG9yPjxhdXRob3I+SXdhdHN1Ym8sIFQuPC9hdXRo

b3I+PGF1dGhvcj5KYWNrLCBDLiBSLiwgSnIuPC9hdXRob3I+PGF1dGhvcj5LYXllLCBKLjwvYXV0

aG9yPjxhdXRob3I+TW9udGluZSwgVC4gSi48L2F1dGhvcj48YXV0aG9yPlBhcmssIEQuIEMuPC9h

dXRob3I+PGF1dGhvcj5SZWltYW4sIEUuIE0uPC9hdXRob3I+PGF1dGhvcj5Sb3dlLCBDLiBDLjwv

YXV0aG9yPjxhdXRob3I+U2llbWVycywgRS48L2F1dGhvcj48YXV0aG9yPlN0ZXJuLCBZLjwvYXV0

aG9yPjxhdXRob3I+WWFmZmUsIEsuPC9hdXRob3I+PGF1dGhvcj5DYXJyaWxsbywgTS4gQy48L2F1

dGhvcj48YXV0aG9yPlRoaWVzLCBCLjwvYXV0aG9yPjxhdXRob3I+TW9ycmlzb24tQm9nb3JhZCwg

TS48L2F1dGhvcj48YXV0aG9yPldhZ3N0ZXIsIE0uIFYuPC9hdXRob3I+PGF1dGhvcj5QaGVscHMs

IEMuIEguPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+Q2Vu

dGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2ggYW5kIFRyZWF0bWVudCwgRGVwYXJ0bWVudCBvZiBO

ZXVyb2xvZ3ksIEJyaWdoYW0gYW5kIFdvbWVuJmFwb3M7cyBIb3NwaXRhbCwgSGFydmFyZCBNZWRp

Y2FsIFNjaG9vbCwgQm9zdG9uLCBNQSwgVVNBLiByZWlzYUByaWNzLmJ3aC5oYXJ2YXJkLmVkdTwv

YXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRvd2FyZCBkZWZpbmluZyB0aGUgcHJlY2xpbmlj

YWwgc3RhZ2VzIG9mIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogcmVjb21tZW5kYXRpb25zIGZy

b20gdGhlIE5hdGlvbmFsIEluc3RpdHV0ZSBvbiBBZ2luZy1BbHpoZWltZXImYXBvcztzIEFzc29j

aWF0aW9uIHdvcmtncm91cHMgb24gZGlhZ25vc3RpYyBndWlkZWxpbmVzIGZvciBBbHpoZWltZXIm

YXBvcztzIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWx6aGVpbWVycyBEZW1lbnQ8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MjgwLTkyPC9wYWdlcz48dm9sdW1lPjc8

L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERp

c2Vhc2UvKmRpYWdub3Npcy9waHlzaW9wYXRob2xvZ3kvcHN5Y2hvbG9neTwva2V5d29yZD48a2V5

d29yZD5CaW9tYXJrZXJzL2FuYWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbiBEaXNv

cmRlcnMvKmRpYWdub3Npcy9waHlzaW9wYXRob2xvZ3kvcHN5Y2hvbG9neTwva2V5d29yZD48a2V5

d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TmF0aW9uYWwgSW5zdGl0dXRlIG9uIEFnaW5n

IChVLlMuKS8qc3RhbmRhcmRzPC9rZXl3b3JkPjxrZXl3b3JkPlByYWN0aWNlIEd1aWRlbGluZXMg

YXMgVG9waWMvKnN0YW5kYXJkczwva2V5d29yZD48a2V5d29yZD5Vbml0ZWQgU3RhdGVzPC9rZXl3

b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5N

YXk8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTUyLTUyNzkgKEVsZWN0cm9uaWMp

JiN4RDsxNTUyLTUyNjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIxNTE0MjQ4PC9h

Y2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxt

Lm5paC5nb3YvcHVibWVkLzIxNTE0MjQ4PC91cmw+PHVybD5odHRwczovL2FjLmVscy1jZG4uY29t

L1MxNTUyNTI2MDExMDAwOTk5LzEtczIuMC1TMTU1MjUyNjAxMTAwMDk5OS1tYWluLnBkZj9fdGlk

PWFjYzA5MjJjLTM1NjEtNGIzYy04MmVjLTAwNTkwZTNhZjZkMiZhbXA7YWNkbmF0PTE1MzQ0OTQ4

MjBfMGUyNTdiN2E0ZTM3ZDczNjc0NDNkMWRlYzUwOTRmYTE8L3VybD48L3JlbGF0ZWQtdXJscz48

L3VybHM+PGN1c3RvbTI+UE1DMzIyMDk0NjwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+MTAuMTAxNi9qLmphbHouMjAxMS4wMy4wMDM8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwv

cmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 407. Yet, from a neurobiological perspective, AD leads to neuronal death, synapse loss and decrease of cognitive function for reasons still unknown, and progresses in a continuum. Therefore, it is difficult to divide into defined stages. For these reasons, the NIA-AA has released a research framework suggesting a biological definition of AD based largely on biomarkers from living patients combined with cognitive tests PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KYWNrPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj

TnVtPjEyMzk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij41

NTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEyMzk8L3JlYy1udW1i

ZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBo

cGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDQyNTk3NiI+MTIzOTwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SmFjaywgQy4gUi4sIEpyLjwvYXV0aG9yPjxh

dXRob3I+QmVubmV0dCwgRC4gQS48L2F1dGhvcj48YXV0aG9yPkJsZW5ub3csIEsuPC9hdXRob3I+

PGF1dGhvcj5DYXJyaWxsbywgTS4gQy48L2F1dGhvcj48YXV0aG9yPkR1bm4sIEIuPC9hdXRob3I+

PGF1dGhvcj5IYWViZXJsZWluLCBTLiBCLjwvYXV0aG9yPjxhdXRob3I+SG9sdHptYW4sIEQuIE0u

PC9hdXRob3I+PGF1dGhvcj5KYWd1c3QsIFcuPC9hdXRob3I+PGF1dGhvcj5KZXNzZW4sIEYuPC9h

dXRob3I+PGF1dGhvcj5LYXJsYXdpc2gsIEouPC9hdXRob3I+PGF1dGhvcj5MaXUsIEUuPC9hdXRo

b3I+PGF1dGhvcj5Nb2xpbnVldm8sIEouIEwuPC9hdXRob3I+PGF1dGhvcj5Nb250aW5lLCBULjwv

YXV0aG9yPjxhdXRob3I+UGhlbHBzLCBDLjwvYXV0aG9yPjxhdXRob3I+UmFua2luLCBLLiBQLjwv

YXV0aG9yPjxhdXRob3I+Um93ZSwgQy4gQy48L2F1dGhvcj48YXV0aG9yPlNjaGVsdGVucywgUC48

L2F1dGhvcj48YXV0aG9yPlNpZW1lcnMsIEUuPC9hdXRob3I+PGF1dGhvcj5TbnlkZXIsIEguIE0u

PC9hdXRob3I+PGF1dGhvcj5TcGVybGluZywgUi48L2F1dGhvcj48YXV0aG9yPkNvbnRyaWJ1dG9y

cyw8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRt

ZW50IG9mIFJhZGlvbG9neSwgTWF5byBDbGluaWMsIFJvY2hlc3RlciwgTU4sIFVTQS4gRWxlY3Ry

b25pYyBhZGRyZXNzOiBqYWNrLmNsaWZmb3JkQG1heW8uZWR1LiYjeEQ7RGVwYXJ0bWVudCBvZiBO

ZXVyb2xvZ2ljYWwgU2NpZW5jZXMsIFJ1c2ggVW5pdmVyc2l0eSwgQ2hpY2FnbywgSUwsIFVTQS4m

I3hEO0RlcGFydG1lbnQgb2YgUHN5Y2hpYXRyeSBhbmQgTmV1cm9jaGVtaXN0cnksIFVuaXZlcnNp

dHkgb2YgR290aGVuYnVyZywgR290aGVuYnVyZywgU3dlZGVuLiYjeEQ7TWVkaWNhbCAmYW1wOyBT

Y2llbnRpZmljIFJlbGF0aW9ucywgQWx6aGVpbWVyJmFwb3M7cyBBc3NvY2lhdGlvbiwgQ2hpY2Fn

bywgSUwsIFVTQS4mI3hEO09mZmljZSBvZiBEcnVnIEV2YWx1YXRpb24sIEZEQSwgU2lsdmVyIFNw

cmluZywgTUQsIFVTQS4mI3hEO0Jpb2dlbiwgQ2FtYnJpZGdlLCBNQSwgVVNBLiYjeEQ7RGVwYXJ0

bWVudCBvZiBOZXVyb2xvZ3ksIFdhc2hpbmd0b24gVW5pdmVyc2l0eSwgU3QuIExvdWlzLCBNTywg

VVNBLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoIGFuZCBOZXVyb3NjaWVuY2UsIFVu

aXZlcnNpdHkgb2YgQ2FsaWZvcm5pYSBCZXJrZWxleSwgQmVya2VsZXksIENBLCBVU0EuJiN4RDtE

ZXBhcnRtZW50IG9mIFBzeWNoaWF0cnksIFVuaXZlcnNpdHkgb2YgQ29sb2duZSwgTWVkaWNhbCBG

YWN1bHR5LCBDb2xvZ25lLCBHZXJtYW55LiYjeEQ7RGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgVW5p

dmVyc2l0eSBvZiBQZW5uc3lsdmFuaWEsIFBoaWxhZGVscGhpYSwgUEEsIFVTQS4mI3hEO1Byb3Ro

ZW5hIEJpb3NjaWVuY2VzLCBJbmMuLCBTYW4gRnJhbmNpc2NvLCBDQSwgVVNBLiYjeEQ7QmFyY2Vs

b25hQmV0YSBCcmFpbiBSZXNlYXJjaCBDZW50ZXIsIFBhc3F1YWwgTWFyYWdhbGwgRm91bmRhdGlv

biBhbmQgSG9zcGl0YWwgQ2xpbmljLUlESUJBUFMsIEJhcmNlbG9uYSwgU3BhaW4uJiN4RDtEZXBh

cnRtZW50IG9mIFBhdGhvbG9neSwgU3RhbmZvcmQgVW5pdmVyc2l0eSwgU3RhbmRmb3JkLCBDQSwg

VVNBLiYjeEQ7Rm9ybWVybHkgYXQgTmF0aW9uYWwgSW5zdGl0dXRlIG9uIEFnaW5nLCBCZXRoZXNk

YSwgTUQsIFVTQS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IG9mIENh

bGlmb3JuaWEgU2FuIEZyYW5jaXNjbywgU2FuIEZyYW5jaXNjbywgQ0EsIFVTQS4mI3hEO0RlcGFy

dG1lbnQgb2YgTW9sZWN1bGFyIEltYWdpbmcsIEF1c3RpbiBIZWFsdGgsIFVuaXZlcnNpdHkgb2Yg

TWVsYm91cm5lLCBNZWxib3VybmUsIEF1c3RyYWxpYS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9s

b2d5LCBWVSBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBBbXN0ZXJkYW0sIE5ldGhlcmxhbmRz

LiYjeEQ7Rm9ybWVybHkgYXQgRWxpIExpbGx5IGFuZCBDb21wYW55LCBJbmRpYW5hcG9saXMsIElO

LCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgQnJpZ2hhbSBhbmQgV29tZW4mYXBv

cztzIEhvc3BpdGFsLCBCb3N0b24sIE1BLCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+TklBLUFBIFJlc2VhcmNoIEZyYW1ld29yazogVG93YXJkIGEgYmlvbG9naWNhbCBkZWZpbml0

aW9uIG9mIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5B

bHpoZWltZXJzIERlbWVudDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz41MzUtNTYy

PC9wYWdlcz48dm9sdW1lPjE0PC92b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PGtleXdvcmRzPjxr

ZXl3b3JkPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZSBkaWFnbm9zaXM8L2tleXdvcmQ+PGtleXdv

cmQ+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+QW15

bG9pZCBQRVQ8L2tleXdvcmQ+PGtleXdvcmQ+QmlvbWFya2VycyBBbHpoZWltZXImYXBvcztzIGRp

c2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Q1NGIGJpb21hcmtlcnMgQWx6aGVpbWVyJmFwb3M7cyBk

aXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPlByZWNsaW5pY2FsIEFsemhlaW1lciZhcG9zO3MgZGlz

ZWFzZTwva2V5d29yZD48a2V5d29yZD5UYXUgUEVUPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVz

Pjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BcHI8L2RhdGU+PC9wdWItZGF0ZXM+

PC9kYXRlcz48aXNibj4xNTUyLTUyNzkgKEVsZWN0cm9uaWMpJiN4RDsxNTUyLTUyNjAgKExpbmtp

bmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5NjUzNjA2PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxy

ZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yOTY1

MzYwNjwvdXJsPjx1cmw+aHR0cHM6Ly9hYy5lbHMtY2RuLmNvbS9TMTU1MjUyNjAxODMwMDcyNC8x

LXMyLjAtUzE1NTI1MjYwMTgzMDA3MjQtbWFpbi5wZGY/X3RpZD1kZmFjYzM3Zi0yMDE0LTRiOWMt

YTViZS05NDlhMzliMTA2ZTMmYW1wO2FjZG5hdD0xNTM0NDk0OTAwX2NlNjM0NjZkMmJhM2UwZmI0

MjJmMWQwODJiZjAzY2E5PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzU5

NTg2MjU8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5qYWx6LjIw

MTguMDIuMDE4PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmRO

b3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KYWNrPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj

TnVtPjEyMzk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij41

NTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEyMzk8L3JlYy1udW1i

ZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBo

cGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDQyNTk3NiI+MTIzOTwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SmFjaywgQy4gUi4sIEpyLjwvYXV0aG9yPjxh

dXRob3I+QmVubmV0dCwgRC4gQS48L2F1dGhvcj48YXV0aG9yPkJsZW5ub3csIEsuPC9hdXRob3I+

PGF1dGhvcj5DYXJyaWxsbywgTS4gQy48L2F1dGhvcj48YXV0aG9yPkR1bm4sIEIuPC9hdXRob3I+

PGF1dGhvcj5IYWViZXJsZWluLCBTLiBCLjwvYXV0aG9yPjxhdXRob3I+SG9sdHptYW4sIEQuIE0u

PC9hdXRob3I+PGF1dGhvcj5KYWd1c3QsIFcuPC9hdXRob3I+PGF1dGhvcj5KZXNzZW4sIEYuPC9h

dXRob3I+PGF1dGhvcj5LYXJsYXdpc2gsIEouPC9hdXRob3I+PGF1dGhvcj5MaXUsIEUuPC9hdXRo

b3I+PGF1dGhvcj5Nb2xpbnVldm8sIEouIEwuPC9hdXRob3I+PGF1dGhvcj5Nb250aW5lLCBULjwv

YXV0aG9yPjxhdXRob3I+UGhlbHBzLCBDLjwvYXV0aG9yPjxhdXRob3I+UmFua2luLCBLLiBQLjwv

YXV0aG9yPjxhdXRob3I+Um93ZSwgQy4gQy48L2F1dGhvcj48YXV0aG9yPlNjaGVsdGVucywgUC48

L2F1dGhvcj48YXV0aG9yPlNpZW1lcnMsIEUuPC9hdXRob3I+PGF1dGhvcj5TbnlkZXIsIEguIE0u

PC9hdXRob3I+PGF1dGhvcj5TcGVybGluZywgUi48L2F1dGhvcj48YXV0aG9yPkNvbnRyaWJ1dG9y

cyw8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRt

ZW50IG9mIFJhZGlvbG9neSwgTWF5byBDbGluaWMsIFJvY2hlc3RlciwgTU4sIFVTQS4gRWxlY3Ry

b25pYyBhZGRyZXNzOiBqYWNrLmNsaWZmb3JkQG1heW8uZWR1LiYjeEQ7RGVwYXJ0bWVudCBvZiBO

ZXVyb2xvZ2ljYWwgU2NpZW5jZXMsIFJ1c2ggVW5pdmVyc2l0eSwgQ2hpY2FnbywgSUwsIFVTQS4m

I3hEO0RlcGFydG1lbnQgb2YgUHN5Y2hpYXRyeSBhbmQgTmV1cm9jaGVtaXN0cnksIFVuaXZlcnNp

dHkgb2YgR290aGVuYnVyZywgR290aGVuYnVyZywgU3dlZGVuLiYjeEQ7TWVkaWNhbCAmYW1wOyBT

Y2llbnRpZmljIFJlbGF0aW9ucywgQWx6aGVpbWVyJmFwb3M7cyBBc3NvY2lhdGlvbiwgQ2hpY2Fn

bywgSUwsIFVTQS4mI3hEO09mZmljZSBvZiBEcnVnIEV2YWx1YXRpb24sIEZEQSwgU2lsdmVyIFNw

cmluZywgTUQsIFVTQS4mI3hEO0Jpb2dlbiwgQ2FtYnJpZGdlLCBNQSwgVVNBLiYjeEQ7RGVwYXJ0

bWVudCBvZiBOZXVyb2xvZ3ksIFdhc2hpbmd0b24gVW5pdmVyc2l0eSwgU3QuIExvdWlzLCBNTywg

VVNBLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoIGFuZCBOZXVyb3NjaWVuY2UsIFVu

aXZlcnNpdHkgb2YgQ2FsaWZvcm5pYSBCZXJrZWxleSwgQmVya2VsZXksIENBLCBVU0EuJiN4RDtE

ZXBhcnRtZW50IG9mIFBzeWNoaWF0cnksIFVuaXZlcnNpdHkgb2YgQ29sb2duZSwgTWVkaWNhbCBG

YWN1bHR5LCBDb2xvZ25lLCBHZXJtYW55LiYjeEQ7RGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgVW5p

dmVyc2l0eSBvZiBQZW5uc3lsdmFuaWEsIFBoaWxhZGVscGhpYSwgUEEsIFVTQS4mI3hEO1Byb3Ro

ZW5hIEJpb3NjaWVuY2VzLCBJbmMuLCBTYW4gRnJhbmNpc2NvLCBDQSwgVVNBLiYjeEQ7QmFyY2Vs

b25hQmV0YSBCcmFpbiBSZXNlYXJjaCBDZW50ZXIsIFBhc3F1YWwgTWFyYWdhbGwgRm91bmRhdGlv

biBhbmQgSG9zcGl0YWwgQ2xpbmljLUlESUJBUFMsIEJhcmNlbG9uYSwgU3BhaW4uJiN4RDtEZXBh

cnRtZW50IG9mIFBhdGhvbG9neSwgU3RhbmZvcmQgVW5pdmVyc2l0eSwgU3RhbmRmb3JkLCBDQSwg

VVNBLiYjeEQ7Rm9ybWVybHkgYXQgTmF0aW9uYWwgSW5zdGl0dXRlIG9uIEFnaW5nLCBCZXRoZXNk

YSwgTUQsIFVTQS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IG9mIENh

bGlmb3JuaWEgU2FuIEZyYW5jaXNjbywgU2FuIEZyYW5jaXNjbywgQ0EsIFVTQS4mI3hEO0RlcGFy

dG1lbnQgb2YgTW9sZWN1bGFyIEltYWdpbmcsIEF1c3RpbiBIZWFsdGgsIFVuaXZlcnNpdHkgb2Yg

TWVsYm91cm5lLCBNZWxib3VybmUsIEF1c3RyYWxpYS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9s

b2d5LCBWVSBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBBbXN0ZXJkYW0sIE5ldGhlcmxhbmRz

LiYjeEQ7Rm9ybWVybHkgYXQgRWxpIExpbGx5IGFuZCBDb21wYW55LCBJbmRpYW5hcG9saXMsIElO

LCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgQnJpZ2hhbSBhbmQgV29tZW4mYXBv

cztzIEhvc3BpdGFsLCBCb3N0b24sIE1BLCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+TklBLUFBIFJlc2VhcmNoIEZyYW1ld29yazogVG93YXJkIGEgYmlvbG9naWNhbCBkZWZpbml0

aW9uIG9mIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5B

bHpoZWltZXJzIERlbWVudDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz41MzUtNTYy

PC9wYWdlcz48dm9sdW1lPjE0PC92b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PGtleXdvcmRzPjxr

ZXl3b3JkPkFsemhlaW1lciZhcG9zO3MgZGlzZWFzZSBkaWFnbm9zaXM8L2tleXdvcmQ+PGtleXdv

cmQ+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+QW15

bG9pZCBQRVQ8L2tleXdvcmQ+PGtleXdvcmQ+QmlvbWFya2VycyBBbHpoZWltZXImYXBvcztzIGRp

c2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Q1NGIGJpb21hcmtlcnMgQWx6aGVpbWVyJmFwb3M7cyBk

aXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPlByZWNsaW5pY2FsIEFsemhlaW1lciZhcG9zO3MgZGlz

ZWFzZTwva2V5d29yZD48a2V5d29yZD5UYXUgUEVUPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVz

Pjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BcHI8L2RhdGU+PC9wdWItZGF0ZXM+

PC9kYXRlcz48aXNibj4xNTUyLTUyNzkgKEVsZWN0cm9uaWMpJiN4RDsxNTUyLTUyNjAgKExpbmtp

bmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5NjUzNjA2PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxy

ZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yOTY1

MzYwNjwvdXJsPjx1cmw+aHR0cHM6Ly9hYy5lbHMtY2RuLmNvbS9TMTU1MjUyNjAxODMwMDcyNC8x

LXMyLjAtUzE1NTI1MjYwMTgzMDA3MjQtbWFpbi5wZGY/X3RpZD1kZmFjYzM3Zi0yMDE0LTRiOWMt

YTViZS05NDlhMzliMTA2ZTMmYW1wO2FjZG5hdD0xNTM0NDk0OTAwX2NlNjM0NjZkMmJhM2UwZmI0

MjJmMWQwODJiZjAzY2E5PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzU5

NTg2MjU8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5qYWx6LjIw

MTguMDIuMDE4PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmRO

b3RlPgB=

ADDIN EN.CITE.DATA 55. These guidelines represent an effort to help more accurate characterizations of the etiology of AD and help intervention studies targeting specific pathways involved in AD. Nevertheless, a clear stratification of AD requires much more research into the newly discovered mechanisms of disease progression. In this work, we have revised the new risk factors that involve different pathways influencing AD development. However, screenings for all of these pathways are challenging for the clinic, sometimes requiring advanced techniques such as mass spectroscopy or special tracers PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Jc21haWw8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS

ZWNOdW0+MjYzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDI4PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjYzPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzEiPjI2Mzwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SXNtYWlsLCBNLiBBLjwvYXV0aG9yPjxhdXRo

b3I+TWF0ZW9zLCBMLjwvYXV0aG9yPjxhdXRob3I+TWFpb2xpLCBTLjwvYXV0aG9yPjxhdXRob3I+

TWVyaW5vLVNlcnJhaXMsIFAuPC9hdXRob3I+PGF1dGhvcj5BbGksIFouPC9hdXRob3I+PGF1dGhv

cj5Mb2RlaXJvLCBNLjwvYXV0aG9yPjxhdXRob3I+V2VzdG1hbiwgRS48L2F1dGhvcj48YXV0aG9y

PkxlaXRlcnNkb3JmLCBFLjwvYXV0aG9yPjxhdXRob3I+R3VseWFzLCBCLjwvYXV0aG9yPjxhdXRo

b3I+T2xvZi1XYWhsdW5kLCBMLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48

YXV0aG9yPlNhdml0Y2hldmEsIEkuPC9hdXRob3I+PGF1dGhvcj5Cam9ya2hlbSwgSS48L2F1dGhv

cj48YXV0aG9yPkNlZGF6by1NaW5ndWV6LCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0cmljcywgQ2VudGVyIGZv

ciBBbHpoZWltZXIgUmVzZWFyY2gsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNj

aWVuY2VzLCBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCAxNDEgODYgU3RvY2to

b2xtLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBDbGluaWNhbCBDaGVtaXN0cnksIERlcGFydG1l

bnQgb2YgTGFib3JhdG9yeSBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFs

LCAxNDEgODYgSHVkZGluZ2UsIFN3ZWRlbi4mI3hEO0RpdmlzaW9uIG9mIENsaW5pY2FsIEdlcmlh

dHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5ldXJv

YmlvbG9neSwgQ2FyZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0dXRl

dCwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7Q2VudGVyIGZvciBSZXNlYXJjaCwgUHJl

dmVudGlvbiwgYW5kIFRyZWF0bWVudCBvZiBBdGhlcm9zY2xlcm9zaXMsIEhhZGFzc2FoIEhlYnJl

dyBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBKZXJ1c2FsZW0gOTExMjAsIElzcmFlbC4mI3hE

O0NlbnRyZSBmb3IgUHN5Y2hpYXRyeSBSZXNlYXJjaCwgRGVwYXJ0bWVudCBvZiBDbGluaWNhbCBO

ZXVyb3NjaWVuY2UsIEthcm9saW5za2EgSW5zdGl0dXRldCwgMTcxIDc3IFN0b2NraG9sbSwgU3dl

ZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBSYWRpb2xvZ3ksIEthcm9saW5za2EgVW5pdmVyc2l0eSBI

b3NwaXRhbCwgMTQxIDg2IEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBOZXVyb2dl

cmlhdHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5l

dXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0

dXRldCwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuIEFuZ2VsLkNlZGF6by1NaW5ndWV6QGtpLnNl

LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPjI3LUh5ZHJveHljaG9sZXN0ZXJvbCBpbXBh

aXJzIG5ldXJvbmFsIGdsdWNvc2UgdXB0YWtlIHRocm91Z2ggYW4gSVJBUC9HTFVUNCBzeXN0ZW0g

ZHlzcmVndWxhdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEV4cCBNZWQ8L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGFnZXM+Njk5LTcxNzwvcGFnZXM+PHZvbHVtZT4yMTQ8L3ZvbHVt

ZT48bnVtYmVyPjM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5naW90ZW5zaW4gSUkvYW5h

bG9ncyAmYW1wOyBkZXJpdmF0aXZlcy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW5p

bWFsczwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0YW5ldHJpb2wgMjYtTW9ub294eWdlbmFzZS9w

aHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sL21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+Q3lzdGlueWwgQW1pbm9wZXB0aWRhc2UvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+R2x1Y29zZS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5HbHVjb3NlIFRy

YW5zcG9ydGVyIFR5cGUgNC8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tl

eXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy8qcGhhcm1hY29sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkxpdmVyIFggUmVjZXB0b3JzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdv

cmQ+TmV1cm9ucy8qbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWFyIDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48aXNibj4xNTQwLTk1MzggKEVsZWN0cm9uaWMpJiN4RDswMDIyLTEwMDcgKExpbmtpbmcpPC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjI4MjEzNTEyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI4MjEzNTEyPC91

cmw+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3BtYy9hcnRpY2xlcy9QTUM1MzM5

NjY5L3BkZi9KRU1fMjAxNjA1MzQucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0

b20yPlBNQzUzMzk2Njk8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwODQv

amVtLjIwMTYwNTM0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Jc21haWw8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS

ZWNOdW0+MjYzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDI4PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjYzPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzE3NzUyNzEiPjI2Mzwva2V5PjwvZm9y

ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48

Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SXNtYWlsLCBNLiBBLjwvYXV0aG9yPjxhdXRo

b3I+TWF0ZW9zLCBMLjwvYXV0aG9yPjxhdXRob3I+TWFpb2xpLCBTLjwvYXV0aG9yPjxhdXRob3I+

TWVyaW5vLVNlcnJhaXMsIFAuPC9hdXRob3I+PGF1dGhvcj5BbGksIFouPC9hdXRob3I+PGF1dGhv

cj5Mb2RlaXJvLCBNLjwvYXV0aG9yPjxhdXRob3I+V2VzdG1hbiwgRS48L2F1dGhvcj48YXV0aG9y

PkxlaXRlcnNkb3JmLCBFLjwvYXV0aG9yPjxhdXRob3I+R3VseWFzLCBCLjwvYXV0aG9yPjxhdXRo

b3I+T2xvZi1XYWhsdW5kLCBMLjwvYXV0aG9yPjxhdXRob3I+V2luYmxhZCwgQi48L2F1dGhvcj48

YXV0aG9yPlNhdml0Y2hldmEsIEkuPC9hdXRob3I+PGF1dGhvcj5Cam9ya2hlbSwgSS48L2F1dGhv

cj48YXV0aG9yPkNlZGF6by1NaW5ndWV6LCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0cmljcywgQ2VudGVyIGZv

ciBBbHpoZWltZXIgUmVzZWFyY2gsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNj

aWVuY2VzLCBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCAxNDEgODYgU3RvY2to

b2xtLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBDbGluaWNhbCBDaGVtaXN0cnksIERlcGFydG1l

bnQgb2YgTGFib3JhdG9yeSBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFs

LCAxNDEgODYgSHVkZGluZ2UsIFN3ZWRlbi4mI3hEO0RpdmlzaW9uIG9mIENsaW5pY2FsIEdlcmlh

dHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5ldXJv

YmlvbG9neSwgQ2FyZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0dXRl

dCwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7Q2VudGVyIGZvciBSZXNlYXJjaCwgUHJl

dmVudGlvbiwgYW5kIFRyZWF0bWVudCBvZiBBdGhlcm9zY2xlcm9zaXMsIEhhZGFzc2FoIEhlYnJl

dyBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBKZXJ1c2FsZW0gOTExMjAsIElzcmFlbC4mI3hE

O0NlbnRyZSBmb3IgUHN5Y2hpYXRyeSBSZXNlYXJjaCwgRGVwYXJ0bWVudCBvZiBDbGluaWNhbCBO

ZXVyb3NjaWVuY2UsIEthcm9saW5za2EgSW5zdGl0dXRldCwgMTcxIDc3IFN0b2NraG9sbSwgU3dl

ZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBSYWRpb2xvZ3ksIEthcm9saW5za2EgVW5pdmVyc2l0eSBI

b3NwaXRhbCwgMTQxIDg2IEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtEaXZpc2lvbiBvZiBOZXVyb2dl

cmlhdHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEZXBhcnRtZW50IG9mIE5l

dXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcywgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5zdGl0

dXRldCwgMTQxIDg2IFN0b2NraG9sbSwgU3dlZGVuIEFuZ2VsLkNlZGF6by1NaW5ndWV6QGtpLnNl

LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPjI3LUh5ZHJveHljaG9sZXN0ZXJvbCBpbXBh

aXJzIG5ldXJvbmFsIGdsdWNvc2UgdXB0YWtlIHRocm91Z2ggYW4gSVJBUC9HTFVUNCBzeXN0ZW0g

ZHlzcmVndWxhdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEV4cCBNZWQ8L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGFnZXM+Njk5LTcxNzwvcGFnZXM+PHZvbHVtZT4yMTQ8L3ZvbHVt

ZT48bnVtYmVyPjM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5naW90ZW5zaW4gSUkvYW5h

bG9ncyAmYW1wOyBkZXJpdmF0aXZlcy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW5p

bWFsczwva2V5d29yZD48a2V5d29yZD5DaG9sZXN0YW5ldHJpb2wgMjYtTW9ub294eWdlbmFzZS9w

aHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNob2xlc3Rlcm9sL21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+Q3lzdGlueWwgQW1pbm9wZXB0aWRhc2UvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+R2x1Y29zZS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5HbHVjb3NlIFRy

YW5zcG9ydGVyIFR5cGUgNC8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tl

eXdvcmQ+PGtleXdvcmQ+SHlkcm94eWNob2xlc3Rlcm9scy8qcGhhcm1hY29sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkxpdmVyIFggUmVjZXB0b3JzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdv

cmQ+TmV1cm9ucy8qbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWFyIDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48aXNibj4xNTQwLTk1MzggKEVsZWN0cm9uaWMpJiN4RDswMDIyLTEwMDcgKExpbmtpbmcpPC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjI4MjEzNTEyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI4MjEzNTEyPC91

cmw+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3BtYy9hcnRpY2xlcy9QTUM1MzM5

NjY5L3BkZi9KRU1fMjAxNjA1MzQucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0

b20yPlBNQzUzMzk2Njk8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwODQv

amVtLjIwMTYwNTM0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPn==

ADDIN EN.CITE.DATA 428. Many of these methods require considerable technical knowledge or are too expensive for basic diagnostic laboratories. Still, the importance of novel biomarker detection lies in the possibility for intervention PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJlbmdvbmk8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFy

PjxSZWNOdW0+MzU5PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjM2LDQwMSw0MDM8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4z

NTk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1

MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjU0ODYzNCI+MzU5

PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8

L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5NYXJlbmdvbmksIEEuPC9h

dXRob3I+PGF1dGhvcj5SaXp6dXRvLCBELjwvYXV0aG9yPjxhdXRob3I+RnJhdGlnbGlvbmksIEwu

PC9hdXRob3I+PGF1dGhvcj5BbnRpa2FpbmVuLCBSLjwvYXV0aG9yPjxhdXRob3I+TGFhdGlrYWlu

ZW4sIFQuPC9hdXRob3I+PGF1dGhvcj5MZWh0aXNhbG8sIEouPC9hdXRob3I+PGF1dGhvcj5QZWx0

b25lbiwgTS48L2F1dGhvcj48YXV0aG9yPlNvaW5pbmVuLCBILjwvYXV0aG9yPjxhdXRob3I+U3Ry

YW5kYmVyZywgVC48L2F1dGhvcj48YXV0aG9yPlR1b21pbGVodG8sIEouPC9hdXRob3I+PGF1dGhv

cj5LaXZpcGVsdG8sIE0uPC9hdXRob3I+PGF1dGhvcj5OZ2FuZHUsIFQuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBDbGluaWNhbCBh

bmQgRXhwZXJpbWVudGFsIFNjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIEJyZXNjaWEsIEJyZXNjaWEs

IEl0YWx5OyBBZ2luZyBSZXNlYXJjaCBDZW50ZXIsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5

LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIGFuZCBT

dG9ja2hvbG0gVW5pdmVyc2l0eSwgU3RvY2tob2xtLCBTd2VkZW4uIEVsZWN0cm9uaWMgYWRkcmVz

czogYWxlc3NhbmRyYS5tYXJlbmdvbmlAa2kuc2UuJiN4RDtBZ2luZyBSZXNlYXJjaCBDZW50ZXIs

IERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBL

YXJvbGluc2thIEluc3RpdHV0ZXQsIGFuZCBTdG9ja2hvbG0gVW5pdmVyc2l0eSwgU3RvY2tob2xt

LCBTd2VkZW4uJiN4RDtBZ2luZyBSZXNlYXJjaCBDZW50ZXIsIERlcGFydG1lbnQgb2YgTmV1cm9i

aW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBLYXJvbGluc2thIEluc3RpdHV0ZXQs

IGFuZCBTdG9ja2hvbG0gVW5pdmVyc2l0eSwgU3RvY2tob2xtLCBTd2VkZW47IFN0b2NraG9sbSBH

ZXJvbnRvbG9neSBSZXNlYXJjaCBDZW50ZXIsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7Q2VudGVy

IGZvciBMaWZlIENvdXJzZSBIZWFsdGggUmVzZWFyY2gvR2VyaWF0cmljcywgVW5pdmVyc2l0eSBv

ZiBPdWx1LCBPdWx1LCBGaW5sYW5kOyBNZWRpY2FsIFJlc2VhcmNoIENlbnRlciBPdWx1LCBPdWx1

IFVuaXZlcnNpdHkgSG9zcGl0YWwsIE91bHUsIEZpbmxhbmQ7IE91bHUgQ2l0eSBIb3NwaXRhbCwg

T3VsdSwgRmlubGFuZC4mI3hEO0RlcGFydG1lbnQgb2YgUHVibGljIEhlYWx0aCBTb2x1dGlvbnMs

IENocm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0ZSBmb3Ig

SGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlubGFuZDsgSW5zdGl0dXRlIG9mIFB1Ymxp

YyBIZWFsdGggYW5kIENsaW5pY2FsIE51dHJpdGlvbiwgVW5pdmVyc2l0eSBvZiBFYXN0ZXJuIEZp

bmxhbmQsIEt1b3BpbywgRmlubGFuZDsgSm9pbnQgbXVuaWNpcGFsIGF1dGhvcml0eSBmb3IgTm9y

dGggS2FyZWxpYSBzb2NpYWwgYW5kIGhlYWx0aCBzZXJ2aWNlcywgSm9lbnN1dSwgRmlubGFuZC4m

I3hEO0RlcGFydG1lbnQgb2YgUHVibGljIEhlYWx0aCBTb2x1dGlvbnMsIENocm9uaWMgRGlzZWFz

ZSBQcmV2ZW50aW9uIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRoIGFuZCBXZWxm

YXJlLCBIZWxzaW5raSwgRmlubGFuZDsgRGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoLCBVbml2

ZXJzaXR5IG9mIEhlbHNpbmtpLCBIZWxzaW5raSwgRmlubGFuZC4mI3hEO0RlcGFydG1lbnQgb2Yg

UHVibGljIEhlYWx0aCBTb2x1dGlvbnMsIENocm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQs

IE5hdGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlu

bGFuZC4mI3hEO0luc3RpdHV0ZSBvZiBDbGluaWNhbCBNZWRpY2luZS9OZXVyb2xvZ3ksIFVuaXZl

cnNpdHkgb2YgRWFzdGVybiBGaW5sYW5kLCBLdW9waW8sIEZpbmxhbmQuJiN4RDtDZW50ZXIgZm9y

IExpZmUgQ291cnNlIEhlYWx0aCBSZXNlYXJjaC9HZXJpYXRyaWNzLCBVbml2ZXJzaXR5IG9mIE91

bHUsIE91bHUsIEZpbmxhbmQ7IE1lZGljYWwgUmVzZWFyY2ggQ2VudGVyIE91bHUsIE91bHUgVW5p

dmVyc2l0eSBIb3NwaXRhbCwgT3VsdSwgRmlubGFuZDsgVW5pdmVyc2l0eSBvZiBIZWxzaW5raSwg

SGVsc2lua2kgVW5pdmVyc2l0eSBIb3NwaXRhbCwgSGVsc2lua2ksIEZpbmxhbmQuJiN4RDtEZXBh

cnRtZW50IG9mIFB1YmxpYyBIZWFsdGggU29sdXRpb25zLCBDaHJvbmljIERpc2Vhc2UgUHJldmVu

dGlvbiBVbml0LCBOYXRpb25hbCBJbnN0aXR1dGUgZm9yIEhlYWx0aCBhbmQgV2VsZmFyZSwgSGVs

c2lua2ksIEZpbmxhbmQ7IERlcGFydG1lbnQgb2YgUHVibGljIEhlYWx0aCwgVW5pdmVyc2l0eSBv

ZiBIZWxzaW5raSwgSGVsc2lua2ksIEZpbmxhbmQ7IFNvdXRoIE9zdHJvYm90aG5pYSBDZW50cmFs

IEhvc3BpdGFsLCBTZWluYWpva2ksIEZpbmxhbmQ7IERhc21hbiBEaWFiZXRlcyBJbnN0aXR1dGUs

IERhc21hbiwgS3V3YWl0OyBEaWFiZXRlcyBSZXNlYXJjaCBHcm91cCwgS2luZyBBYmR1bGF6aXog

VW5pdmVyc2l0eSwgSmVkZGFoLCBTYXVkaSBBcmFiaWEuJiN4RDtBZ2luZyBSZXNlYXJjaCBDZW50

ZXIsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5

LCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIGFuZCBTdG9ja2hvbG0gVW5pdmVyc2l0eSwgU3RvY2to

b2xtLCBTd2VkZW47IERlcGFydG1lbnQgb2YgUHVibGljIEhlYWx0aCBTb2x1dGlvbnMsIENocm9u

aWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRo

IGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlubGFuZDsgSW5zdGl0dXRlIG9mIENsaW5pY2FsIE1l

ZGljaW5lL05ldXJvbG9neSwgVW5pdmVyc2l0eSBvZiBFYXN0ZXJuIEZpbmxhbmQsIEt1b3Bpbywg

RmlubGFuZDsgRGl2aXNpb24gb2YgQ2xpbmljYWwgR2VyaWF0cmljcywgQ2VudGVyIGZvciBBbHpo

ZWltZXIgUmVzZWFyY2gsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2Vz

IGFuZCBTb2NpZXR5LCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVuOyBT

dG9ja2hvbG1zIFNqdWtoZW0sIFJlc2VhcmNoICZhbXA7IERldmVsb3BtZW50IHVuaXQsIFN0b2Nr

aG9sbSwgU3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoIFNvbHV0aW9ucywg

Q2hyb25pYyBEaXNlYXNlIFByZXZlbnRpb24gVW5pdCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBI

ZWFsdGggYW5kIFdlbGZhcmUsIEhlbHNpbmtpLCBGaW5sYW5kOyBEaXZpc2lvbiBvZiBDbGluaWNh

bCBHZXJpYXRyaWNzLCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGVwYXJ0bWVudCBv

ZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5z

dGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+

VGhlIEVmZmVjdCBvZiBhIDItWWVhciBJbnRlcnZlbnRpb24gQ29uc2lzdGluZyBvZiBEaWV0LCBQ

aHlzaWNhbCBFeGVyY2lzZSwgQ29nbml0aXZlIFRyYWluaW5nLCBhbmQgTW9uaXRvcmluZyBvZiBW

YXNjdWxhciBSaXNrIG9uIENocm9uaWMgTW9yYmlkaXR5LXRoZSBGSU5HRVIgUmFuZG9taXplZCBD

b250cm9sbGVkIFRyaWFsPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogQW0gTWVkIERpciBBc3Nv

Yzwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4zNTUtMzYwIGUxPC9wYWdlcz48dm9s

dW1lPjE5PC92b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkRpZXQ8

L2tleXdvcmQ+PGtleXdvcmQ+Y2hyb25pYyBtb3JiaWRpdHk8L2tleXdvcmQ+PGtleXdvcmQ+Y29n

bml0aXZlIHRyYWluaW5nPC9rZXl3b3JkPjxrZXl3b3JkPnBoeXNpY2FsIGV4ZXJjaXNlPC9rZXl3

b3JkPjxrZXl3b3JkPnJhbmRvbWl6ZWQgY2xpbmljYWwgdHJpYWw8L2tleXdvcmQ+PGtleXdvcmQ+

dmFzY3VsYXIgcmlzazwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE4PC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+QXByPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUz

OC05Mzc1IChFbGVjdHJvbmljKSYjeEQ7MTUyNS04NjEwIChMaW5raW5nKTwvaXNibj48YWNjZXNz

aW9uLW51bT4yOTEwODg4ODwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+

aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yOTEwODg4ODwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmphbWRhLjIw

MTcuMDkuMDIwPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+

PEF1dGhvcj5Sb3NlbmJlcmc8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxSZWNOdW0+MzYwPC9S

ZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zNjA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48

a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYi

IHRpbWVzdGFtcD0iMTUzMjU0ODYzNCI+MzYwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5Sb3NlbmJlcmcsIEEuPC9hdXRob3I+PGF1dGhvcj5OZ2FuZHUsIFQuPC9hdXRo

b3I+PGF1dGhvcj5SdXNhbmVuLCBNLjwvYXV0aG9yPjxhdXRob3I+QW50aWthaW5lbiwgUi48L2F1

dGhvcj48YXV0aG9yPkJhY2ttYW4sIEwuPC9hdXRob3I+PGF1dGhvcj5IYXZ1bGlubmEsIFMuPC9h

dXRob3I+PGF1dGhvcj5IYW5uaW5lbiwgVC48L2F1dGhvcj48YXV0aG9yPkxhYXRpa2FpbmVuLCBU

LjwvYXV0aG9yPjxhdXRob3I+TGVodGlzYWxvLCBKLjwvYXV0aG9yPjxhdXRob3I+TGV2YWxhaHRp

LCBFLjwvYXV0aG9yPjxhdXRob3I+TGluZHN0cm9tLCBKLjwvYXV0aG9yPjxhdXRob3I+UGFhamFu

ZW4sIFQuPC9hdXRob3I+PGF1dGhvcj5QZWx0b25lbiwgTS48L2F1dGhvcj48YXV0aG9yPlNvaW5p

bmVuLCBILjwvYXV0aG9yPjxhdXRob3I+U3RpZ3Nkb3R0ZXItTmVlbHksIEEuPC9hdXRob3I+PGF1

dGhvcj5TdHJhbmRiZXJnLCBULjwvYXV0aG9yPjxhdXRob3I+VHVvbWlsZWh0bywgSi48L2F1dGhv

cj48YXV0aG9yPlNvbG9tb24sIEEuPC9hdXRob3I+PGF1dGhvcj5LaXZpcGVsdG8sIE0uPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+SW5zdGl0dXRlIG9mIENs

aW5pY2FsIE1lZGljaW5lLCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgVW5pdmVyc2l0eSBvZiBF

YXN0ZXJuIEZpbmxhbmQsIEt1b3BpbywgRmlubGFuZC4gRWxlY3Ryb25pYyBhZGRyZXNzOiBhbm5h

LnJvc2VuYmVyZ0B1ZWYuZmkuJiN4RDtEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFsdGggU29sdXRp

b25zLCBDaHJvbmljIERpc2Vhc2UgUHJldmVudGlvbiBVbml0LCBOYXRpb25hbCBJbnN0aXR1dGUg

Zm9yIEhlYWx0aCBhbmQgV2VsZmFyZSwgSGVsc2lua2ksIEZpbmxhbmQ7IERpdmlzaW9uIG9mIENs

aW5pY2FsIEdlcmlhdHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBOVlMsIEth

cm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50IG9m

IFB1YmxpYyBIZWFsdGggU29sdXRpb25zLCBDaHJvbmljIERpc2Vhc2UgUHJldmVudGlvbiBVbml0

LCBOYXRpb25hbCBJbnN0aXR1dGUgZm9yIEhlYWx0aCBhbmQgV2VsZmFyZSwgSGVsc2lua2ksIEZp

bmxhbmQ7IERpdmlzaW9uIG9mIENsaW5pY2FsIEdlcmlhdHJpY3MsIENlbnRlciBmb3IgQWx6aGVp

bWVyIFJlc2VhcmNoLCBOVlMsIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2Vk

ZW47IERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBOb3J0aCBLYXJlbGlhIENlbnRyYWwgSG9zcGl0

YWwsIEpvZW5zdXUsIEZpbmxhbmQuJiN4RDtDZW50ZXIgZm9yIExpZmUgQ291cnNlIEhlYWx0aCBS

ZXNlYXJjaC9HZXJpYXRyaWNzLCBVbml2ZXJzaXR5IG9mIE91bHUsIE91bHUsIEZpbmxhbmQ7IE1l

ZGljYWwgUmVzZWFyY2ggQ2VudGVyIE91bHUsIE91bHUgVW5pdmVyc2l0eSBIb3NwaXRhbCwgT3Vs

dSwgRmlubGFuZDsgT3VsdSBDaXR5IEhvc3BpdGFsLCBPdWx1LCBGaW5sYW5kLiYjeEQ7QWdpbmcg

UmVzZWFyY2ggQ2VudGVyLCBLYXJvbGluc2thIEluc3RpdHV0ZXQtU3RvY2tob2xtIFVuaXZlcnNp

dHksIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7QWdpbmcsIERpc2FiaWxpdHkgYW5kIEZ1bmN0aW9u

aW5nIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxz

aW5raSwgRmlubGFuZC4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBLdW9waW8gVW5pdmVy

c2l0eSBIb3NwaXRhbCwgS3VvcGlvLCBGaW5sYW5kLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMg

SGVhbHRoIFNvbHV0aW9ucywgQ2hyb25pYyBEaXNlYXNlIFByZXZlbnRpb24gVW5pdCwgTmF0aW9u

YWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5kIFdlbGZhcmUsIEhlbHNpbmtpLCBGaW5sYW5kOyBJ

bnN0aXR1dGUgb2YgUHVibGljIEhlYWx0aCBhbmQgQ2xpbmljYWwgTnV0cml0aW9uLCBVbml2ZXJz

aXR5IG9mIEVhc3Rlcm4gRmlubGFuZCwgS3VvcGlvLCBGaW5sYW5kOyBKb2ludCBtdW5pY2lwYWwg

YXV0aG9yaXR5IGZvciBOb3J0aCBLYXJlbGlhIFNvY2lhbCBhbmQgSGVhbHRoIHNlcnZpY2VzLCBK

b2Vuc3V1LCBGaW5sYW5kLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoIFNvbHV0aW9u

cywgQ2hyb25pYyBEaXNlYXNlIFByZXZlbnRpb24gVW5pdCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZv

ciBIZWFsdGggYW5kIFdlbGZhcmUsIEhlbHNpbmtpLCBGaW5sYW5kOyBEZXBhcnRtZW50IG9mIFB1

YmxpYyBIZWFsdGgsIFVuaXZlcnNpdHkgb2YgSGVsc2lua2ksIEhlbHNpbmtpLCBGaW5sYW5kLiYj

eEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoIFNvbHV0aW9ucywgQ2hyb25pYyBEaXNlYXNl

IFByZXZlbnRpb24gVW5pdCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5kIFdlbGZh

cmUsIEhlbHNpbmtpLCBGaW5sYW5kLiYjeEQ7RmlubmlzaCBJbnN0aXR1dGUgb2YgT2NjdXBhdGlv

bmFsIEhlYWx0aCwgSGVsc2lua2ksIEZpbmxhbmQuJiN4RDtJbnN0aXR1dGUgb2YgQ2xpbmljYWwg

TWVkaWNpbmUsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IG9mIEVhc3Rlcm4g

RmlubGFuZCwgS3VvcGlvLCBGaW5sYW5kOyBOZXVyb2NlbnRlciwgTmV1cm9sb2d5LCBLdW9waW8g

VW5pdmVyc2l0eSBIb3NwaXRhbCwgS3VvcGlvLCBGaW5sYW5kLiYjeEQ7RGVwYXJ0bWVudCBvZiBQ

c3ljaG9sb2d5LCBVbWVhIFVuaXZlcnNpdHksIFVtZWEsIFN3ZWRlbjsgRGVwYXJ0bWVudCBvZiBT

b2NpYWwgYW5kIFBzeWNob2xvZ2ljYWwgU2NpZW5jZXMsIEthcmxzdGFkIFVuaXZlcnNpdHksIEth

cmxzdGFkLCBTd2VkZW4uJiN4RDtDZW50ZXIgZm9yIExpZmUgQ291cnNlIEhlYWx0aCBSZXNlYXJj

aC9HZXJpYXRyaWNzLCBVbml2ZXJzaXR5IG9mIE91bHUsIE91bHUsIEZpbmxhbmQ7IE1lZGljYWwg

UmVzZWFyY2ggQ2VudGVyIE91bHUsIE91bHUgVW5pdmVyc2l0eSBIb3NwaXRhbCwgT3VsdSwgRmlu

bGFuZDsgVW5pdmVyc2l0eSBvZiBIZWxzaW5raSwgSGVsc2lua2kgVW5pdmVyc2l0eSBIb3NwaXRh

bCwgSGVsc2lua2ksIEZpbmxhbmQuJiN4RDtEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFsdGggU29s

dXRpb25zLCBDaHJvbmljIERpc2Vhc2UgUHJldmVudGlvbiBVbml0LCBOYXRpb25hbCBJbnN0aXR1

dGUgZm9yIEhlYWx0aCBhbmQgV2VsZmFyZSwgSGVsc2lua2ksIEZpbmxhbmQ7IERlcGFydG1lbnQg

b2YgUHVibGljIEhlYWx0aCwgVW5pdmVyc2l0eSBvZiBIZWxzaW5raSwgSGVsc2lua2ksIEZpbmxh

bmQ7IFNvdXRoIE9zdHJvYm90aG5pYSBDZW50cmFsIEhvc3BpdGFsLCBTZWluYWpva2ksIEZpbmxh

bmQuJiN4RDtJbnN0aXR1dGUgb2YgQ2xpbmljYWwgTWVkaWNpbmUsIERlcGFydG1lbnQgb2YgTmV1

cm9sb2d5LCBVbml2ZXJzaXR5IG9mIEVhc3Rlcm4gRmlubGFuZCwgS3VvcGlvLCBGaW5sYW5kOyBE

aXZpc2lvbiBvZiBDbGluaWNhbCBHZXJpYXRyaWNzLCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNl

YXJjaCwgTlZTLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVuOyBBZ2lu

ZyBSZXNlYXJjaCBDZW50ZXIsIEthcm9saW5za2EgSW5zdGl0dXRldC1TdG9ja2hvbG0gVW5pdmVy

c2l0eSwgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtJbnN0aXR1dGUgb2YgQ2xpbmljYWwgTWVkaWNp

bmUsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IG9mIEVhc3Rlcm4gRmlubGFu

ZCwgS3VvcGlvLCBGaW5sYW5kOyBEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFsdGggU29sdXRpb25z

LCBDaHJvbmljIERpc2Vhc2UgUHJldmVudGlvbiBVbml0LCBOYXRpb25hbCBJbnN0aXR1dGUgZm9y

IEhlYWx0aCBhbmQgV2VsZmFyZSwgSGVsc2lua2ksIEZpbmxhbmQ7IERpdmlzaW9uIG9mIENsaW5p

Y2FsIEdlcmlhdHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBOVlMsIEthcm9s

aW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW47IEFnaW5nIFJlc2VhcmNoIENlbnRl

ciwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LVN0b2NraG9sbSBVbml2ZXJzaXR5LCBTdG9ja2hvbG0s

IFN3ZWRlbjsgU3RvY2tob2xtcyBTanVraGVtLCBSZXNlYXJjaCAmYW1wOyBEZXZlbG9wbWVudCBV

bml0LCBTdG9ja2hvbG0sIFN3ZWRlbi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5NdWx0

aWRvbWFpbiBsaWZlc3R5bGUgaW50ZXJ2ZW50aW9uIGJlbmVmaXRzIGEgbGFyZ2UgZWxkZXJseSBw

b3B1bGF0aW9uIGF0IHJpc2sgZm9yIGNvZ25pdGl2ZSBkZWNsaW5lIGFuZCBkZW1lbnRpYSByZWdh

cmRsZXNzIG9mIGJhc2VsaW5lIGNoYXJhY3RlcmlzdGljczogVGhlIEZJTkdFUiB0cmlhbDwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5BbHpoZWltZXJzIERlbWVudDwvc2Vjb25kYXJ5LXRpdGxlPjwv

dGl0bGVzPjxwYWdlcz4yNjMtMjcwPC9wYWdlcz48dm9sdW1lPjE0PC92b2x1bWU+PG51bWJlcj4z

PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPipBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+KkNvZ25pdGl2ZSBpbXBhaXJtZW50PC9rZXl3b3JkPjxrZXl3b3JkPipE

ZW1lbnRpYTwva2V5d29yZD48a2V5d29yZD4qSW50ZXJ2ZW50aW9uPC9rZXl3b3JkPjxrZXl3b3Jk

PipMaWZlc3R5bGU8L2tleXdvcmQ+PGtleXdvcmQ+Kk11bHRpZG9tYWluPC9rZXl3b3JkPjxrZXl3

b3JkPipQcmV2ZW50aW9uPC9rZXl3b3JkPjxrZXl3b3JkPipSYW5kb21pemVkIGNvbnRyb2xsZWQg

dHJpYWw8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxODwveWVhcj48cHViLWRh

dGVzPjxkYXRlPk1hcjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTItNTI3OSAo

RWxlY3Ryb25pYykmI3hEOzE1NTItNTI2MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+

MjkwNTU4MTQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93

d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjkwNTU4MTQ8L3VybD48L3JlbGF0ZWQtdXJscz48

L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5qYWx6LjIwMTcuMDkuMDA2

PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5N

ZWRpbmE8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNOdW0+MjYwPC9SZWNOdW0+PHJlY29y

ZD48cmVjLW51bWJlcj4yNjA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0i

MTUzMTc3NTI3MSI+MjYwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5N

ZWRpbmEsIE0uPC9hdXRob3I+PGF1dGhvcj5LaGFjaGF0dXJpYW4sIFouIFMuPC9hdXRob3I+PGF1

dGhvcj5Sb3Nzb3IsIE0uPC9hdXRob3I+PGF1dGhvcj5BdmlsYSwgSi48L2F1dGhvcj48YXV0aG9y

PkNlZGF6by1NaW5ndWV6LCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0

aC1hZGRyZXNzPkNJQkVSTkVEIChOZXR3b3JrIENlbnRlciBmb3IgQmlvbWVkaWNhbCBSZXNlYXJj

aCBpbiBOZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcyksIElTQ0lJSSwgTWFkcmlkLCBTcGFpbi4m

I3hEO0NJRU4gRm91bmRhdGlvbiwgUmVpbmEgU29maWEgRm91bmRhdGlvbiBBbHpoZWltZXIgQ2Vu

dGVyLCBNYWRyaWQsIFNwYWluLiYjeEQ7UEFEMjAyMCwgUG90b21hYywgTUQsIFVTQS4mI3hEO0lu

c3RpdHV0ZSBvZiBOZXVyb2xvZ3ksIFVuaXZlcnNpdHkgQ29sbGVnZSBMb25kb24sIExvbmRvbiwg

VUsuJiN4RDtOZXVyb2Jpb2xvZ3kgTGFib3JhdG9yeSwgQ2VudGVyIGZvciBNb2xlY3VsYXIgQmlv

bG9neSAmcXVvdDtTZXZlcm8gT2Nob2EmcXVvdDsgQ1NJQy1VQU0sIE1hZHJpZCwgU3BhaW4uJiN4

RDtEaXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5

LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJj

aCwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBTdG9ja2hvbG0sIFN3ZWRlbi48L2F1dGgtYWRkcmVz

cz48dGl0bGVzPjx0aXRsZT5Ub3dhcmQgY29tbW9uIG1lY2hhbmlzbXMgZm9yIHJpc2sgZmFjdG9y

cyBpbiBBbHpoZWltZXImYXBvcztzIHN5bmRyb21lPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFs

emhlaW1lcnMgRGVtZW50IChOIFkpPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+QWx6aGVpbWVycyBEZW1lbnQgKE4gWSk8L2Z1bGwtdGl0bGU+PC9wZXJp

b2RpY2FsPjxwYWdlcz41NzEtNTc4PC9wYWdlcz48dm9sdW1lPjM8L3ZvbHVtZT48bnVtYmVyPjQ8

L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyJmFwb3M7czwva2V5d29yZD48a2V5

d29yZD5EZW1lbnRpYTwva2V5d29yZD48a2V5d29yZD5QYXRob2dlbmVzaXM8L2tleXdvcmQ+PGtl

eXdvcmQ+UHJldmVudGlvbjwva2V5d29yZD48a2V5d29yZD5SaXNrIGZhY3RvcnM8L2tleXdvcmQ+

PGtleXdvcmQ+U3luZHJvbWU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju

PjIzNTItODczNyAoRWxlY3Ryb25pYykmI3hEOzIzNTItODczNyAoTGlua2luZyk8L2lzYm4+PGFj

Y2Vzc2lvbi1udW0+MjkxMjQxMTY8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48

dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjkxMjQxMTY8L3VybD48L3Jl

bGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNTY3MTYyODwvY3VzdG9tMj48ZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLnRyY2kuMjAxNy4wOC4wMDk8L2VsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJlbmdvbmk8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFy

PjxSZWNOdW0+MzU5PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+MjM2LDQwMSw0MDM8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4z

NTk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1

MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMjU0ODYzNCI+MzU5

PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8

L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5NYXJlbmdvbmksIEEuPC9h

dXRob3I+PGF1dGhvcj5SaXp6dXRvLCBELjwvYXV0aG9yPjxhdXRob3I+RnJhdGlnbGlvbmksIEwu

PC9hdXRob3I+PGF1dGhvcj5BbnRpa2FpbmVuLCBSLjwvYXV0aG9yPjxhdXRob3I+TGFhdGlrYWlu

ZW4sIFQuPC9hdXRob3I+PGF1dGhvcj5MZWh0aXNhbG8sIEouPC9hdXRob3I+PGF1dGhvcj5QZWx0

b25lbiwgTS48L2F1dGhvcj48YXV0aG9yPlNvaW5pbmVuLCBILjwvYXV0aG9yPjxhdXRob3I+U3Ry

YW5kYmVyZywgVC48L2F1dGhvcj48YXV0aG9yPlR1b21pbGVodG8sIEouPC9hdXRob3I+PGF1dGhv

cj5LaXZpcGVsdG8sIE0uPC9hdXRob3I+PGF1dGhvcj5OZ2FuZHUsIFQuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBDbGluaWNhbCBh

bmQgRXhwZXJpbWVudGFsIFNjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIEJyZXNjaWEsIEJyZXNjaWEs

IEl0YWx5OyBBZ2luZyBSZXNlYXJjaCBDZW50ZXIsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5

LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIGFuZCBT

dG9ja2hvbG0gVW5pdmVyc2l0eSwgU3RvY2tob2xtLCBTd2VkZW4uIEVsZWN0cm9uaWMgYWRkcmVz

czogYWxlc3NhbmRyYS5tYXJlbmdvbmlAa2kuc2UuJiN4RDtBZ2luZyBSZXNlYXJjaCBDZW50ZXIs

IERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBL

YXJvbGluc2thIEluc3RpdHV0ZXQsIGFuZCBTdG9ja2hvbG0gVW5pdmVyc2l0eSwgU3RvY2tob2xt

LCBTd2VkZW4uJiN4RDtBZ2luZyBSZXNlYXJjaCBDZW50ZXIsIERlcGFydG1lbnQgb2YgTmV1cm9i

aW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBLYXJvbGluc2thIEluc3RpdHV0ZXQs

IGFuZCBTdG9ja2hvbG0gVW5pdmVyc2l0eSwgU3RvY2tob2xtLCBTd2VkZW47IFN0b2NraG9sbSBH

ZXJvbnRvbG9neSBSZXNlYXJjaCBDZW50ZXIsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7Q2VudGVy

IGZvciBMaWZlIENvdXJzZSBIZWFsdGggUmVzZWFyY2gvR2VyaWF0cmljcywgVW5pdmVyc2l0eSBv

ZiBPdWx1LCBPdWx1LCBGaW5sYW5kOyBNZWRpY2FsIFJlc2VhcmNoIENlbnRlciBPdWx1LCBPdWx1

IFVuaXZlcnNpdHkgSG9zcGl0YWwsIE91bHUsIEZpbmxhbmQ7IE91bHUgQ2l0eSBIb3NwaXRhbCwg

T3VsdSwgRmlubGFuZC4mI3hEO0RlcGFydG1lbnQgb2YgUHVibGljIEhlYWx0aCBTb2x1dGlvbnMs

IENocm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0ZSBmb3Ig

SGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlubGFuZDsgSW5zdGl0dXRlIG9mIFB1Ymxp

YyBIZWFsdGggYW5kIENsaW5pY2FsIE51dHJpdGlvbiwgVW5pdmVyc2l0eSBvZiBFYXN0ZXJuIEZp

bmxhbmQsIEt1b3BpbywgRmlubGFuZDsgSm9pbnQgbXVuaWNpcGFsIGF1dGhvcml0eSBmb3IgTm9y

dGggS2FyZWxpYSBzb2NpYWwgYW5kIGhlYWx0aCBzZXJ2aWNlcywgSm9lbnN1dSwgRmlubGFuZC4m

I3hEO0RlcGFydG1lbnQgb2YgUHVibGljIEhlYWx0aCBTb2x1dGlvbnMsIENocm9uaWMgRGlzZWFz

ZSBQcmV2ZW50aW9uIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRoIGFuZCBXZWxm

YXJlLCBIZWxzaW5raSwgRmlubGFuZDsgRGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoLCBVbml2

ZXJzaXR5IG9mIEhlbHNpbmtpLCBIZWxzaW5raSwgRmlubGFuZC4mI3hEO0RlcGFydG1lbnQgb2Yg

UHVibGljIEhlYWx0aCBTb2x1dGlvbnMsIENocm9uaWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQs

IE5hdGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlu

bGFuZC4mI3hEO0luc3RpdHV0ZSBvZiBDbGluaWNhbCBNZWRpY2luZS9OZXVyb2xvZ3ksIFVuaXZl

cnNpdHkgb2YgRWFzdGVybiBGaW5sYW5kLCBLdW9waW8sIEZpbmxhbmQuJiN4RDtDZW50ZXIgZm9y

IExpZmUgQ291cnNlIEhlYWx0aCBSZXNlYXJjaC9HZXJpYXRyaWNzLCBVbml2ZXJzaXR5IG9mIE91

bHUsIE91bHUsIEZpbmxhbmQ7IE1lZGljYWwgUmVzZWFyY2ggQ2VudGVyIE91bHUsIE91bHUgVW5p

dmVyc2l0eSBIb3NwaXRhbCwgT3VsdSwgRmlubGFuZDsgVW5pdmVyc2l0eSBvZiBIZWxzaW5raSwg

SGVsc2lua2kgVW5pdmVyc2l0eSBIb3NwaXRhbCwgSGVsc2lua2ksIEZpbmxhbmQuJiN4RDtEZXBh

cnRtZW50IG9mIFB1YmxpYyBIZWFsdGggU29sdXRpb25zLCBDaHJvbmljIERpc2Vhc2UgUHJldmVu

dGlvbiBVbml0LCBOYXRpb25hbCBJbnN0aXR1dGUgZm9yIEhlYWx0aCBhbmQgV2VsZmFyZSwgSGVs

c2lua2ksIEZpbmxhbmQ7IERlcGFydG1lbnQgb2YgUHVibGljIEhlYWx0aCwgVW5pdmVyc2l0eSBv

ZiBIZWxzaW5raSwgSGVsc2lua2ksIEZpbmxhbmQ7IFNvdXRoIE9zdHJvYm90aG5pYSBDZW50cmFs

IEhvc3BpdGFsLCBTZWluYWpva2ksIEZpbmxhbmQ7IERhc21hbiBEaWFiZXRlcyBJbnN0aXR1dGUs

IERhc21hbiwgS3V3YWl0OyBEaWFiZXRlcyBSZXNlYXJjaCBHcm91cCwgS2luZyBBYmR1bGF6aXog

VW5pdmVyc2l0eSwgSmVkZGFoLCBTYXVkaSBBcmFiaWEuJiN4RDtBZ2luZyBSZXNlYXJjaCBDZW50

ZXIsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5

LCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIGFuZCBTdG9ja2hvbG0gVW5pdmVyc2l0eSwgU3RvY2to

b2xtLCBTd2VkZW47IERlcGFydG1lbnQgb2YgUHVibGljIEhlYWx0aCBTb2x1dGlvbnMsIENocm9u

aWMgRGlzZWFzZSBQcmV2ZW50aW9uIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRo

IGFuZCBXZWxmYXJlLCBIZWxzaW5raSwgRmlubGFuZDsgSW5zdGl0dXRlIG9mIENsaW5pY2FsIE1l

ZGljaW5lL05ldXJvbG9neSwgVW5pdmVyc2l0eSBvZiBFYXN0ZXJuIEZpbmxhbmQsIEt1b3Bpbywg

RmlubGFuZDsgRGl2aXNpb24gb2YgQ2xpbmljYWwgR2VyaWF0cmljcywgQ2VudGVyIGZvciBBbHpo

ZWltZXIgUmVzZWFyY2gsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2Vz

IGFuZCBTb2NpZXR5LCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVuOyBT

dG9ja2hvbG1zIFNqdWtoZW0sIFJlc2VhcmNoICZhbXA7IERldmVsb3BtZW50IHVuaXQsIFN0b2Nr

aG9sbSwgU3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoIFNvbHV0aW9ucywg

Q2hyb25pYyBEaXNlYXNlIFByZXZlbnRpb24gVW5pdCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBI

ZWFsdGggYW5kIFdlbGZhcmUsIEhlbHNpbmtpLCBGaW5sYW5kOyBEaXZpc2lvbiBvZiBDbGluaWNh

bCBHZXJpYXRyaWNzLCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGVwYXJ0bWVudCBv

ZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5jZXMgYW5kIFNvY2lldHksIEthcm9saW5za2EgSW5z

dGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+

VGhlIEVmZmVjdCBvZiBhIDItWWVhciBJbnRlcnZlbnRpb24gQ29uc2lzdGluZyBvZiBEaWV0LCBQ

aHlzaWNhbCBFeGVyY2lzZSwgQ29nbml0aXZlIFRyYWluaW5nLCBhbmQgTW9uaXRvcmluZyBvZiBW

YXNjdWxhciBSaXNrIG9uIENocm9uaWMgTW9yYmlkaXR5LXRoZSBGSU5HRVIgUmFuZG9taXplZCBD

b250cm9sbGVkIFRyaWFsPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogQW0gTWVkIERpciBBc3Nv

Yzwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4zNTUtMzYwIGUxPC9wYWdlcz48dm9s

dW1lPjE5PC92b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkRpZXQ8

L2tleXdvcmQ+PGtleXdvcmQ+Y2hyb25pYyBtb3JiaWRpdHk8L2tleXdvcmQ+PGtleXdvcmQ+Y29n

bml0aXZlIHRyYWluaW5nPC9rZXl3b3JkPjxrZXl3b3JkPnBoeXNpY2FsIGV4ZXJjaXNlPC9rZXl3

b3JkPjxrZXl3b3JkPnJhbmRvbWl6ZWQgY2xpbmljYWwgdHJpYWw8L2tleXdvcmQ+PGtleXdvcmQ+

dmFzY3VsYXIgcmlzazwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE4PC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+QXByPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUz

OC05Mzc1IChFbGVjdHJvbmljKSYjeEQ7MTUyNS04NjEwIChMaW5raW5nKTwvaXNibj48YWNjZXNz

aW9uLW51bT4yOTEwODg4ODwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+

aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yOTEwODg4ODwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmphbWRhLjIw

MTcuMDkuMDIwPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+

PEF1dGhvcj5Sb3NlbmJlcmc8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxSZWNOdW0+MzYwPC9S

ZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zNjA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48

a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYi

IHRpbWVzdGFtcD0iMTUzMjU0ODYzNCI+MzYwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5Sb3NlbmJlcmcsIEEuPC9hdXRob3I+PGF1dGhvcj5OZ2FuZHUsIFQuPC9hdXRo

b3I+PGF1dGhvcj5SdXNhbmVuLCBNLjwvYXV0aG9yPjxhdXRob3I+QW50aWthaW5lbiwgUi48L2F1

dGhvcj48YXV0aG9yPkJhY2ttYW4sIEwuPC9hdXRob3I+PGF1dGhvcj5IYXZ1bGlubmEsIFMuPC9h

dXRob3I+PGF1dGhvcj5IYW5uaW5lbiwgVC48L2F1dGhvcj48YXV0aG9yPkxhYXRpa2FpbmVuLCBU

LjwvYXV0aG9yPjxhdXRob3I+TGVodGlzYWxvLCBKLjwvYXV0aG9yPjxhdXRob3I+TGV2YWxhaHRp

LCBFLjwvYXV0aG9yPjxhdXRob3I+TGluZHN0cm9tLCBKLjwvYXV0aG9yPjxhdXRob3I+UGFhamFu

ZW4sIFQuPC9hdXRob3I+PGF1dGhvcj5QZWx0b25lbiwgTS48L2F1dGhvcj48YXV0aG9yPlNvaW5p

bmVuLCBILjwvYXV0aG9yPjxhdXRob3I+U3RpZ3Nkb3R0ZXItTmVlbHksIEEuPC9hdXRob3I+PGF1

dGhvcj5TdHJhbmRiZXJnLCBULjwvYXV0aG9yPjxhdXRob3I+VHVvbWlsZWh0bywgSi48L2F1dGhv

cj48YXV0aG9yPlNvbG9tb24sIEEuPC9hdXRob3I+PGF1dGhvcj5LaXZpcGVsdG8sIE0uPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+SW5zdGl0dXRlIG9mIENs

aW5pY2FsIE1lZGljaW5lLCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgVW5pdmVyc2l0eSBvZiBF

YXN0ZXJuIEZpbmxhbmQsIEt1b3BpbywgRmlubGFuZC4gRWxlY3Ryb25pYyBhZGRyZXNzOiBhbm5h

LnJvc2VuYmVyZ0B1ZWYuZmkuJiN4RDtEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFsdGggU29sdXRp

b25zLCBDaHJvbmljIERpc2Vhc2UgUHJldmVudGlvbiBVbml0LCBOYXRpb25hbCBJbnN0aXR1dGUg

Zm9yIEhlYWx0aCBhbmQgV2VsZmFyZSwgSGVsc2lua2ksIEZpbmxhbmQ7IERpdmlzaW9uIG9mIENs

aW5pY2FsIEdlcmlhdHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBOVlMsIEth

cm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtEZXBhcnRtZW50IG9m

IFB1YmxpYyBIZWFsdGggU29sdXRpb25zLCBDaHJvbmljIERpc2Vhc2UgUHJldmVudGlvbiBVbml0

LCBOYXRpb25hbCBJbnN0aXR1dGUgZm9yIEhlYWx0aCBhbmQgV2VsZmFyZSwgSGVsc2lua2ksIEZp

bmxhbmQ7IERpdmlzaW9uIG9mIENsaW5pY2FsIEdlcmlhdHJpY3MsIENlbnRlciBmb3IgQWx6aGVp

bWVyIFJlc2VhcmNoLCBOVlMsIEthcm9saW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2Vk

ZW47IERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBOb3J0aCBLYXJlbGlhIENlbnRyYWwgSG9zcGl0

YWwsIEpvZW5zdXUsIEZpbmxhbmQuJiN4RDtDZW50ZXIgZm9yIExpZmUgQ291cnNlIEhlYWx0aCBS

ZXNlYXJjaC9HZXJpYXRyaWNzLCBVbml2ZXJzaXR5IG9mIE91bHUsIE91bHUsIEZpbmxhbmQ7IE1l

ZGljYWwgUmVzZWFyY2ggQ2VudGVyIE91bHUsIE91bHUgVW5pdmVyc2l0eSBIb3NwaXRhbCwgT3Vs

dSwgRmlubGFuZDsgT3VsdSBDaXR5IEhvc3BpdGFsLCBPdWx1LCBGaW5sYW5kLiYjeEQ7QWdpbmcg

UmVzZWFyY2ggQ2VudGVyLCBLYXJvbGluc2thIEluc3RpdHV0ZXQtU3RvY2tob2xtIFVuaXZlcnNp

dHksIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7QWdpbmcsIERpc2FiaWxpdHkgYW5kIEZ1bmN0aW9u

aW5nIFVuaXQsIE5hdGlvbmFsIEluc3RpdHV0ZSBmb3IgSGVhbHRoIGFuZCBXZWxmYXJlLCBIZWxz

aW5raSwgRmlubGFuZC4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBLdW9waW8gVW5pdmVy

c2l0eSBIb3NwaXRhbCwgS3VvcGlvLCBGaW5sYW5kLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMg

SGVhbHRoIFNvbHV0aW9ucywgQ2hyb25pYyBEaXNlYXNlIFByZXZlbnRpb24gVW5pdCwgTmF0aW9u

YWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5kIFdlbGZhcmUsIEhlbHNpbmtpLCBGaW5sYW5kOyBJ

bnN0aXR1dGUgb2YgUHVibGljIEhlYWx0aCBhbmQgQ2xpbmljYWwgTnV0cml0aW9uLCBVbml2ZXJz

aXR5IG9mIEVhc3Rlcm4gRmlubGFuZCwgS3VvcGlvLCBGaW5sYW5kOyBKb2ludCBtdW5pY2lwYWwg

YXV0aG9yaXR5IGZvciBOb3J0aCBLYXJlbGlhIFNvY2lhbCBhbmQgSGVhbHRoIHNlcnZpY2VzLCBK

b2Vuc3V1LCBGaW5sYW5kLiYjeEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoIFNvbHV0aW9u

cywgQ2hyb25pYyBEaXNlYXNlIFByZXZlbnRpb24gVW5pdCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZv

ciBIZWFsdGggYW5kIFdlbGZhcmUsIEhlbHNpbmtpLCBGaW5sYW5kOyBEZXBhcnRtZW50IG9mIFB1

YmxpYyBIZWFsdGgsIFVuaXZlcnNpdHkgb2YgSGVsc2lua2ksIEhlbHNpbmtpLCBGaW5sYW5kLiYj

eEQ7RGVwYXJ0bWVudCBvZiBQdWJsaWMgSGVhbHRoIFNvbHV0aW9ucywgQ2hyb25pYyBEaXNlYXNl

IFByZXZlbnRpb24gVW5pdCwgTmF0aW9uYWwgSW5zdGl0dXRlIGZvciBIZWFsdGggYW5kIFdlbGZh

cmUsIEhlbHNpbmtpLCBGaW5sYW5kLiYjeEQ7RmlubmlzaCBJbnN0aXR1dGUgb2YgT2NjdXBhdGlv

bmFsIEhlYWx0aCwgSGVsc2lua2ksIEZpbmxhbmQuJiN4RDtJbnN0aXR1dGUgb2YgQ2xpbmljYWwg

TWVkaWNpbmUsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IG9mIEVhc3Rlcm4g

RmlubGFuZCwgS3VvcGlvLCBGaW5sYW5kOyBOZXVyb2NlbnRlciwgTmV1cm9sb2d5LCBLdW9waW8g

VW5pdmVyc2l0eSBIb3NwaXRhbCwgS3VvcGlvLCBGaW5sYW5kLiYjeEQ7RGVwYXJ0bWVudCBvZiBQ

c3ljaG9sb2d5LCBVbWVhIFVuaXZlcnNpdHksIFVtZWEsIFN3ZWRlbjsgRGVwYXJ0bWVudCBvZiBT

b2NpYWwgYW5kIFBzeWNob2xvZ2ljYWwgU2NpZW5jZXMsIEthcmxzdGFkIFVuaXZlcnNpdHksIEth

cmxzdGFkLCBTd2VkZW4uJiN4RDtDZW50ZXIgZm9yIExpZmUgQ291cnNlIEhlYWx0aCBSZXNlYXJj

aC9HZXJpYXRyaWNzLCBVbml2ZXJzaXR5IG9mIE91bHUsIE91bHUsIEZpbmxhbmQ7IE1lZGljYWwg

UmVzZWFyY2ggQ2VudGVyIE91bHUsIE91bHUgVW5pdmVyc2l0eSBIb3NwaXRhbCwgT3VsdSwgRmlu

bGFuZDsgVW5pdmVyc2l0eSBvZiBIZWxzaW5raSwgSGVsc2lua2kgVW5pdmVyc2l0eSBIb3NwaXRh

bCwgSGVsc2lua2ksIEZpbmxhbmQuJiN4RDtEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFsdGggU29s

dXRpb25zLCBDaHJvbmljIERpc2Vhc2UgUHJldmVudGlvbiBVbml0LCBOYXRpb25hbCBJbnN0aXR1

dGUgZm9yIEhlYWx0aCBhbmQgV2VsZmFyZSwgSGVsc2lua2ksIEZpbmxhbmQ7IERlcGFydG1lbnQg

b2YgUHVibGljIEhlYWx0aCwgVW5pdmVyc2l0eSBvZiBIZWxzaW5raSwgSGVsc2lua2ksIEZpbmxh

bmQ7IFNvdXRoIE9zdHJvYm90aG5pYSBDZW50cmFsIEhvc3BpdGFsLCBTZWluYWpva2ksIEZpbmxh

bmQuJiN4RDtJbnN0aXR1dGUgb2YgQ2xpbmljYWwgTWVkaWNpbmUsIERlcGFydG1lbnQgb2YgTmV1

cm9sb2d5LCBVbml2ZXJzaXR5IG9mIEVhc3Rlcm4gRmlubGFuZCwgS3VvcGlvLCBGaW5sYW5kOyBE

aXZpc2lvbiBvZiBDbGluaWNhbCBHZXJpYXRyaWNzLCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNl

YXJjaCwgTlZTLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVuOyBBZ2lu

ZyBSZXNlYXJjaCBDZW50ZXIsIEthcm9saW5za2EgSW5zdGl0dXRldC1TdG9ja2hvbG0gVW5pdmVy

c2l0eSwgU3RvY2tob2xtLCBTd2VkZW4uJiN4RDtJbnN0aXR1dGUgb2YgQ2xpbmljYWwgTWVkaWNp

bmUsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IG9mIEVhc3Rlcm4gRmlubGFu

ZCwgS3VvcGlvLCBGaW5sYW5kOyBEZXBhcnRtZW50IG9mIFB1YmxpYyBIZWFsdGggU29sdXRpb25z

LCBDaHJvbmljIERpc2Vhc2UgUHJldmVudGlvbiBVbml0LCBOYXRpb25hbCBJbnN0aXR1dGUgZm9y

IEhlYWx0aCBhbmQgV2VsZmFyZSwgSGVsc2lua2ksIEZpbmxhbmQ7IERpdmlzaW9uIG9mIENsaW5p

Y2FsIEdlcmlhdHJpY3MsIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBOVlMsIEthcm9s

aW5za2EgSW5zdGl0dXRldCwgU3RvY2tob2xtLCBTd2VkZW47IEFnaW5nIFJlc2VhcmNoIENlbnRl

ciwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LVN0b2NraG9sbSBVbml2ZXJzaXR5LCBTdG9ja2hvbG0s

IFN3ZWRlbjsgU3RvY2tob2xtcyBTanVraGVtLCBSZXNlYXJjaCAmYW1wOyBEZXZlbG9wbWVudCBV

bml0LCBTdG9ja2hvbG0sIFN3ZWRlbi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5NdWx0

aWRvbWFpbiBsaWZlc3R5bGUgaW50ZXJ2ZW50aW9uIGJlbmVmaXRzIGEgbGFyZ2UgZWxkZXJseSBw

b3B1bGF0aW9uIGF0IHJpc2sgZm9yIGNvZ25pdGl2ZSBkZWNsaW5lIGFuZCBkZW1lbnRpYSByZWdh

cmRsZXNzIG9mIGJhc2VsaW5lIGNoYXJhY3RlcmlzdGljczogVGhlIEZJTkdFUiB0cmlhbDwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5BbHpoZWltZXJzIERlbWVudDwvc2Vjb25kYXJ5LXRpdGxlPjwv

dGl0bGVzPjxwYWdlcz4yNjMtMjcwPC9wYWdlcz48dm9sdW1lPjE0PC92b2x1bWU+PG51bWJlcj4z

PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPipBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8L2tl

eXdvcmQ+PGtleXdvcmQ+KkNvZ25pdGl2ZSBpbXBhaXJtZW50PC9rZXl3b3JkPjxrZXl3b3JkPipE

ZW1lbnRpYTwva2V5d29yZD48a2V5d29yZD4qSW50ZXJ2ZW50aW9uPC9rZXl3b3JkPjxrZXl3b3Jk

PipMaWZlc3R5bGU8L2tleXdvcmQ+PGtleXdvcmQ+Kk11bHRpZG9tYWluPC9rZXl3b3JkPjxrZXl3

b3JkPipQcmV2ZW50aW9uPC9rZXl3b3JkPjxrZXl3b3JkPipSYW5kb21pemVkIGNvbnRyb2xsZWQg

dHJpYWw8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxODwveWVhcj48cHViLWRh

dGVzPjxkYXRlPk1hcjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTItNTI3OSAo

RWxlY3Ryb25pYykmI3hEOzE1NTItNTI2MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+

MjkwNTU4MTQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93

d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjkwNTU4MTQ8L3VybD48L3JlbGF0ZWQtdXJscz48

L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5qYWx6LjIwMTcuMDkuMDA2

PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5N

ZWRpbmE8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNOdW0+MjYwPC9SZWNOdW0+PHJlY29y

ZD48cmVjLW51bWJlcj4yNjA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0i

MTUzMTc3NTI3MSI+MjYwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5N

ZWRpbmEsIE0uPC9hdXRob3I+PGF1dGhvcj5LaGFjaGF0dXJpYW4sIFouIFMuPC9hdXRob3I+PGF1

dGhvcj5Sb3Nzb3IsIE0uPC9hdXRob3I+PGF1dGhvcj5BdmlsYSwgSi48L2F1dGhvcj48YXV0aG9y

PkNlZGF6by1NaW5ndWV6LCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0

aC1hZGRyZXNzPkNJQkVSTkVEIChOZXR3b3JrIENlbnRlciBmb3IgQmlvbWVkaWNhbCBSZXNlYXJj

aCBpbiBOZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcyksIElTQ0lJSSwgTWFkcmlkLCBTcGFpbi4m

I3hEO0NJRU4gRm91bmRhdGlvbiwgUmVpbmEgU29maWEgRm91bmRhdGlvbiBBbHpoZWltZXIgQ2Vu

dGVyLCBNYWRyaWQsIFNwYWluLiYjeEQ7UEFEMjAyMCwgUG90b21hYywgTUQsIFVTQS4mI3hEO0lu

c3RpdHV0ZSBvZiBOZXVyb2xvZ3ksIFVuaXZlcnNpdHkgQ29sbGVnZSBMb25kb24sIExvbmRvbiwg

VUsuJiN4RDtOZXVyb2Jpb2xvZ3kgTGFib3JhdG9yeSwgQ2VudGVyIGZvciBNb2xlY3VsYXIgQmlv

bG9neSAmcXVvdDtTZXZlcm8gT2Nob2EmcXVvdDsgQ1NJQy1VQU0sIE1hZHJpZCwgU3BhaW4uJiN4

RDtEaXZpc2lvbiBvZiBOZXVyb2dlcmlhdHJpY3MsIERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5

LCBDYXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJj

aCwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBTdG9ja2hvbG0sIFN3ZWRlbi48L2F1dGgtYWRkcmVz

cz48dGl0bGVzPjx0aXRsZT5Ub3dhcmQgY29tbW9uIG1lY2hhbmlzbXMgZm9yIHJpc2sgZmFjdG9y

cyBpbiBBbHpoZWltZXImYXBvcztzIHN5bmRyb21lPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFs

emhlaW1lcnMgRGVtZW50IChOIFkpPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+QWx6aGVpbWVycyBEZW1lbnQgKE4gWSk8L2Z1bGwtdGl0bGU+PC9wZXJp

b2RpY2FsPjxwYWdlcz41NzEtNTc4PC9wYWdlcz48dm9sdW1lPjM8L3ZvbHVtZT48bnVtYmVyPjQ8

L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyJmFwb3M7czwva2V5d29yZD48a2V5

d29yZD5EZW1lbnRpYTwva2V5d29yZD48a2V5d29yZD5QYXRob2dlbmVzaXM8L2tleXdvcmQ+PGtl

eXdvcmQ+UHJldmVudGlvbjwva2V5d29yZD48a2V5d29yZD5SaXNrIGZhY3RvcnM8L2tleXdvcmQ+

PGtleXdvcmQ+U3luZHJvbWU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNzwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju

PjIzNTItODczNyAoRWxlY3Ryb25pYykmI3hEOzIzNTItODczNyAoTGlua2luZyk8L2lzYm4+PGFj

Y2Vzc2lvbi1udW0+MjkxMjQxMTY8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48

dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjkxMjQxMTY8L3VybD48L3Jl

bGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNTY3MTYyODwvY3VzdG9tMj48ZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLnRyY2kuMjAxNy4wOC4wMDk8L2VsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 236,401,403, rather than a prediction of AD progression and thus, represent valuable lines of research. These new genes and molecules hold the potential to allow us categorization of AD subtypes based on the clinical history of the patient PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYW5pdGFsbGllPC9BdXRob3I+PFllYXI+MjAxMzwvWWVh

cj48UmVjTnVtPjEyNDE8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2Ny

aXB0Ij40MzgsNDM5PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTI0

MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUy

cHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0NDI4MjYzIj4xMjQx

PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8

L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5WYW5pdGFsbGllLCBULiBC

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1l

bnQgb2YgTWVkaWNpbmUsIERpdmlzaW9uIG9mIEVuZG9jcmlub2xvZ3ksIERpYWJldGVzLCBhbmQg

TnV0cml0aW9uLCBTdC4gTHVrZSZhcG9zO3MtUm9vc2V2ZWx0IEhvc3BpdGFsIENlbnRlciwgQ29s

dW1iaWEgVW5pdmVyc2l0eSBDb2xsZWdlIG9mIFBoeXNpY2lhbnMgJmFtcDsgU3VyZ2VvbnMsIE5l

dyBZb3JrLCBOWSAxMDAyNS4gZHJ2YW5pdGFsbGllQGNvbWNhc3QubmV0PC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+UHJlY2xpbmljYWwgc3BvcmFkaWMgQWx6aGVpbWVyJmFwb3M7cyBkaXNl

YXNlOiB0YXJnZXQgZm9yIHBlcnNvbmFsaXplZCBkaWFnbm9zaXMgYW5kIHByZXZlbnRpdmUgaW50

ZXJ2ZW50aW9uPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk1ldGFib2xpc208L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+UzMwLTM8L3BhZ2VzPjx2b2x1bWU+NjIgU3VwcGwgMTwvdm9s

dW1lPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2UgRmFjdG9yczwva2V5d29yZD48a2V5d29yZD5BbHpo

ZWltZXIgRGlzZWFzZS8qZGlhZ25vc2lzL2V0aW9sb2d5LypnZW5ldGljcy9tZXRhYm9saXNtL3Bh

dGhvbG9neS9wcmV2ZW50aW9uICZhbXA7PC9rZXl3b3JkPjxrZXl3b3JkPmNvbnRyb2w8L2tleXdv

cmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxr

ZXl3b3JkPkFwb2xpcG9wcm90ZWluIEU0LypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5CcmFp

bi8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DZWxsdWxhciBTZW5lc2NlbmNlLypnZW5l

dGljczwva2V5d29yZD48a2V5d29yZD5EaXNlYXNlIFByb2dyZXNzaW9uPC9rZXl3b3JkPjxrZXl3

b3JkPkVhcmx5IERpYWdub3Npczwva2V5d29yZD48a2V5d29yZD5GbHVvcm9kZW94eWdsdWNvc2Ug

RjE4L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+KkdlbmV0aWMgTWFya2Vyczwva2V5d29y

ZD48a2V5d29yZD5HZW5ldGljIFByZWRpc3Bvc2l0aW9uIHRvIERpc2Vhc2U8L2tleXdvcmQ+PGtl

eXdvcmQ+R2x1Y29zZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29y

ZD48a2V5d29yZD5NYWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5N

YXNzIFNjcmVlbmluZzwva2V5d29yZD48a2V5d29yZD5NaXRvY2hvbmRyaWEvZ2VuZXRpY3MvbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5OZXVyb2ltYWdpbmcvbWV0aG9kczwva2V5d29yZD48

a2V5d29yZD5Qb3NpdHJvbi1FbWlzc2lvbiBUb21vZ3JhcGh5L21ldGhvZHM8L2tleXdvcmQ+PGtl

eXdvcmQ+KlByZWNpc2lvbiBNZWRpY2luZS9tZXRob2RzL3RyZW5kczwva2V5d29yZD48a2V5d29y

ZD5SYWRpb3BoYXJtYWNldXRpY2Fsczwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tl

eXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRl

PkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1MzItODYwMCAoRWxlY3Ryb25p

YykmI3hEOzAwMjYtMDQ5NSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjMwMjEwMzg8

L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmku

bmxtLm5paC5nb3YvcHVibWVkLzIzMDIxMDM4PC91cmw+PHVybD5odHRwczovL2FjLmVscy1jZG4u

Y29tL1MwMDI2MDQ5NTEyMDAzMjg5LzEtczIuMC1TMDAyNjA0OTUxMjAwMzI4OS1tYWluLnBkZj9f

dGlkPTY3MjAwM2VjLTljNTItNGE4MC05ZTM1LTVkMDkxOTJjNGVmYSZhbXA7YWNkbmF0PTE1MzQ0

OTQ5MTdfYjU3YTVlYjJlNjBkOWQ1ZTllM2MxNTY4MTY5MTU5OWI8L3VybD48L3JlbGF0ZWQtdXJs

cz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5tZXRhYm9sLjIwMTIu

MDguMDI0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1

dGhvcj5WYW5pdGFsbGllPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVtPjEyNDE8L1Jl

Y051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEyNDE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48

a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYi

IHRpbWVzdGFtcD0iMTUzNDQyODI2MyI+MTI0MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlw

ZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRo

b3JzPjxhdXRob3I+VmFuaXRhbGxpZSwgVC4gQi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli

dXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE1lZGljaW5lLCBEaXZpc2lvbiBvZiBF

bmRvY3Jpbm9sb2d5LCBEaWFiZXRlcywgYW5kIE51dHJpdGlvbiwgU3QuIEx1a2UmYXBvcztzLVJv

b3NldmVsdCBIb3NwaXRhbCBDZW50ZXIsIENvbHVtYmlhIFVuaXZlcnNpdHkgQ29sbGVnZSBvZiBQ

aHlzaWNpYW5zICZhbXA7IFN1cmdlb25zLCBOZXcgWW9yaywgTlkgMTAwMjUuIGRydmFuaXRhbGxp

ZUBjb21jYXN0Lm5ldDwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlByZWNsaW5pY2FsIHNw

b3JhZGljIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogdGFyZ2V0IGZvciBwZXJzb25hbGl6ZWQg

ZGlhZ25vc2lzIGFuZCBwcmV2ZW50aXZlIGludGVydmVudGlvbjwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5NZXRhYm9saXNtPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPlMzMC0zPC9w

YWdlcz48dm9sdW1lPjYyIFN1cHBsIDE8L3ZvbHVtZT48a2V5d29yZHM+PGtleXdvcmQ+QWdlIEZh

Y3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRpYWdub3Npcy9ldGlv

bG9neS8qZ2VuZXRpY3MvbWV0YWJvbGlzbS9wYXRob2xvZ3kvcHJldmVudGlvbiAmYW1wOzwva2V5

d29yZD48a2V5d29yZD5jb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0

aWRlcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbiBFNC8qZ2Vu

ZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+Q2VsbHVsYXIgU2VuZXNjZW5jZS8qZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFz

ZSBQcm9ncmVzc2lvbjwva2V5d29yZD48a2V5d29yZD5FYXJseSBEaWFnbm9zaXM8L2tleXdvcmQ+

PGtleXdvcmQ+Rmx1b3JvZGVveHlnbHVjb3NlIEYxOC9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3

b3JkPipHZW5ldGljIE1hcmtlcnM8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXRpYyBQcmVkaXNwb3Np

dGlvbiB0byBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkdsdWNvc2UvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFnbmV0aWMgUmVzb25hbmNl

IEltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+TWFzcyBTY3JlZW5pbmc8L2tleXdvcmQ+PGtleXdv

cmQ+TWl0b2Nob25kcmlhL2dlbmV0aWNzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TmV1

cm9pbWFnaW5nL21ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+UG9zaXRyb24tRW1pc3Npb24gVG9t

b2dyYXBoeS9tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPipQcmVjaXNpb24gTWVkaWNpbmUvbWV0

aG9kcy90cmVuZHM8L2tleXdvcmQ+PGtleXdvcmQ+UmFkaW9waGFybWFjZXV0aWNhbHM8L2tleXdv

cmQ+PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFy

PjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KYW48L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48aXNibj4xNTMyLTg2MDAgKEVsZWN0cm9uaWMpJiN4RDswMDI2LTA0OTUgKExpbmtpbmcpPC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjIzMDIxMDM4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMzAyMTAzODwv

dXJsPjx1cmw+aHR0cHM6Ly9hYy5lbHMtY2RuLmNvbS9TMDAyNjA0OTUxMjAwMzI4OS8xLXMyLjAt

UzAwMjYwNDk1MTIwMDMyODktbWFpbi5wZGY/X3RpZD02NzIwMDNlYy05YzUyLTRhODAtOWUzNS01

ZDA5MTkyYzRlZmEmYW1wO2FjZG5hdD0xNTM0NDk0OTE3X2I1N2E1ZWIyZTYwZDlkNWU5ZTNjMTU2

ODE2OTE1OTliPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNl

LW51bT4xMC4xMDE2L2oubWV0YWJvbC4yMDEyLjA4LjAyNDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+U2lsdmVzdHJlPC9BdXRob3I+PFllYXI+

MjAxNzwvWWVhcj48UmVjTnVtPjEyNDI8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEyNDI8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDQyODY2MCI+MTI0Mjwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U2lsdmVzdHJlLCBGLiBKLjwv

YXV0aG9yPjxhdXRob3I+TGF1cml0YW5vLCBELjwvYXV0aG9yPjxhdXRob3I+Q2FyaW5jaSwgRi48

L2F1dGhvcj48YXV0aG9yPlNpbHZlc3RyZS1SYW5naWwsIEouPC9hdXRob3I+PGF1dGhvcj5NYXJ0

aW5lei1IZXJyZXJhLCBNLjwvYXV0aG9yPjxhdXRob3I+RGVsIE9sbW8sIEEuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+U3RvbWF0b2xvZ3kgYW5kIE9yYWwg

U3VyZ2VyeSwgRHIgUGVzZXQgVW5pdmVyc2l0eSBIb3NwaXRhbCwgRGVwYXJ0bWVudCBvZiBTdG9t

YXRvbG9neSwgVW5pdmVyc2l0eSBvZiBWYWxlbmNpYSwgU3BhaW4uJiN4RDtEZXBhcnRtZW50IG9m

IE1lZGljaW5lIGFuZCBTdXJnZXJ5LCBVbml2ZXJzaXR5IG9mIE1pbGFuLUJpY29jY2EsIE1vbnph

LCBJdGFseS4mI3hEO0RlcGFydG1lbnQgb2YgTW9ycGhvbG9neSwgU3VyZ2VyeSBhbmQgRXhwZXJp

bWVudGFsIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIEZlcnJhcmEsIEZlcnJhcmEsIEl0YWx5LiYj

eEQ7TmV1cm9sb2d5LCBEciBQZXNldCBVbml2ZXJzaXR5IEhvc3BpdGFsLCBEZXBhcnRtZW50IG9m

IE1lZGljaW5lIFVuaXZlcnNpdHkgb2YgVmFsZW5jaWEsIFNwYWluLjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPk5ldXJvaW5mbGFtbWF0aW9uLCBBbHpoZWltZXJzIGRpc2Vhc2UgYW5kIHBl

cmlvZG9udGFsIGRpc2Vhc2U6IGlzIHRoZXJlIGFuIGFzc29jaWF0aW9uIGJldHdlZW4gdGhlIHR3

byBwcm9jZXNzZXM/PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogQmlvbCBSZWd1bCBIb21lb3N0

IEFnZW50czwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xODktMTk2PC9wYWdlcz48

dm9sdW1lPjMxPC92b2x1bWU+PG51bWJlcj4yIFN1cHBsIDE8L251bWJlcj48ZGF0ZXM+PHllYXI+

MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkFwci1KdW48L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4wMzkzLTk3NFggKFByaW50KSYjeEQ7MDM5My05NzRYIChMaW5raW5nKTwvaXNi

bj48YWNjZXNzaW9uLW51bT4yODY5MTQ3MjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11

cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjg2OTE0NzI8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYW5pdGFsbGllPC9BdXRob3I+PFllYXI+MjAxMzwvWWVh

cj48UmVjTnVtPjEyNDE8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2Ny

aXB0Ij40MzgsNDM5PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTI0

MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUy

cHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM0NDI4MjYzIj4xMjQx

PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8

L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5WYW5pdGFsbGllLCBULiBC

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1l

bnQgb2YgTWVkaWNpbmUsIERpdmlzaW9uIG9mIEVuZG9jcmlub2xvZ3ksIERpYWJldGVzLCBhbmQg

TnV0cml0aW9uLCBTdC4gTHVrZSZhcG9zO3MtUm9vc2V2ZWx0IEhvc3BpdGFsIENlbnRlciwgQ29s

dW1iaWEgVW5pdmVyc2l0eSBDb2xsZWdlIG9mIFBoeXNpY2lhbnMgJmFtcDsgU3VyZ2VvbnMsIE5l

dyBZb3JrLCBOWSAxMDAyNS4gZHJ2YW5pdGFsbGllQGNvbWNhc3QubmV0PC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+UHJlY2xpbmljYWwgc3BvcmFkaWMgQWx6aGVpbWVyJmFwb3M7cyBkaXNl

YXNlOiB0YXJnZXQgZm9yIHBlcnNvbmFsaXplZCBkaWFnbm9zaXMgYW5kIHByZXZlbnRpdmUgaW50

ZXJ2ZW50aW9uPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk1ldGFib2xpc208L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGFnZXM+UzMwLTM8L3BhZ2VzPjx2b2x1bWU+NjIgU3VwcGwgMTwvdm9s

dW1lPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2UgRmFjdG9yczwva2V5d29yZD48a2V5d29yZD5BbHpo

ZWltZXIgRGlzZWFzZS8qZGlhZ25vc2lzL2V0aW9sb2d5LypnZW5ldGljcy9tZXRhYm9saXNtL3Bh

dGhvbG9neS9wcmV2ZW50aW9uICZhbXA7PC9rZXl3b3JkPjxrZXl3b3JkPmNvbnRyb2w8L2tleXdv

cmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxr

ZXl3b3JkPkFwb2xpcG9wcm90ZWluIEU0LypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5CcmFp

bi8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DZWxsdWxhciBTZW5lc2NlbmNlLypnZW5l

dGljczwva2V5d29yZD48a2V5d29yZD5EaXNlYXNlIFByb2dyZXNzaW9uPC9rZXl3b3JkPjxrZXl3

b3JkPkVhcmx5IERpYWdub3Npczwva2V5d29yZD48a2V5d29yZD5GbHVvcm9kZW94eWdsdWNvc2Ug

RjE4L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+KkdlbmV0aWMgTWFya2Vyczwva2V5d29y

ZD48a2V5d29yZD5HZW5ldGljIFByZWRpc3Bvc2l0aW9uIHRvIERpc2Vhc2U8L2tleXdvcmQ+PGtl

eXdvcmQ+R2x1Y29zZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29y

ZD48a2V5d29yZD5NYWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5N

YXNzIFNjcmVlbmluZzwva2V5d29yZD48a2V5d29yZD5NaXRvY2hvbmRyaWEvZ2VuZXRpY3MvbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5OZXVyb2ltYWdpbmcvbWV0aG9kczwva2V5d29yZD48

a2V5d29yZD5Qb3NpdHJvbi1FbWlzc2lvbiBUb21vZ3JhcGh5L21ldGhvZHM8L2tleXdvcmQ+PGtl

eXdvcmQ+KlByZWNpc2lvbiBNZWRpY2luZS9tZXRob2RzL3RyZW5kczwva2V5d29yZD48a2V5d29y

ZD5SYWRpb3BoYXJtYWNldXRpY2Fsczwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tl

eXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRl

PkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1MzItODYwMCAoRWxlY3Ryb25p

YykmI3hEOzAwMjYtMDQ5NSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjMwMjEwMzg8

L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmku

bmxtLm5paC5nb3YvcHVibWVkLzIzMDIxMDM4PC91cmw+PHVybD5odHRwczovL2FjLmVscy1jZG4u

Y29tL1MwMDI2MDQ5NTEyMDAzMjg5LzEtczIuMC1TMDAyNjA0OTUxMjAwMzI4OS1tYWluLnBkZj9f

dGlkPTY3MjAwM2VjLTljNTItNGE4MC05ZTM1LTVkMDkxOTJjNGVmYSZhbXA7YWNkbmF0PTE1MzQ0

OTQ5MTdfYjU3YTVlYjJlNjBkOWQ1ZTllM2MxNTY4MTY5MTU5OWI8L3VybD48L3JlbGF0ZWQtdXJs

cz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5tZXRhYm9sLjIwMTIu

MDguMDI0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1

dGhvcj5WYW5pdGFsbGllPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVtPjEyNDE8L1Jl

Y051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEyNDE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48

a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYi

IHRpbWVzdGFtcD0iMTUzNDQyODI2MyI+MTI0MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlw

ZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRo

b3JzPjxhdXRob3I+VmFuaXRhbGxpZSwgVC4gQi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli

dXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE1lZGljaW5lLCBEaXZpc2lvbiBvZiBF

bmRvY3Jpbm9sb2d5LCBEaWFiZXRlcywgYW5kIE51dHJpdGlvbiwgU3QuIEx1a2UmYXBvcztzLVJv

b3NldmVsdCBIb3NwaXRhbCBDZW50ZXIsIENvbHVtYmlhIFVuaXZlcnNpdHkgQ29sbGVnZSBvZiBQ

aHlzaWNpYW5zICZhbXA7IFN1cmdlb25zLCBOZXcgWW9yaywgTlkgMTAwMjUuIGRydmFuaXRhbGxp

ZUBjb21jYXN0Lm5ldDwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlByZWNsaW5pY2FsIHNw

b3JhZGljIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTogdGFyZ2V0IGZvciBwZXJzb25hbGl6ZWQg

ZGlhZ25vc2lzIGFuZCBwcmV2ZW50aXZlIGludGVydmVudGlvbjwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5NZXRhYm9saXNtPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPlMzMC0zPC9w

YWdlcz48dm9sdW1lPjYyIFN1cHBsIDE8L3ZvbHVtZT48a2V5d29yZHM+PGtleXdvcmQ+QWdlIEZh

Y3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmRpYWdub3Npcy9ldGlv

bG9neS8qZ2VuZXRpY3MvbWV0YWJvbGlzbS9wYXRob2xvZ3kvcHJldmVudGlvbiAmYW1wOzwva2V5

d29yZD48a2V5d29yZD5jb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0

aWRlcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbiBFNC8qZ2Vu

ZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+Q2VsbHVsYXIgU2VuZXNjZW5jZS8qZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFz

ZSBQcm9ncmVzc2lvbjwva2V5d29yZD48a2V5d29yZD5FYXJseSBEaWFnbm9zaXM8L2tleXdvcmQ+

PGtleXdvcmQ+Rmx1b3JvZGVveHlnbHVjb3NlIEYxOC9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3

b3JkPipHZW5ldGljIE1hcmtlcnM8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXRpYyBQcmVkaXNwb3Np

dGlvbiB0byBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkdsdWNvc2UvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFnbmV0aWMgUmVzb25hbmNl

IEltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+TWFzcyBTY3JlZW5pbmc8L2tleXdvcmQ+PGtleXdv

cmQ+TWl0b2Nob25kcmlhL2dlbmV0aWNzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TmV1

cm9pbWFnaW5nL21ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+UG9zaXRyb24tRW1pc3Npb24gVG9t

b2dyYXBoeS9tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPipQcmVjaXNpb24gTWVkaWNpbmUvbWV0

aG9kcy90cmVuZHM8L2tleXdvcmQ+PGtleXdvcmQ+UmFkaW9waGFybWFjZXV0aWNhbHM8L2tleXdv

cmQ+PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFy

PjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KYW48L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48aXNibj4xNTMyLTg2MDAgKEVsZWN0cm9uaWMpJiN4RDswMDI2LTA0OTUgKExpbmtpbmcpPC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjIzMDIxMDM4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMzAyMTAzODwv

dXJsPjx1cmw+aHR0cHM6Ly9hYy5lbHMtY2RuLmNvbS9TMDAyNjA0OTUxMjAwMzI4OS8xLXMyLjAt

UzAwMjYwNDk1MTIwMDMyODktbWFpbi5wZGY/X3RpZD02NzIwMDNlYy05YzUyLTRhODAtOWUzNS01

ZDA5MTkyYzRlZmEmYW1wO2FjZG5hdD0xNTM0NDk0OTE3X2I1N2E1ZWIyZTYwZDlkNWU5ZTNjMTU2

ODE2OTE1OTliPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNl

LW51bT4xMC4xMDE2L2oubWV0YWJvbC4yMDEyLjA4LjAyNDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+U2lsdmVzdHJlPC9BdXRob3I+PFllYXI+

MjAxNzwvWWVhcj48UmVjTnVtPjEyNDI8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEyNDI8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDQyODY2MCI+MTI0Mjwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U2lsdmVzdHJlLCBGLiBKLjwv

YXV0aG9yPjxhdXRob3I+TGF1cml0YW5vLCBELjwvYXV0aG9yPjxhdXRob3I+Q2FyaW5jaSwgRi48

L2F1dGhvcj48YXV0aG9yPlNpbHZlc3RyZS1SYW5naWwsIEouPC9hdXRob3I+PGF1dGhvcj5NYXJ0

aW5lei1IZXJyZXJhLCBNLjwvYXV0aG9yPjxhdXRob3I+RGVsIE9sbW8sIEEuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+U3RvbWF0b2xvZ3kgYW5kIE9yYWwg

U3VyZ2VyeSwgRHIgUGVzZXQgVW5pdmVyc2l0eSBIb3NwaXRhbCwgRGVwYXJ0bWVudCBvZiBTdG9t

YXRvbG9neSwgVW5pdmVyc2l0eSBvZiBWYWxlbmNpYSwgU3BhaW4uJiN4RDtEZXBhcnRtZW50IG9m

IE1lZGljaW5lIGFuZCBTdXJnZXJ5LCBVbml2ZXJzaXR5IG9mIE1pbGFuLUJpY29jY2EsIE1vbnph

LCBJdGFseS4mI3hEO0RlcGFydG1lbnQgb2YgTW9ycGhvbG9neSwgU3VyZ2VyeSBhbmQgRXhwZXJp

bWVudGFsIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIEZlcnJhcmEsIEZlcnJhcmEsIEl0YWx5LiYj

eEQ7TmV1cm9sb2d5LCBEciBQZXNldCBVbml2ZXJzaXR5IEhvc3BpdGFsLCBEZXBhcnRtZW50IG9m

IE1lZGljaW5lIFVuaXZlcnNpdHkgb2YgVmFsZW5jaWEsIFNwYWluLjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPk5ldXJvaW5mbGFtbWF0aW9uLCBBbHpoZWltZXJzIGRpc2Vhc2UgYW5kIHBl

cmlvZG9udGFsIGRpc2Vhc2U6IGlzIHRoZXJlIGFuIGFzc29jaWF0aW9uIGJldHdlZW4gdGhlIHR3

byBwcm9jZXNzZXM/PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogQmlvbCBSZWd1bCBIb21lb3N0

IEFnZW50czwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4xODktMTk2PC9wYWdlcz48

dm9sdW1lPjMxPC92b2x1bWU+PG51bWJlcj4yIFN1cHBsIDE8L251bWJlcj48ZGF0ZXM+PHllYXI+

MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkFwci1KdW48L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4wMzkzLTk3NFggKFByaW50KSYjeEQ7MDM5My05NzRYIChMaW5raW5nKTwvaXNi

bj48YWNjZXNzaW9uLW51bT4yODY5MTQ3MjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11

cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjg2OTE0NzI8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 438,439, improving, in turn, the predictions about the evolution of the disease and eventually, choosing a more personalized therapeutic strategy. Clinical trials for NGF gene delivery in the hippocampus require complex procedures involving invasive injections in specific nuclei in the brain. It is possible that small deviations in the injection site can render the therapy ineffective in terms of improving cognition in subjects ADDIN EN.CITE <EndNote><Cite><Author>Rafii</Author><Year>2018</Year><RecNum>1243</RecNum><DisplayText><style face="superscript">440</style></DisplayText><record><rec-number>1243</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1534429273">1243</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rafii, M. S.</author><author>Tuszynski, M. H.</author><author>Thomas, R. G.</author><author>Barba, D.</author><author>Brewer, J. B.</author><author>Rissman, R. A.</author><author>Siffert, J.</author><author>Aisen, P. S.</author><author>Aav Ngf Study Team</author></authors></contributors><auth-address>Alzheimer&apos;s Therapeutic Research Institute, University of Southern California, San Diego.&#xD;Department of Neuroscience, University of California in San Diego, San Diego.&#xD;Department of Neurosurgery, University of California in San Diego, San Diego.&#xD;Veterans Affairs Medical Center, San Diego, California.&#xD;Nestle Health Science, Florham Park, New Jersey.</auth-address><titles><title>Adeno-Associated Viral Vector (Serotype 2)-Nerve Growth Factor for Patients With Alzheimer Disease: A Randomized Clinical Trial</title><secondary-title>JAMA Neurol</secondary-title></titles><periodical><full-title>JAMA Neurol</full-title></periodical><pages>834-841</pages><volume>75</volume><number>7</number><dates><year>2018</year><pub-dates><date>Jul 1</date></pub-dates></dates><isbn>2168-6157 (Electronic)&#xD;2168-6149 (Linking)</isbn><accession-num>29582053</accession-num><urls><related-urls><url>, although NGF cell therapy remains promising and under clinical research PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FeWpvbGZzZG90dGlyPC9BdXRob3I+PFllYXI+MjAxNjwv

WWVhcj48UmVjTnVtPjQ2NDE8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVy

c2NyaXB0Ij4xNTM8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40NjQx

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDM5MjA5MjYiPjQ2NDE8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkV5am9sZnNkb3R0aXIsIEgu

PC9hdXRob3I+PGF1dGhvcj5Fcmlrc2RvdHRlciwgTS48L2F1dGhvcj48YXV0aG9yPkxpbmRlcm90

aCwgQi48L2F1dGhvcj48YXV0aG9yPkxpbmQsIEcuPC9hdXRob3I+PGF1dGhvcj5KdWxpdXNzb24s

IEIuPC9hdXRob3I+PGF1dGhvcj5LdXNrLCBQLjwvYXV0aG9yPjxhdXRob3I+QWxta3Zpc3QsIE8u

PC9hdXRob3I+PGF1dGhvcj5BbmRyZWFzZW4sIE4uPC9hdXRob3I+PGF1dGhvcj5CbGVubm93LCBL

LjwvYXV0aG9yPjxhdXRob3I+RmVycmVpcmEsIEQuPC9hdXRob3I+PGF1dGhvcj5XZXN0bWFuLCBF

LjwvYXV0aG9yPjxhdXRob3I+TmVubmVzbW8sIEkuPC9hdXRob3I+PGF1dGhvcj5LYXJhbWksIEEu

PC9hdXRob3I+PGF1dGhvcj5EYXJyZWgtU2hvcmksIFQuPC9hdXRob3I+PGF1dGhvcj5LYWRpciwg

QS48L2F1dGhvcj48YXV0aG9yPk5vcmRiZXJnLCBBLjwvYXV0aG9yPjxhdXRob3I+U3VuZHN0cm9t

LCBFLjwvYXV0aG9yPjxhdXRob3I+V2FobHVuZCwgTC4gTy48L2F1dGhvcj48YXV0aG9yPldhbGws

IEEuPC9hdXRob3I+PGF1dGhvcj5XaWJlcmcsIE0uPC9hdXRob3I+PGF1dGhvcj5XaW5ibGFkLCBC

LjwvYXV0aG9yPjxhdXRob3I+U2VpZ2VyLCBBLjwvYXV0aG9yPjxhdXRob3I+V2FobGJlcmcsIEwu

PC9hdXRob3I+PGF1dGhvcj5BbG1xdmlzdCwgUC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli

dXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2ll

bmNlcyBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCAxNzEgNzcsIFN0b2NraG9s

bSwgU3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBHZXJpYXRyaWNzLCBLYXJvbGluc2thIFVuaXZl

cnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCAxNzEgNzYsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7

RGVwYXJ0bWVudCBvZiBDbGluaWNhbCBOZXVyb3NjaWVuY2UsIEthcm9saW5za2EgSW5zdGl0dXRl

dCwgMTcxIDc3LCBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9zdXJn

ZXJ5LCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwgU29sbmEsIEJ1aWxkaW5nIFIzOjAy

LCAxNzEgNzYsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7TnNHZW5lIEluYy4sIDIyNSBDaGFwbWFu

IFN0cmVldCwgUHJvdmlkZW5jZSwgUkksIDAyOTA1LTQ1MzMsIFVTQS4mI3hEO0NsaW5pY2FsIE5l

dXJvY2hlbWlzdHJ5IExhYm9yYXRvcnksIERlcGFydG1lbnQgb2YgQ2xpbmljYWwgTmV1cm9zY2ll

bmNlLCBVbml2ZXJzaXR5IG9mIEdvdGhlbmJ1cmcsIDQxMzQ1LCBHb3RoZW5idXJnLCBTd2VkZW4u

JiN4RDtEZXBhcnRtZW50IG9mIExhYm9yYXRvcnkgTWVkaWNpbmUsIFNlY3Rpb24gb2YgUGF0aG9s

b2d5LCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIDE3MSA3NiwgU3RvY2tob2xtLCBT

d2VkZW4uJiN4RDtTdGlmdGVsc2VuIFN0b2NraG9sbXMgU2p1a2hlbSwgTWFyaWViZXJnc2dhdGFu

IDIyLCAxMTIgMzUsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBTdXJnaWNh

bCBTY2llbmNlcywgU2VjdGlvbiBvZiBOdWNsZWFyIE1lZGljaW5lIGFuZCBQRVQsIFVwcHNhbGEg

VW5pdmVyc2l0eSBIb3NwaXRhbCwgNzUxODUsIFVwcHNhbGEsIFN3ZWRlbi4mI3hEO0RlcGFydG1l

bnQgb2YgQ2xpbmljYWwgU2NpZW5jZSwgSW50ZXJ2ZW50aW9uIGFuZCBUZWNobm9sb2d5LCBEaXZp

c2lvbiBvZiBNZWRpY2FsIEltYWdpbmcgYW5kIFRlY2hub2xvZ3ksIEthcm9saW5za2EgSW5zdGl0

dXRldCwgMTcxIDc3LCBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0RlcGFydG1lbnQgb2YgUmFkaW9s

b2d5LCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIDE3MSA3NiwgU3RvY2tob2xtLCBT

d2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIENsaW5pY2FsIE5ldXJvc2NpZW5jZSwgS2Fyb2xpbnNr

YSBJbnN0aXR1dGV0LCAxNzEgNzcsIFN0b2NraG9sbSwgU3dlZGVuLiBwZXIuYWxtcXZpc3RAa2ku

c2UuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvc3VyZ2VyeSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5

IEhvc3BpdGFsIFNvbG5hLCBCdWlsZGluZyBSMzowMiwgMTcxIDc2LCBTdG9ja2hvbG0sIFN3ZWRl

bi4gcGVyLmFsbXF2aXN0QGtpLnNlLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRhcmdl

dGVkIGRlbGl2ZXJ5IG9mIG5lcnZlIGdyb3d0aCBmYWN0b3IgdG8gdGhlIGNob2xpbmVyZ2ljIGJh

c2FsIGZvcmVicmFpbiBvZiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgcGF0aWVudHM6IGFwcGxp

Y2F0aW9uIG9mIGEgc2Vjb25kLWdlbmVyYXRpb24gZW5jYXBzdWxhdGVkIGNlbGwgYmlvZGVsaXZl

cnkgZGV2aWNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFsemhlaW1lcnMgUmVzIFRoZXI8L3Nl

Y29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbHpoZWltZXJz

IFJlcyBUaGVyPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzA8L3BhZ2VzPjx2b2x1

bWU+ODwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxlZGl0aW9uPjIwMTYvMDcvMDk8L2VkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPkFjZXR5bGNob2xpbmVzdGVyYXNlL21ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9j

ZXJlYnJvc3BpbmFsIGZsdWlkL2RpYWdub3N0aWMgaW1hZ2luZy8qZHJ1ZyB0aGVyYXB5PC9rZXl3

b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9jZXJlYnJvc3BpbmFsIGZsdWlkPC9r

ZXl3b3JkPjxrZXl3b3JkPkJhc2FsIEZvcmVicmFpbi9kaWFnbm9zdGljIGltYWdpbmcvKmRydWcg

ZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5DYXBzdWxlczwva2V5d29yZD48a2V5d29yZD5DZWxs

IExpbmU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGluZSBPLUFjZXR5bHRyYW5zZmVyYXNlL2NlcmVi

cm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+Q29nbml0aW9uIERpc29yZGVycy9ldGlv

bG9neTwva2V5d29yZD48a2V5d29yZD5Db2hvcnQgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5E

b3NlLVJlc3BvbnNlIFJlbGF0aW9uc2hpcCwgRHJ1Zzwva2V5d29yZD48a2V5d29yZD4qRHJ1ZyBE

ZWxpdmVyeSBTeXN0ZW1zPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29y

ZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUg

QWdlZDwva2V5d29yZD48a2V5d29yZD5OZXJ2ZSBHcm93dGggRmFjdG9yLyphZG1pbmlzdHJhdGlv

biAmYW1wOyBkb3NhZ2U8L2tleXdvcmQ+PGtleXdvcmQ+TmVydmUgVGlzc3VlIFByb3RlaW5zL2Nl

cmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+UGVwdGlkZSBGcmFnbWVudHMvY2Vy

ZWJyb3NwaW5hbCBmbHVpZDwva2V5d29yZD48a2V5d29yZD5UcmVhdG1lbnQgT3V0Y29tZTwva2V5

d29yZD48a2V5d29yZD50YXUgUHJvdGVpbnMvY2VyZWJyb3NwaW5hbCBmbHVpZDwva2V5d29yZD48

a2V5d29yZD4qQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPipFbmNh

cHN1bGF0ZWQgY2VsbCBiaW9kZWxpdmVyeTwva2V5d29yZD48a2V5d29yZD4qTmVydmUgZ3Jvd3Ro

IGZhY3Rvcjwva2V5d29yZD48a2V5d29yZD4qUmVnZW5lcmF0aXZlIG1lZGljaW5lPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWwg

NzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE3NTgtOTE5MyAoRWxlY3Ryb25pYyk8

L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjczODk0MDI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0

ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI3Mzg5NDAy

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQ5MzYwMjA8L2N1c3RvbTI+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExODYvczEzMTk1LTAxNi0wMTk1LTk8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FeWpvbGZzZG90dGlyPC9BdXRob3I+PFllYXI+MjAxNjwv

WWVhcj48UmVjTnVtPjQ2NDE8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVy

c2NyaXB0Ij4xNTM8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40NjQx

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1NDM5MjA5MjYiPjQ2NDE8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkV5am9sZnNkb3R0aXIsIEgu

PC9hdXRob3I+PGF1dGhvcj5Fcmlrc2RvdHRlciwgTS48L2F1dGhvcj48YXV0aG9yPkxpbmRlcm90

aCwgQi48L2F1dGhvcj48YXV0aG9yPkxpbmQsIEcuPC9hdXRob3I+PGF1dGhvcj5KdWxpdXNzb24s

IEIuPC9hdXRob3I+PGF1dGhvcj5LdXNrLCBQLjwvYXV0aG9yPjxhdXRob3I+QWxta3Zpc3QsIE8u

PC9hdXRob3I+PGF1dGhvcj5BbmRyZWFzZW4sIE4uPC9hdXRob3I+PGF1dGhvcj5CbGVubm93LCBL

LjwvYXV0aG9yPjxhdXRob3I+RmVycmVpcmEsIEQuPC9hdXRob3I+PGF1dGhvcj5XZXN0bWFuLCBF

LjwvYXV0aG9yPjxhdXRob3I+TmVubmVzbW8sIEkuPC9hdXRob3I+PGF1dGhvcj5LYXJhbWksIEEu

PC9hdXRob3I+PGF1dGhvcj5EYXJyZWgtU2hvcmksIFQuPC9hdXRob3I+PGF1dGhvcj5LYWRpciwg

QS48L2F1dGhvcj48YXV0aG9yPk5vcmRiZXJnLCBBLjwvYXV0aG9yPjxhdXRob3I+U3VuZHN0cm9t

LCBFLjwvYXV0aG9yPjxhdXRob3I+V2FobHVuZCwgTC4gTy48L2F1dGhvcj48YXV0aG9yPldhbGws

IEEuPC9hdXRob3I+PGF1dGhvcj5XaWJlcmcsIE0uPC9hdXRob3I+PGF1dGhvcj5XaW5ibGFkLCBC

LjwvYXV0aG9yPjxhdXRob3I+U2VpZ2VyLCBBLjwvYXV0aG9yPjxhdXRob3I+V2FobGJlcmcsIEwu

PC9hdXRob3I+PGF1dGhvcj5BbG1xdmlzdCwgUC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli

dXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2ll

bmNlcyBhbmQgU29jaWV0eSwgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCAxNzEgNzcsIFN0b2NraG9s

bSwgU3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBHZXJpYXRyaWNzLCBLYXJvbGluc2thIFVuaXZl

cnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCAxNzEgNzYsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7

RGVwYXJ0bWVudCBvZiBDbGluaWNhbCBOZXVyb3NjaWVuY2UsIEthcm9saW5za2EgSW5zdGl0dXRl

dCwgMTcxIDc3LCBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9zdXJn

ZXJ5LCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwgU29sbmEsIEJ1aWxkaW5nIFIzOjAy

LCAxNzEgNzYsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7TnNHZW5lIEluYy4sIDIyNSBDaGFwbWFu

IFN0cmVldCwgUHJvdmlkZW5jZSwgUkksIDAyOTA1LTQ1MzMsIFVTQS4mI3hEO0NsaW5pY2FsIE5l

dXJvY2hlbWlzdHJ5IExhYm9yYXRvcnksIERlcGFydG1lbnQgb2YgQ2xpbmljYWwgTmV1cm9zY2ll

bmNlLCBVbml2ZXJzaXR5IG9mIEdvdGhlbmJ1cmcsIDQxMzQ1LCBHb3RoZW5idXJnLCBTd2VkZW4u

JiN4RDtEZXBhcnRtZW50IG9mIExhYm9yYXRvcnkgTWVkaWNpbmUsIFNlY3Rpb24gb2YgUGF0aG9s

b2d5LCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIDE3MSA3NiwgU3RvY2tob2xtLCBT

d2VkZW4uJiN4RDtTdGlmdGVsc2VuIFN0b2NraG9sbXMgU2p1a2hlbSwgTWFyaWViZXJnc2dhdGFu

IDIyLCAxMTIgMzUsIFN0b2NraG9sbSwgU3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBTdXJnaWNh

bCBTY2llbmNlcywgU2VjdGlvbiBvZiBOdWNsZWFyIE1lZGljaW5lIGFuZCBQRVQsIFVwcHNhbGEg

VW5pdmVyc2l0eSBIb3NwaXRhbCwgNzUxODUsIFVwcHNhbGEsIFN3ZWRlbi4mI3hEO0RlcGFydG1l

bnQgb2YgQ2xpbmljYWwgU2NpZW5jZSwgSW50ZXJ2ZW50aW9uIGFuZCBUZWNobm9sb2d5LCBEaXZp

c2lvbiBvZiBNZWRpY2FsIEltYWdpbmcgYW5kIFRlY2hub2xvZ3ksIEthcm9saW5za2EgSW5zdGl0

dXRldCwgMTcxIDc3LCBTdG9ja2hvbG0sIFN3ZWRlbi4mI3hEO0RlcGFydG1lbnQgb2YgUmFkaW9s

b2d5LCBLYXJvbGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIDE3MSA3NiwgU3RvY2tob2xtLCBT

d2VkZW4uJiN4RDtEZXBhcnRtZW50IG9mIENsaW5pY2FsIE5ldXJvc2NpZW5jZSwgS2Fyb2xpbnNr

YSBJbnN0aXR1dGV0LCAxNzEgNzcsIFN0b2NraG9sbSwgU3dlZGVuLiBwZXIuYWxtcXZpc3RAa2ku

c2UuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvc3VyZ2VyeSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5

IEhvc3BpdGFsIFNvbG5hLCBCdWlsZGluZyBSMzowMiwgMTcxIDc2LCBTdG9ja2hvbG0sIFN3ZWRl

bi4gcGVyLmFsbXF2aXN0QGtpLnNlLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRhcmdl

dGVkIGRlbGl2ZXJ5IG9mIG5lcnZlIGdyb3d0aCBmYWN0b3IgdG8gdGhlIGNob2xpbmVyZ2ljIGJh

c2FsIGZvcmVicmFpbiBvZiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgcGF0aWVudHM6IGFwcGxp

Y2F0aW9uIG9mIGEgc2Vjb25kLWdlbmVyYXRpb24gZW5jYXBzdWxhdGVkIGNlbGwgYmlvZGVsaXZl

cnkgZGV2aWNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFsemhlaW1lcnMgUmVzIFRoZXI8L3Nl

Y29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbHpoZWltZXJz

IFJlcyBUaGVyPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzA8L3BhZ2VzPjx2b2x1

bWU+ODwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxlZGl0aW9uPjIwMTYvMDcvMDk8L2VkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPkFjZXR5bGNob2xpbmVzdGVyYXNlL21ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9j

ZXJlYnJvc3BpbmFsIGZsdWlkL2RpYWdub3N0aWMgaW1hZ2luZy8qZHJ1ZyB0aGVyYXB5PC9rZXl3

b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9jZXJlYnJvc3BpbmFsIGZsdWlkPC9r

ZXl3b3JkPjxrZXl3b3JkPkJhc2FsIEZvcmVicmFpbi9kaWFnbm9zdGljIGltYWdpbmcvKmRydWcg

ZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5DYXBzdWxlczwva2V5d29yZD48a2V5d29yZD5DZWxs

IExpbmU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hvbGluZSBPLUFjZXR5bHRyYW5zZmVyYXNlL2NlcmVi

cm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+Q29nbml0aW9uIERpc29yZGVycy9ldGlv

bG9neTwva2V5d29yZD48a2V5d29yZD5Db2hvcnQgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5E

b3NlLVJlc3BvbnNlIFJlbGF0aW9uc2hpcCwgRHJ1Zzwva2V5d29yZD48a2V5d29yZD4qRHJ1ZyBE

ZWxpdmVyeSBTeXN0ZW1zPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29y

ZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUg

QWdlZDwva2V5d29yZD48a2V5d29yZD5OZXJ2ZSBHcm93dGggRmFjdG9yLyphZG1pbmlzdHJhdGlv

biAmYW1wOyBkb3NhZ2U8L2tleXdvcmQ+PGtleXdvcmQ+TmVydmUgVGlzc3VlIFByb3RlaW5zL2Nl

cmVicm9zcGluYWwgZmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+UGVwdGlkZSBGcmFnbWVudHMvY2Vy

ZWJyb3NwaW5hbCBmbHVpZDwva2V5d29yZD48a2V5d29yZD5UcmVhdG1lbnQgT3V0Y29tZTwva2V5

d29yZD48a2V5d29yZD50YXUgUHJvdGVpbnMvY2VyZWJyb3NwaW5hbCBmbHVpZDwva2V5d29yZD48

a2V5d29yZD4qQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPipFbmNh

cHN1bGF0ZWQgY2VsbCBiaW9kZWxpdmVyeTwva2V5d29yZD48a2V5d29yZD4qTmVydmUgZ3Jvd3Ro

IGZhY3Rvcjwva2V5d29yZD48a2V5d29yZD4qUmVnZW5lcmF0aXZlIG1lZGljaW5lPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWwg

NzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE3NTgtOTE5MyAoRWxlY3Ryb25pYyk8

L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjczODk0MDI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0

ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI3Mzg5NDAy

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQ5MzYwMjA8L2N1c3RvbTI+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExODYvczEzMTk1LTAxNi0wMTk1LTk8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 153. The unknown origin of the disease, mixed with complex genetic and environmental factors contributing to pathogenesis, have challenged clinical trials worldwide PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaGFjaGF0dXJpYW48L0F1dGhvcj48WWVhcj4yMDE4PC9Z

ZWFyPjxSZWNOdW0+MTI0MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJz

Y3JpcHQiPjQ0MTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEyNDA8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDQyNTk3NiI+MTI0MDwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+S2hhY2hhdHVyaWFuLCBBLiBT

LjwvYXV0aG9yPjxhdXRob3I+SGF5ZGVuLCBLLiBNLjwvYXV0aG9yPjxhdXRob3I+TWllbGtlLCBN

LiBNLjwvYXV0aG9yPjxhdXRob3I+VGFuZywgWS48L2F1dGhvcj48YXV0aG9yPkx1dHosIE0uIFcu

PC9hdXRob3I+PGF1dGhvcj5HdXN0YWZzb24sIEQuIFIuPC9hdXRob3I+PGF1dGhvcj5LdWt1bGws

IFcuIEEuPC9hdXRob3I+PGF1dGhvcj5Nb2hzLCBSLjwvYXV0aG9yPjxhdXRob3I+S2hhY2hhdHVy

aWFuLCBaLiBTLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNz

PkFsemhlaW1lciZhcG9zO3MgJmFtcDsgRGVtZW50aWE6IFRoZSBKb3VybmFsIG9mIHRoZSBBbHpo

ZWltZXImYXBvcztzIEFzc29jaWF0aW9uLCBSb2NrdmlsbGUsIE1ELCBVU0EuIEVsZWN0cm9uaWMg

YWRkcmVzczogYWRqX3hlZEBrcmEubmV0LiYjeEQ7QXNzb2NpYXRlIFByb2Zlc3NvciwgRGl2aXNp

b24gb2YgUHVibGljIEhlYWx0aCBTY2llbmNlcywgRGVwYXJ0bWVudCBvZiBTb2NpYWwgU2NpZW5j

ZXMgYW5kIEhlYWx0aCBQb2xpY3ksIFN0aWNodCBDZW50ZXIgZm9yIEhlYWx0aHkgQWdpbmcgYW5k

IEFsemhlaW1lciZhcG9zO3MgUHJldmVudGlvbiwgV2FrZSBGb3Jlc3QgU2Nob29sIG9mIE1lZGlj

aW5lLCBXaW5zdG9uLVNhbGVtLCBOQywgVVNBLiYjeEQ7UHJvZmVzc29yIG9mIEVwaWRlbWlvbG9n

eSwgRGVwYXJ0bWVudCBvZiBIZWFsdGggU2NpZW5jZXMgUmVzZWFyY2gsIFByb2Zlc3NvciBvZiBO

ZXVyb2xvZ3ksIE1heW8gQ2xpbmljIENvbGxlZ2Ugb2YgTWVkaWNpbmUsIFJvY2hlc3RlciwgTU4s

IFVTQS4mI3hEO0Fzc29jaWF0ZSBQcm9mZXNzb3IsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBY

dWFuIFd1IEhvc3BpdGFsLCBCZWlqaW5nLCBDaGluYS4mI3hEO0Fzc2lzdGFudCBQcm9mZXNzb3Ig

b2YgTmV1cm9sb2d5LCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgRHVrZSBVbml2ZXJzaXR5IFNj

aG9vbCBvZiBNZWRpY2luZSwgRHVyaGFtLCBOQywgVVNBLiYjeEQ7UHJvZmVzc29yLCBTZWN0aW9u

IGZvciBOZXVyb0VwaWRlbWlvbG9neSwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIFN0YXRlIFVu

aXZlcnNpdHkgb2YgTmV3IFlvcmstRG93bnN0YXRlIE1lZGljYWwgQ2VudGVyLCBCcm9va2x5biwg

TlksIFVTQS4mI3hEO1Byb2Zlc3NvciwgRGVwYXJ0bWVudCBvZiBFcGlkZW1pb2xvZ3ksIFNjaG9v

bCBvZiBQdWJsaWMgSGVhbHRoLCBVbml2ZXJzaXR5IG9mIFdhc2hpbmd0b24sIFNlYXR0bGUsIFdB

LCBVU0EuJiN4RDtTZW5pb3IgQXNzb2NpYXRlIEVkaXRvciwgQWx6aGVpbWVyJmFwb3M7cyAmYW1w

OyBEZW1lbnRpYTogVGhlIEpvdXJuYWwgb2YgdGhlIEFsemhlaW1lciZhcG9zO3MgQXNzb2NpYXRp

b24sIENoaWNhZ28sIElMLCBVU0EuJiN4RDtBbHpoZWltZXImYXBvcztzICZhbXA7IERlbWVudGlh

OiBUaGUgSm91cm5hbCBvZiB0aGUgQWx6aGVpbWVyJmFwb3M7cyBBc3NvY2lhdGlvbiwgUm9ja3Zp

bGxlLCBNRCwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkZ1dHVyZSBwcm9zcGVj

dHMgYW5kIGNoYWxsZW5nZXMgZm9yIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZSBkcnVnIGRldmVs

b3BtZW50IGluIHRoZSBlcmEgb2YgdGhlIE5JQS1BQSBSZXNlYXJjaCBGcmFtZXdvcms8L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+QWx6aGVpbWVycyBEZW1lbnQ8L3NlY29uZGFyeS10aXRsZT48L3Rp

dGxlcz48cGFnZXM+NTMyLTUzNDwvcGFnZXM+PHZvbHVtZT4xNDwvdm9sdW1lPjxudW1iZXI+NDwv

bnVtYmVyPjxkYXRlcz48eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXByPC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU1Mi01Mjc5IChFbGVjdHJvbmljKSYjeEQ7MTU1

Mi01MjYwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yOTY1MzYwNTwvYWNjZXNzaW9u

LW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdv

di9wdWJtZWQvMjk2NTM2MDU8L3VybD48dXJsPmh0dHBzOi8vYWMuZWxzLWNkbi5jb20vUzE1NTI1

MjYwMTgzMDA4MTUvMS1zMi4wLVMxNTUyNTI2MDE4MzAwODE1LW1haW4ucGRmP190aWQ9OTZiNjkz

NmYtOTMyOC00MTA1LWFjYjMtNzFkOGZhOWNiODJjJmFtcDthY2RuYXQ9MTUzNDQ5NDkwNF80Mzhh

NTEyN2RjZWM2N2Y1NzgwYzFjNjhhMmY1YTRjZDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmphbHouMjAxOC4wMy4wMDM8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaGFjaGF0dXJpYW48L0F1dGhvcj48WWVhcj4yMDE4PC9Z

ZWFyPjxSZWNOdW0+MTI0MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJz

Y3JpcHQiPjQ0MTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEyNDA8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDQyNTk3NiI+MTI0MDwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+S2hhY2hhdHVyaWFuLCBBLiBT

LjwvYXV0aG9yPjxhdXRob3I+SGF5ZGVuLCBLLiBNLjwvYXV0aG9yPjxhdXRob3I+TWllbGtlLCBN

LiBNLjwvYXV0aG9yPjxhdXRob3I+VGFuZywgWS48L2F1dGhvcj48YXV0aG9yPkx1dHosIE0uIFcu

PC9hdXRob3I+PGF1dGhvcj5HdXN0YWZzb24sIEQuIFIuPC9hdXRob3I+PGF1dGhvcj5LdWt1bGws

IFcuIEEuPC9hdXRob3I+PGF1dGhvcj5Nb2hzLCBSLjwvYXV0aG9yPjxhdXRob3I+S2hhY2hhdHVy

aWFuLCBaLiBTLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNz

PkFsemhlaW1lciZhcG9zO3MgJmFtcDsgRGVtZW50aWE6IFRoZSBKb3VybmFsIG9mIHRoZSBBbHpo

ZWltZXImYXBvcztzIEFzc29jaWF0aW9uLCBSb2NrdmlsbGUsIE1ELCBVU0EuIEVsZWN0cm9uaWMg

YWRkcmVzczogYWRqX3hlZEBrcmEubmV0LiYjeEQ7QXNzb2NpYXRlIFByb2Zlc3NvciwgRGl2aXNp

b24gb2YgUHVibGljIEhlYWx0aCBTY2llbmNlcywgRGVwYXJ0bWVudCBvZiBTb2NpYWwgU2NpZW5j

ZXMgYW5kIEhlYWx0aCBQb2xpY3ksIFN0aWNodCBDZW50ZXIgZm9yIEhlYWx0aHkgQWdpbmcgYW5k

IEFsemhlaW1lciZhcG9zO3MgUHJldmVudGlvbiwgV2FrZSBGb3Jlc3QgU2Nob29sIG9mIE1lZGlj

aW5lLCBXaW5zdG9uLVNhbGVtLCBOQywgVVNBLiYjeEQ7UHJvZmVzc29yIG9mIEVwaWRlbWlvbG9n

eSwgRGVwYXJ0bWVudCBvZiBIZWFsdGggU2NpZW5jZXMgUmVzZWFyY2gsIFByb2Zlc3NvciBvZiBO

ZXVyb2xvZ3ksIE1heW8gQ2xpbmljIENvbGxlZ2Ugb2YgTWVkaWNpbmUsIFJvY2hlc3RlciwgTU4s

IFVTQS4mI3hEO0Fzc29jaWF0ZSBQcm9mZXNzb3IsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBY

dWFuIFd1IEhvc3BpdGFsLCBCZWlqaW5nLCBDaGluYS4mI3hEO0Fzc2lzdGFudCBQcm9mZXNzb3Ig

b2YgTmV1cm9sb2d5LCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgRHVrZSBVbml2ZXJzaXR5IFNj

aG9vbCBvZiBNZWRpY2luZSwgRHVyaGFtLCBOQywgVVNBLiYjeEQ7UHJvZmVzc29yLCBTZWN0aW9u

IGZvciBOZXVyb0VwaWRlbWlvbG9neSwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIFN0YXRlIFVu

aXZlcnNpdHkgb2YgTmV3IFlvcmstRG93bnN0YXRlIE1lZGljYWwgQ2VudGVyLCBCcm9va2x5biwg

TlksIFVTQS4mI3hEO1Byb2Zlc3NvciwgRGVwYXJ0bWVudCBvZiBFcGlkZW1pb2xvZ3ksIFNjaG9v

bCBvZiBQdWJsaWMgSGVhbHRoLCBVbml2ZXJzaXR5IG9mIFdhc2hpbmd0b24sIFNlYXR0bGUsIFdB

LCBVU0EuJiN4RDtTZW5pb3IgQXNzb2NpYXRlIEVkaXRvciwgQWx6aGVpbWVyJmFwb3M7cyAmYW1w

OyBEZW1lbnRpYTogVGhlIEpvdXJuYWwgb2YgdGhlIEFsemhlaW1lciZhcG9zO3MgQXNzb2NpYXRp

b24sIENoaWNhZ28sIElMLCBVU0EuJiN4RDtBbHpoZWltZXImYXBvcztzICZhbXA7IERlbWVudGlh

OiBUaGUgSm91cm5hbCBvZiB0aGUgQWx6aGVpbWVyJmFwb3M7cyBBc3NvY2lhdGlvbiwgUm9ja3Zp

bGxlLCBNRCwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkZ1dHVyZSBwcm9zcGVj

dHMgYW5kIGNoYWxsZW5nZXMgZm9yIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZSBkcnVnIGRldmVs

b3BtZW50IGluIHRoZSBlcmEgb2YgdGhlIE5JQS1BQSBSZXNlYXJjaCBGcmFtZXdvcms8L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+QWx6aGVpbWVycyBEZW1lbnQ8L3NlY29uZGFyeS10aXRsZT48L3Rp

dGxlcz48cGFnZXM+NTMyLTUzNDwvcGFnZXM+PHZvbHVtZT4xNDwvdm9sdW1lPjxudW1iZXI+NDwv

bnVtYmVyPjxkYXRlcz48eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXByPC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU1Mi01Mjc5IChFbGVjdHJvbmljKSYjeEQ7MTU1

Mi01MjYwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yOTY1MzYwNTwvYWNjZXNzaW9u

LW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdv

di9wdWJtZWQvMjk2NTM2MDU8L3VybD48dXJsPmh0dHBzOi8vYWMuZWxzLWNkbi5jb20vUzE1NTI1

MjYwMTgzMDA4MTUvMS1zMi4wLVMxNTUyNTI2MDE4MzAwODE1LW1haW4ucGRmP190aWQ9OTZiNjkz

NmYtOTMyOC00MTA1LWFjYjMtNzFkOGZhOWNiODJjJmFtcDthY2RuYXQ9MTUzNDQ5NDkwNF80Mzhh

NTEyN2RjZWM2N2Y1NzgwYzFjNjhhMmY1YTRjZDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmphbHouMjAxOC4wMy4wMDM8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 441. It follows that investment in AD research from the private sectors decrease and is virtually inexistent for promising mechanisms such as vesicular trafficking or autophagy ADDIN EN.CITE <EndNote><Cite><Author>Kodamullil</Author><Year>2017</Year><RecNum>2483</RecNum><DisplayText><style face="superscript">442</style></DisplayText><record><rec-number>2483</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535014945">2483</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kodamullil, A. T.</author><author>Zekri, F.</author><author>Sood, M.</author><author>Hengerer, B.</author><author>Canard, L.</author><author>McHale, D.</author><author>Hofmann-Apitius, M.</author></authors></contributors><auth-address>Fraunhofer Institute for Algorithms and Scientific Computing, Sankt Augustin 53754, Germany.&#xD;University of Sfax, B.P. 1088, 3018, Tunisia.&#xD;Boehringer Ingelheim Pharma, 88397 Biberach an der Riss, Germany.&#xD;Sanofi, Chilly-Mazarin Cedex 91385, France.&#xD;UCB Pharma, Belgium. Present address: Weatherden Ltd, Canterbury, Kent CT3 1TB, UK.</auth-address><titles><title>Trial watch: Tracing investment in drug development for Alzheimer disease</title><secondary-title>Nat Rev Drug Discov</secondary-title></titles><pages>819</pages><volume>16</volume><number>12</number><edition>2017/10/24</edition><dates><year>2017</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1474-1784 (Electronic)&#xD;1474-1776 (Linking)</isbn><accession-num>29056749</accession-num><urls><related-urls><url>. Still, there are some hopes for drugs tested in previous trials that have failed in phase II stages. The FDA grants accelerated approval of drugs that comply with guidelines classified as a determinant for a disease. With the aforementioned NIA-AA new definitions on AD based on biomarkers, these drugs could still get FDA approval should they show changes in any of the important biomarkers in CSF at early stages. Indeed, the preclinical stage is the go-to stage for testing some of these agents for improving the predictors of AD progression in any way PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaGFjaGF0dXJpYW48L0F1dGhvcj48WWVhcj4yMDE4PC9Z

ZWFyPjxSZWNOdW0+MTI0MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJz

Y3JpcHQiPjQ0MSw0NDM8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4x

MjQwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4

NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ0MjU5NzYiPjEy

NDA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x

NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPktoYWNoYXR1cmlhbiwg

QS4gUy48L2F1dGhvcj48YXV0aG9yPkhheWRlbiwgSy4gTS48L2F1dGhvcj48YXV0aG9yPk1pZWxr

ZSwgTS4gTS48L2F1dGhvcj48YXV0aG9yPlRhbmcsIFkuPC9hdXRob3I+PGF1dGhvcj5MdXR6LCBN

LiBXLjwvYXV0aG9yPjxhdXRob3I+R3VzdGFmc29uLCBELiBSLjwvYXV0aG9yPjxhdXRob3I+S3Vr

dWxsLCBXLiBBLjwvYXV0aG9yPjxhdXRob3I+TW9ocywgUi48L2F1dGhvcj48YXV0aG9yPktoYWNo

YXR1cmlhbiwgWi4gUy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk

cmVzcz5BbHpoZWltZXImYXBvcztzICZhbXA7IERlbWVudGlhOiBUaGUgSm91cm5hbCBvZiB0aGUg

QWx6aGVpbWVyJmFwb3M7cyBBc3NvY2lhdGlvbiwgUm9ja3ZpbGxlLCBNRCwgVVNBLiBFbGVjdHJv

bmljIGFkZHJlc3M6IGFkal94ZWRAa3JhLm5ldC4mI3hEO0Fzc29jaWF0ZSBQcm9mZXNzb3IsIERp

dmlzaW9uIG9mIFB1YmxpYyBIZWFsdGggU2NpZW5jZXMsIERlcGFydG1lbnQgb2YgU29jaWFsIFNj

aWVuY2VzIGFuZCBIZWFsdGggUG9saWN5LCBTdGljaHQgQ2VudGVyIGZvciBIZWFsdGh5IEFnaW5n

IGFuZCBBbHpoZWltZXImYXBvcztzIFByZXZlbnRpb24sIFdha2UgRm9yZXN0IFNjaG9vbCBvZiBN

ZWRpY2luZSwgV2luc3Rvbi1TYWxlbSwgTkMsIFVTQS4mI3hEO1Byb2Zlc3NvciBvZiBFcGlkZW1p

b2xvZ3ksIERlcGFydG1lbnQgb2YgSGVhbHRoIFNjaWVuY2VzIFJlc2VhcmNoLCBQcm9mZXNzb3Ig

b2YgTmV1cm9sb2d5LCBNYXlvIENsaW5pYyBDb2xsZWdlIG9mIE1lZGljaW5lLCBSb2NoZXN0ZXIs

IE1OLCBVU0EuJiN4RDtBc3NvY2lhdGUgUHJvZmVzc29yLCBEZXBhcnRtZW50IG9mIE5ldXJvbG9n

eSwgWHVhbiBXdSBIb3NwaXRhbCwgQmVpamluZywgQ2hpbmEuJiN4RDtBc3Npc3RhbnQgUHJvZmVz

c29yIG9mIE5ldXJvbG9neSwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIER1a2UgVW5pdmVyc2l0

eSBTY2hvb2wgb2YgTWVkaWNpbmUsIER1cmhhbSwgTkMsIFVTQS4mI3hEO1Byb2Zlc3NvciwgU2Vj

dGlvbiBmb3IgTmV1cm9FcGlkZW1pb2xvZ3ksIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBTdGF0

ZSBVbml2ZXJzaXR5IG9mIE5ldyBZb3JrLURvd25zdGF0ZSBNZWRpY2FsIENlbnRlciwgQnJvb2ts

eW4sIE5ZLCBVU0EuJiN4RDtQcm9mZXNzb3IsIERlcGFydG1lbnQgb2YgRXBpZGVtaW9sb2d5LCBT

Y2hvb2wgb2YgUHVibGljIEhlYWx0aCwgVW5pdmVyc2l0eSBvZiBXYXNoaW5ndG9uLCBTZWF0dGxl

LCBXQSwgVVNBLiYjeEQ7U2VuaW9yIEFzc29jaWF0ZSBFZGl0b3IsIEFsemhlaW1lciZhcG9zO3Mg

JmFtcDsgRGVtZW50aWE6IFRoZSBKb3VybmFsIG9mIHRoZSBBbHpoZWltZXImYXBvcztzIEFzc29j

aWF0aW9uLCBDaGljYWdvLCBJTCwgVVNBLiYjeEQ7QWx6aGVpbWVyJmFwb3M7cyAmYW1wOyBEZW1l

bnRpYTogVGhlIEpvdXJuYWwgb2YgdGhlIEFsemhlaW1lciZhcG9zO3MgQXNzb2NpYXRpb24sIFJv

Y2t2aWxsZSwgTUQsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5GdXR1cmUgcHJv

c3BlY3RzIGFuZCBjaGFsbGVuZ2VzIGZvciBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgZHJ1ZyBk

ZXZlbG9wbWVudCBpbiB0aGUgZXJhIG9mIHRoZSBOSUEtQUEgUmVzZWFyY2ggRnJhbWV3b3JrPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFsemhlaW1lcnMgRGVtZW50PC9zZWNvbmRhcnktdGl0bGU+

PC90aXRsZXM+PHBhZ2VzPjUzMi01MzQ8L3BhZ2VzPjx2b2x1bWU+MTQ8L3ZvbHVtZT48bnVtYmVy

PjQ8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxODwveWVhcj48cHViLWRhdGVzPjxkYXRlPkFwcjwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTItNTI3OSAoRWxlY3Ryb25pYykmI3hE

OzE1NTItNTI2MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjk2NTM2MDU8L2FjY2Vz

c2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5p

aC5nb3YvcHVibWVkLzI5NjUzNjA1PC91cmw+PHVybD5odHRwczovL2FjLmVscy1jZG4uY29tL1Mx

NTUyNTI2MDE4MzAwODE1LzEtczIuMC1TMTU1MjUyNjAxODMwMDgxNS1tYWluLnBkZj9fdGlkPTk2

YjY5MzZmLTkzMjgtNDEwNS1hY2IzLTcxZDhmYTljYjgyYyZhbXA7YWNkbmF0PTE1MzQ0OTQ5MDRf

NDM4YTUxMjdkY2VjNjdmNTc4MGMxYzY4YTJmNWE0Y2Q8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5qYWx6LjIwMTguMDMuMDAzPC9l

bGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5LaGFj

aGF0dXJpYW48L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNOdW0+MTI0NzwvUmVjTnVtPjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTI0NzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0

YW1wPSIxNTM0NDMxMzExIj4xMjQ3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5LaGFjaGF0dXJpYW4sIFouIFMuPC9hdXRob3I+PGF1dGhvcj5NZXN1bGFtLCBNLiBNLjwv

YXV0aG9yPjxhdXRob3I+S2hhY2hhdHVyaWFuLCBBLiBTLjwvYXV0aG9yPjxhdXRob3I+TW9ocywg

Ui4gQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5FZGl0

b3JzLCBTcGVjaWFsIFRvcGljcyBTZWN0aW9uIG9mIEFsemhlaW1lciZhcG9zO3MgJmFtcDsgRGVt

ZW50aWEuJiN4RDtFZGl0b3JzLCBTcGVjaWFsIFRvcGljcyBTZWN0aW9uIG9mIEFsemhlaW1lciZh

cG9zO3MgJmFtcDsgRGVtZW50aWEuIEVsZWN0cm9uaWMgYWRkcmVzczogYWRqX3hlZEBrcmEubmV0

LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSBTcGVjaWFsIFRvcGljcyBTZWN0aW9u

IG9mIEFsemhlaW1lciZhcG9zO3MgJmFtcDsgRGVtZW50aWE8L3RpdGxlPjxzZWNvbmRhcnktdGl0

bGU+QWx6aGVpbWVycyBEZW1lbnQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTI2

MS00PC9wYWdlcz48dm9sdW1lPjExPC92b2x1bWU+PG51bWJlcj4xMTwvbnVtYmVyPjxrZXl3b3Jk

cz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9wYXRob2xvZ3kvKnBoeXNpb3BhdGhvbG9neS90

aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL3BhdGhvbG9neS9waHlzaW9wYXRob2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+RGVtZW50aWEvcGF0aG9sb2d5LypwaHlzaW9wYXRob2xvZ3kvdGhl

cmFweTwva2V5d29yZD48a2V5d29yZD4qRWRpdG9yaWFsIFBvbGljaWVzPC9rZXl3b3JkPjxrZXl3

b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5Nb2RlbHMsIE5ldXJvbG9naWNhbDwva2V5d29y

ZD48a2V5d29yZD4qUGVyaW9kaWNhbHMgYXMgVG9waWM8L2tleXdvcmQ+PGtleXdvcmQ+UmV2aWV3

IExpdGVyYXR1cmUgYXMgVG9waWM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAx

NTwveWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxp

c2JuPjE1NTItNTI3OSAoRWxlY3Ryb25pYykmI3hEOzE1NTItNTI2MCAoTGlua2luZyk8L2lzYm4+

PGFjY2Vzc2lvbi1udW0+MjY1ODk2Njc8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJs

cz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI2NTg5NjY3PC91cmw+

PHVybD5odHRwczovL2FjLmVscy1jZG4uY29tL1MxNTUyNTI2MDE1MDI5MTY3LzEtczIuMC1TMTU1

MjUyNjAxNTAyOTE2Ny1tYWluLnBkZj9fdGlkPWI0OTJlODcyLTg2MTYtNDI5Mi04ZTUyLWVjOTI0

ZTM1MjIyMiZhbXA7YWNkbmF0PTE1MzQ0OTQ5MDhfZmRjZGY2MWUxNzExOWMxN2M4MTZkZWE2NmJh

NzllNWE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjEwLjEwMTYvai5qYWx6LjIwMTUuMTAuMDAyPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3Jl

Y29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaGFjaGF0dXJpYW48L0F1dGhvcj48WWVhcj4yMDE4PC9Z

ZWFyPjxSZWNOdW0+MTI0MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJz

Y3JpcHQiPjQ0MSw0NDM8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4x

MjQwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4

NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzQ0MjU5NzYiPjEy

NDA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x

NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPktoYWNoYXR1cmlhbiwg

QS4gUy48L2F1dGhvcj48YXV0aG9yPkhheWRlbiwgSy4gTS48L2F1dGhvcj48YXV0aG9yPk1pZWxr

ZSwgTS4gTS48L2F1dGhvcj48YXV0aG9yPlRhbmcsIFkuPC9hdXRob3I+PGF1dGhvcj5MdXR6LCBN

LiBXLjwvYXV0aG9yPjxhdXRob3I+R3VzdGFmc29uLCBELiBSLjwvYXV0aG9yPjxhdXRob3I+S3Vr

dWxsLCBXLiBBLjwvYXV0aG9yPjxhdXRob3I+TW9ocywgUi48L2F1dGhvcj48YXV0aG9yPktoYWNo

YXR1cmlhbiwgWi4gUy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk

cmVzcz5BbHpoZWltZXImYXBvcztzICZhbXA7IERlbWVudGlhOiBUaGUgSm91cm5hbCBvZiB0aGUg

QWx6aGVpbWVyJmFwb3M7cyBBc3NvY2lhdGlvbiwgUm9ja3ZpbGxlLCBNRCwgVVNBLiBFbGVjdHJv

bmljIGFkZHJlc3M6IGFkal94ZWRAa3JhLm5ldC4mI3hEO0Fzc29jaWF0ZSBQcm9mZXNzb3IsIERp

dmlzaW9uIG9mIFB1YmxpYyBIZWFsdGggU2NpZW5jZXMsIERlcGFydG1lbnQgb2YgU29jaWFsIFNj

aWVuY2VzIGFuZCBIZWFsdGggUG9saWN5LCBTdGljaHQgQ2VudGVyIGZvciBIZWFsdGh5IEFnaW5n

IGFuZCBBbHpoZWltZXImYXBvcztzIFByZXZlbnRpb24sIFdha2UgRm9yZXN0IFNjaG9vbCBvZiBN

ZWRpY2luZSwgV2luc3Rvbi1TYWxlbSwgTkMsIFVTQS4mI3hEO1Byb2Zlc3NvciBvZiBFcGlkZW1p

b2xvZ3ksIERlcGFydG1lbnQgb2YgSGVhbHRoIFNjaWVuY2VzIFJlc2VhcmNoLCBQcm9mZXNzb3Ig

b2YgTmV1cm9sb2d5LCBNYXlvIENsaW5pYyBDb2xsZWdlIG9mIE1lZGljaW5lLCBSb2NoZXN0ZXIs

IE1OLCBVU0EuJiN4RDtBc3NvY2lhdGUgUHJvZmVzc29yLCBEZXBhcnRtZW50IG9mIE5ldXJvbG9n

eSwgWHVhbiBXdSBIb3NwaXRhbCwgQmVpamluZywgQ2hpbmEuJiN4RDtBc3Npc3RhbnQgUHJvZmVz

c29yIG9mIE5ldXJvbG9neSwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIER1a2UgVW5pdmVyc2l0

eSBTY2hvb2wgb2YgTWVkaWNpbmUsIER1cmhhbSwgTkMsIFVTQS4mI3hEO1Byb2Zlc3NvciwgU2Vj

dGlvbiBmb3IgTmV1cm9FcGlkZW1pb2xvZ3ksIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBTdGF0

ZSBVbml2ZXJzaXR5IG9mIE5ldyBZb3JrLURvd25zdGF0ZSBNZWRpY2FsIENlbnRlciwgQnJvb2ts

eW4sIE5ZLCBVU0EuJiN4RDtQcm9mZXNzb3IsIERlcGFydG1lbnQgb2YgRXBpZGVtaW9sb2d5LCBT

Y2hvb2wgb2YgUHVibGljIEhlYWx0aCwgVW5pdmVyc2l0eSBvZiBXYXNoaW5ndG9uLCBTZWF0dGxl

LCBXQSwgVVNBLiYjeEQ7U2VuaW9yIEFzc29jaWF0ZSBFZGl0b3IsIEFsemhlaW1lciZhcG9zO3Mg

JmFtcDsgRGVtZW50aWE6IFRoZSBKb3VybmFsIG9mIHRoZSBBbHpoZWltZXImYXBvcztzIEFzc29j

aWF0aW9uLCBDaGljYWdvLCBJTCwgVVNBLiYjeEQ7QWx6aGVpbWVyJmFwb3M7cyAmYW1wOyBEZW1l

bnRpYTogVGhlIEpvdXJuYWwgb2YgdGhlIEFsemhlaW1lciZhcG9zO3MgQXNzb2NpYXRpb24sIFJv

Y2t2aWxsZSwgTUQsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5GdXR1cmUgcHJv

c3BlY3RzIGFuZCBjaGFsbGVuZ2VzIGZvciBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgZHJ1ZyBk

ZXZlbG9wbWVudCBpbiB0aGUgZXJhIG9mIHRoZSBOSUEtQUEgUmVzZWFyY2ggRnJhbWV3b3JrPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFsemhlaW1lcnMgRGVtZW50PC9zZWNvbmRhcnktdGl0bGU+

PC90aXRsZXM+PHBhZ2VzPjUzMi01MzQ8L3BhZ2VzPjx2b2x1bWU+MTQ8L3ZvbHVtZT48bnVtYmVy

PjQ8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxODwveWVhcj48cHViLWRhdGVzPjxkYXRlPkFwcjwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTItNTI3OSAoRWxlY3Ryb25pYykmI3hE

OzE1NTItNTI2MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjk2NTM2MDU8L2FjY2Vz

c2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5p

aC5nb3YvcHVibWVkLzI5NjUzNjA1PC91cmw+PHVybD5odHRwczovL2FjLmVscy1jZG4uY29tL1Mx

NTUyNTI2MDE4MzAwODE1LzEtczIuMC1TMTU1MjUyNjAxODMwMDgxNS1tYWluLnBkZj9fdGlkPTk2

YjY5MzZmLTkzMjgtNDEwNS1hY2IzLTcxZDhmYTljYjgyYyZhbXA7YWNkbmF0PTE1MzQ0OTQ5MDRf

NDM4YTUxMjdkY2VjNjdmNTc4MGMxYzY4YTJmNWE0Y2Q8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5qYWx6LjIwMTguMDMuMDAzPC9l

bGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5LaGFj

aGF0dXJpYW48L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNOdW0+MTI0NzwvUmVjTnVtPjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTI0NzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0

YW1wPSIxNTM0NDMxMzExIj4xMjQ3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5LaGFjaGF0dXJpYW4sIFouIFMuPC9hdXRob3I+PGF1dGhvcj5NZXN1bGFtLCBNLiBNLjwv

YXV0aG9yPjxhdXRob3I+S2hhY2hhdHVyaWFuLCBBLiBTLjwvYXV0aG9yPjxhdXRob3I+TW9ocywg

Ui4gQy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5FZGl0

b3JzLCBTcGVjaWFsIFRvcGljcyBTZWN0aW9uIG9mIEFsemhlaW1lciZhcG9zO3MgJmFtcDsgRGVt

ZW50aWEuJiN4RDtFZGl0b3JzLCBTcGVjaWFsIFRvcGljcyBTZWN0aW9uIG9mIEFsemhlaW1lciZh

cG9zO3MgJmFtcDsgRGVtZW50aWEuIEVsZWN0cm9uaWMgYWRkcmVzczogYWRqX3hlZEBrcmEubmV0

LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSBTcGVjaWFsIFRvcGljcyBTZWN0aW9u

IG9mIEFsemhlaW1lciZhcG9zO3MgJmFtcDsgRGVtZW50aWE8L3RpdGxlPjxzZWNvbmRhcnktdGl0

bGU+QWx6aGVpbWVycyBEZW1lbnQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTI2

MS00PC9wYWdlcz48dm9sdW1lPjExPC92b2x1bWU+PG51bWJlcj4xMTwvbnVtYmVyPjxrZXl3b3Jk

cz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS9wYXRob2xvZ3kvKnBoeXNpb3BhdGhvbG9neS90

aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL3BhdGhvbG9neS9waHlzaW9wYXRob2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+RGVtZW50aWEvcGF0aG9sb2d5LypwaHlzaW9wYXRob2xvZ3kvdGhl

cmFweTwva2V5d29yZD48a2V5d29yZD4qRWRpdG9yaWFsIFBvbGljaWVzPC9rZXl3b3JkPjxrZXl3

b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5Nb2RlbHMsIE5ldXJvbG9naWNhbDwva2V5d29y

ZD48a2V5d29yZD4qUGVyaW9kaWNhbHMgYXMgVG9waWM8L2tleXdvcmQ+PGtleXdvcmQ+UmV2aWV3

IExpdGVyYXR1cmUgYXMgVG9waWM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAx

NTwveWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxp

c2JuPjE1NTItNTI3OSAoRWxlY3Ryb25pYykmI3hEOzE1NTItNTI2MCAoTGlua2luZyk8L2lzYm4+

PGFjY2Vzc2lvbi1udW0+MjY1ODk2Njc8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJs

cz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI2NTg5NjY3PC91cmw+

PHVybD5odHRwczovL2FjLmVscy1jZG4uY29tL1MxNTUyNTI2MDE1MDI5MTY3LzEtczIuMC1TMTU1

MjUyNjAxNTAyOTE2Ny1tYWluLnBkZj9fdGlkPWI0OTJlODcyLTg2MTYtNDI5Mi04ZTUyLWVjOTI0

ZTM1MjIyMiZhbXA7YWNkbmF0PTE1MzQ0OTQ5MDhfZmRjZGY2MWUxNzExOWMxN2M4MTZkZWE2NmJh

NzllNWE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjEwLjEwMTYvai5qYWx6LjIwMTUuMTAuMDAyPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3Jl

Y29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA 441,443. Gene editing and control of gene expression in the brain are technologies in very early stages for clinical application ADDIN EN.CITE <EndNote><Cite><Author>Haapaniemi</Author><Year>2018</Year><RecNum>1244</RecNum><DisplayText><style face="superscript">444</style></DisplayText><record><rec-number>1244</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1534429900">1244</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Haapaniemi, E.</author><author>Botla, S.</author><author>Persson, J.</author><author>Schmierer, B.</author><author>Taipale, J.</author></authors></contributors><auth-address>Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.&#xD;Genome-Scale Biology Program, University of Helsinki, Helsinki, Finland.&#xD;Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden. bernhard.schmierer@ki.se.&#xD;Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden. ajt208@cam.ac.uk.&#xD;Genome-Scale Biology Program, University of Helsinki, Helsinki, Finland. ajt208@cam.ac.uk.&#xD;Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom. ajt208@cam.ac.uk.</auth-address><titles><title>CRISPR-Cas9 genome editing induces a p53-mediated DNA damage response</title><secondary-title>Nat Med</secondary-title></titles><pages>927-930</pages><volume>24</volume><number>7</number><dates><year>2018</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1546-170X (Electronic)&#xD;1078-8956 (Linking)</isbn><accession-num>29892067</accession-num><urls><related-urls><url>, however they are good future approaches in modifying mechanisms such as synaptic plasticity and epigenetics, as discussed earlier in this work. We have revised many approaches directed towards restoring insulin balance in the brain, or restore microbiota communities to anti-inflammatory states. Moreover, combination of the therapeutic approaches revised here and others remain largely unexplored and have great potential to alter AD progression. The establishment of new biomarkers also corresponds to the discovery of new disease pathways related to increased risk of developing AD. Now several studies aim to evaluate the effect of statins in AD from a mechanistic focus, evaluating new biomarker molecules such as neprilysin PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZYW1hbW90bzwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+

PFJlY051bT4yNDg2PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+NDQ1LDQ0Njwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI0ODY8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTAxODMyNCI+MjQ4Njwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+WWFtYW1vdG8sIE4uPC9hdXRo

b3I+PGF1dGhvcj5GdWppaSwgWS48L2F1dGhvcj48YXV0aG9yPkthc2FoYXJhLCBSLjwvYXV0aG9y

PjxhdXRob3I+VGFuaWRhLCBNLjwvYXV0aG9yPjxhdXRob3I+T2hvcmEsIEsuPC9hdXRob3I+PGF1

dGhvcj5Pbm8sIFkuPC9hdXRob3I+PGF1dGhvcj5TdXp1a2ksIEsuPC9hdXRob3I+PGF1dGhvcj5T

b2J1ZSwgSy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5G

YWN1bHR5IG9mIFBoYXJtYWNldXRpY2FsIFNjaWVuY2VzLCBIb2t1cmlrdSBVbml2ZXJzaXR5LCBL

YW5hemF3YSwgSXNoaWthd2EsIDkyMC0xMTgxLCBKYXBhbi4mI3hEO0xhYm9yYXRvcnkgb2YgTmV1

cm9jaGVtaXN0cnksIERlcGFydG1lbnQgb2YgUGhhcm1hY3ksIENvbGxlZ2Ugb2YgUGhhcm1hY2V1

dGljYWwgU2NpZW5jZXMsIFJpdHN1bWVpa2FuIFVuaXZlcnNpdHksIEt1c2F0c3UsIFNoaWdhLCA1

MjUtODU3NywgSmFwYW4uJiN4RDtEZXBhcnRtZW50IG9mIFBoeXNpb2xvZ3kgSUksIEthbmF6YXdh

IE1lZGljYWwgVW5pdmVyc2l0eSwgVWNoaW5hZGEsIElzaGlrYXdhLCA5MjAtMDI5MywgSmFwYW4u

JiN4RDtMYWJvcmF0b3J5IG9mIE1vbGVjdWxhciBNZWRpY2luYWwgU2NpZW5jZSwgRGVwYXJ0bWVu

dCBvZiBQaGFybWFjeSwgQ29sbGVnZSBvZiBQaGFybWFjZXV0aWNhbCBTY2llbmNlcywgUml0c3Vt

ZWlrYW4gVW5pdmVyc2l0eSwgS3VzYXRzdSwgU2hpZ2EsIDUyNS04NTc3LCBKYXBhbi4mI3hEO0Rl

cGFydG1lbnQgb2YgQW5lc3RoZXNpb2xvZ3kgYW5kIE1lZGljYWwgQ3Jpc2lzIE1hbmFnZW1lbnQs

IE5hZ295YSBDaXR5IFVuaXZlcnNpdHkgR3JhZHVhdGUgU2Nob29sIG9mIE1lZGljYWwgU2NpZW5j

ZXMsIE5hZ295YSBDaXR5LCBBaWNoaSwgNDY3LTg2MjIsIEphcGFuLjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPlNpbXZhc3RhdGluIGFuZCBhdG9ydmFzdGF0aW4gZmFjaWxpdGF0ZXMgYW15

bG9pZCBiZXRhLXByb3RlaW4gZGVncmFkYXRpb24gaW4gZXh0cmFjZWxsdWxhciBzcGFjZXMgYnkg

aW5jcmVhc2luZyBuZXByaWx5c2luIHNlY3JldGlvbiBmcm9tIGFzdHJvY3l0ZXMgdGhyb3VnaCBh

Y3RpdmF0aW9uIG9mIE1BUEsvRXJrMS8yIHBhdGh3YXlzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PkdsaWE8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+OTUyLTYyPC9wYWdlcz48dm9s

dW1lPjY0PC92b2x1bWU+PG51bWJlcj42PC9udW1iZXI+PGVkaXRpb24+MjAxNi8wMi8xNjwvZWRp

dGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzLyptZXRhYm9saXNt

PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0cm9jeXRlcy8q

ZHJ1ZyBlZmZlY3RzL21ldGFib2xpc20vc2VjcmV0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkF0b3J2

YXN0YXRpbiBDYWxjaXVtLypwaGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vZHJ1

ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkRpc2Vhc2UgTW9kZWxzLCBBbmltYWw8L2tleXdv

cmQ+PGtleXdvcmQ+RXh0cmFjZWxsdWxhciBTaWduYWwtUmVndWxhdGVkIE1BUCBLaW5hc2VzL2Ry

dWcgZWZmZWN0cy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkV4dHJhY2VsbHVsYXIgU3Bh

Y2UvKmRydWcgZWZmZWN0cy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1BUCBLaW5hc2Ug

U2lnbmFsaW5nIFN5c3RlbS8qZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPk5lcHJpbHlz

aW4vbWV0YWJvbGlzbS8qc2VjcmV0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlJhdHMsIFNwcmFndWUt

RGF3bGV5PC9rZXl3b3JkPjxrZXl3b3JkPlNpbXZhc3RhdGluLypwaGFybWFjb2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPmNo

b2xlc3Rlcm9sPC9rZXl3b3JkPjxrZXl3b3JkPnByb3RlaW4gbWV0YWJvbGlzbTwva2V5d29yZD48

L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVuPC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA5OC0xMTM2IChFbGVjdHJvbmljKSYjeEQ7

MDg5NC0xNDkxIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNjg3NTgxODwvYWNjZXNz

aW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmlo

Lmdvdi9wdWJtZWQvMjY4NzU4MTg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjEwLjEwMDIvZ2xpYS4yMjk3NDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+SmFuc29uPC9BdXRob3I+PFllYXI+MjAx

NjwvWWVhcj48UmVjTnVtPjI0ODc8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjI0ODc8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTAxODQzNCI+MjQ4Nzwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SmFuc29uLCBDaHJpc3RvcGhlciBH

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5EaXZlcnNl

IGVmZmVjdHMgb2Ygc3RhdGlucyBpbiBBbHpoZWltZXLigJlzIGRpc2Vhc2U8L3RpdGxlPjxzZWNv

bmRhcnktdGl0bGU+U2NpZW5jZSBUcmFuc2xhdGlvbmFsIE1lZGljaW5lPC9zZWNvbmRhcnktdGl0

bGU+PC90aXRsZXM+PHBhZ2VzPjMzMGVjNDQtMzMwZWM0NDwvcGFnZXM+PHZvbHVtZT44PC92b2x1

bWU+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDE2LTAzLTE2IDAw

OjAwOjAwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZYW1hbW90bzwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+

PFJlY051bT4yNDg2PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw

dCI+NDQ1LDQ0Njwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI0ODY8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3

OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTAxODMyNCI+MjQ4Njwv

a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y

ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+WWFtYW1vdG8sIE4uPC9hdXRo

b3I+PGF1dGhvcj5GdWppaSwgWS48L2F1dGhvcj48YXV0aG9yPkthc2FoYXJhLCBSLjwvYXV0aG9y

PjxhdXRob3I+VGFuaWRhLCBNLjwvYXV0aG9yPjxhdXRob3I+T2hvcmEsIEsuPC9hdXRob3I+PGF1

dGhvcj5Pbm8sIFkuPC9hdXRob3I+PGF1dGhvcj5TdXp1a2ksIEsuPC9hdXRob3I+PGF1dGhvcj5T

b2J1ZSwgSy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5G

YWN1bHR5IG9mIFBoYXJtYWNldXRpY2FsIFNjaWVuY2VzLCBIb2t1cmlrdSBVbml2ZXJzaXR5LCBL

YW5hemF3YSwgSXNoaWthd2EsIDkyMC0xMTgxLCBKYXBhbi4mI3hEO0xhYm9yYXRvcnkgb2YgTmV1

cm9jaGVtaXN0cnksIERlcGFydG1lbnQgb2YgUGhhcm1hY3ksIENvbGxlZ2Ugb2YgUGhhcm1hY2V1

dGljYWwgU2NpZW5jZXMsIFJpdHN1bWVpa2FuIFVuaXZlcnNpdHksIEt1c2F0c3UsIFNoaWdhLCA1

MjUtODU3NywgSmFwYW4uJiN4RDtEZXBhcnRtZW50IG9mIFBoeXNpb2xvZ3kgSUksIEthbmF6YXdh

IE1lZGljYWwgVW5pdmVyc2l0eSwgVWNoaW5hZGEsIElzaGlrYXdhLCA5MjAtMDI5MywgSmFwYW4u

JiN4RDtMYWJvcmF0b3J5IG9mIE1vbGVjdWxhciBNZWRpY2luYWwgU2NpZW5jZSwgRGVwYXJ0bWVu

dCBvZiBQaGFybWFjeSwgQ29sbGVnZSBvZiBQaGFybWFjZXV0aWNhbCBTY2llbmNlcywgUml0c3Vt

ZWlrYW4gVW5pdmVyc2l0eSwgS3VzYXRzdSwgU2hpZ2EsIDUyNS04NTc3LCBKYXBhbi4mI3hEO0Rl

cGFydG1lbnQgb2YgQW5lc3RoZXNpb2xvZ3kgYW5kIE1lZGljYWwgQ3Jpc2lzIE1hbmFnZW1lbnQs

IE5hZ295YSBDaXR5IFVuaXZlcnNpdHkgR3JhZHVhdGUgU2Nob29sIG9mIE1lZGljYWwgU2NpZW5j

ZXMsIE5hZ295YSBDaXR5LCBBaWNoaSwgNDY3LTg2MjIsIEphcGFuLjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPlNpbXZhc3RhdGluIGFuZCBhdG9ydmFzdGF0aW4gZmFjaWxpdGF0ZXMgYW15

bG9pZCBiZXRhLXByb3RlaW4gZGVncmFkYXRpb24gaW4gZXh0cmFjZWxsdWxhciBzcGFjZXMgYnkg

aW5jcmVhc2luZyBuZXByaWx5c2luIHNlY3JldGlvbiBmcm9tIGFzdHJvY3l0ZXMgdGhyb3VnaCBh

Y3RpdmF0aW9uIG9mIE1BUEsvRXJrMS8yIHBhdGh3YXlzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PkdsaWE8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+OTUyLTYyPC9wYWdlcz48dm9s

dW1lPjY0PC92b2x1bWU+PG51bWJlcj42PC9udW1iZXI+PGVkaXRpb24+MjAxNi8wMi8xNjwvZWRp

dGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBlcHRpZGVzLyptZXRhYm9saXNt

PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0cm9jeXRlcy8q

ZHJ1ZyBlZmZlY3RzL21ldGFib2xpc20vc2VjcmV0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkF0b3J2

YXN0YXRpbiBDYWxjaXVtLypwaGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vZHJ1

ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkRpc2Vhc2UgTW9kZWxzLCBBbmltYWw8L2tleXdv

cmQ+PGtleXdvcmQ+RXh0cmFjZWxsdWxhciBTaWduYWwtUmVndWxhdGVkIE1BUCBLaW5hc2VzL2Ry

dWcgZWZmZWN0cy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkV4dHJhY2VsbHVsYXIgU3Bh

Y2UvKmRydWcgZWZmZWN0cy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1BUCBLaW5hc2Ug

U2lnbmFsaW5nIFN5c3RlbS8qZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPk5lcHJpbHlz

aW4vbWV0YWJvbGlzbS8qc2VjcmV0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlJhdHMsIFNwcmFndWUt

RGF3bGV5PC9rZXl3b3JkPjxrZXl3b3JkPlNpbXZhc3RhdGluLypwaGFybWFjb2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPmNo

b2xlc3Rlcm9sPC9rZXl3b3JkPjxrZXl3b3JkPnByb3RlaW4gbWV0YWJvbGlzbTwva2V5d29yZD48

L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVuPC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA5OC0xMTM2IChFbGVjdHJvbmljKSYjeEQ7

MDg5NC0xNDkxIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNjg3NTgxODwvYWNjZXNz

aW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmlo

Lmdvdi9wdWJtZWQvMjY4NzU4MTg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjEwLjEwMDIvZ2xpYS4yMjk3NDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1u

dW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+SmFuc29uPC9BdXRob3I+PFllYXI+MjAx

NjwvWWVhcj48UmVjTnVtPjI0ODc8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjI0ODc8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTAxODQzNCI+MjQ4Nzwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SmFuc29uLCBDaHJpc3RvcGhlciBH

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5EaXZlcnNl

IGVmZmVjdHMgb2Ygc3RhdGlucyBpbiBBbHpoZWltZXLigJlzIGRpc2Vhc2U8L3RpdGxlPjxzZWNv

bmRhcnktdGl0bGU+U2NpZW5jZSBUcmFuc2xhdGlvbmFsIE1lZGljaW5lPC9zZWNvbmRhcnktdGl0

bGU+PC90aXRsZXM+PHBhZ2VzPjMzMGVjNDQtMzMwZWM0NDwvcGFnZXM+PHZvbHVtZT44PC92b2x1

bWU+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDE2LTAzLTE2IDAw

OjAwOjAwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 445,446. It is now evident that the field of AD research is starting to integrate knowledge from diverse disciplines. For example, micro RNAs have shown important roles regulating pathways during AD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QdXR0ZWVyYWo8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFy

PjxSZWNOdW0+MTA0MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjE2NSwxNjYsNDQ3PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+

MTA0MDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTBy

eDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyODY1Njc5Ij4x

MDQwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+

MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5QdXR0ZWVyYWosIE1h

bmlzaDwvYXV0aG9yPjxhdXRob3I+RmFpcnV6LCBZYWhheWEgTW9oYW1hZDwvYXV0aG9yPjxhdXRo

b3I+VGVvaCwgU2VvbmcgTGluPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRs

ZXM+PHRpdGxlPk1pY3JvUk5BIER5c3JlZ3VsYXRpb24gaW4gQWx6aGVpbWVyJmFwb3M7cyBEaXNl

YXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNOUyAmYW1wOyBOZXVyb2xvZ2ljYWwgRGlzb3Jk

ZXJzIC0gRHJ1ZyBUYXJnZXRzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHZvbHVtZT4xNjwv

dm9sdW1lPjxudW1iZXI+OTwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0

ZXM+PGRhdGU+MjAxOC8wMS8xOTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxwdWJsaXNoZXI+

QmVudGhhbSBTY2llbmNlIFB1Ymxpc2hlcnMgTHRkLjwvcHVibGlzaGVyPjxpc2JuPjE4NzEtNTI3

MzwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMjE3

NC8xODcxNTI3MzE2NjY2MTcwODA3MTQyMzExPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxl

bGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4yMTc0LzE4NzE1MjczMTY2NjYxNzA4MDcxNDIzMTE8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlNh

bHRhPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48UmVjTnVtPjIxNzI8L1JlY051bT48cmVjb3Jk

PjxyZWMtbnVtYmVyPjIxNzI8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0i

MTUzNDg2NDEyMSI+MjE3Mjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy

bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+

U2FsdGEsIEUuPC9hdXRob3I+PGF1dGhvcj5EZSBTdHJvb3BlciwgQi48L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5WbGFhbXMgSW5zdGl0dXV0IHZvb3IgQmlv

dGVjaG5vbG9naWUgKFZJQikgQ2VudGVyIGZvciBCcmFpbiBhbmQgRGlzZWFzZSwgVklCLUxldXZl

biwgTGV1dmVuLCBCZWxnaXVtOyBldmdlbmlhLnNhbHRhQGNtZS52aWIta3VsZXV2ZW4uYmUuJiN4

RDtDZW50ZXIgZm9yIEh1bWFuIEdlbmV0aWNzLCBVbml2ZXJzaXRhaXJlIFppZWtlbmh1aXplbiBh

bmQgTGV1dmVuIFJlc2VhcmNoIEluc3RpdHV0ZSBmb3IgTmV1cm9zY2llbmNlIGFuZCBEaXNlYXNl

LCBLVS1MZXV2ZW4sIExldXZlbiwgQmVsZ2l1bTsgYW5kLiYjeEQ7VmxhYW1zIEluc3RpdHV1dCB2

b29yIEJpb3RlY2hub2xvZ2llIChWSUIpIENlbnRlciBmb3IgQnJhaW4gYW5kIERpc2Vhc2UsIFZJ

Qi1MZXV2ZW4sIExldXZlbiwgQmVsZ2l1bTsgYmFydC5kZXN0cm9vcGVyQGNtZS52aWIta3VsZXV2

ZW4uYmUuJiN4RDtJbnN0aXR1dGUgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IENvbGxlZ2UgTG9u

ZG9uLCBMb25kb24sIFVuaXRlZCBLaW5nZG9tLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxl

Pm1pY3JvUk5BLTEzMjogYSBrZXkgbm9uY29kaW5nIFJOQSBvcGVyYXRpbmcgaW4gdGhlIGNlbGx1

bGFyIHBoYXNlIG9mIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5GQVNFQiBKPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwt

dGl0bGU+RkFTRUIgSjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjQyNC00MzM8L3Bh

Z2VzPjx2b2x1bWU+MzE8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48ZWRpdGlvbj4yMDE3LzAy

LzA2PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qbWV0YWJv

bGlzbTwva2V5d29yZD48a2V5d29yZD5DZW50cmFsIE5lcnZvdXMgU3lzdGVtLypwaHlzaW9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPkdlbmUgRXhwcmVzc2lvbiBSZWd1bGF0aW9uLypwaHlzaW9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NaWNyb1JOQXMvZ2Vu

ZXRpY3MvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+KmFteWxvaWQvVEFVIHBhdGhvbG9n

eTwva2V5d29yZD48a2V5d29yZD4qbmV1cm9kZWdlbmVyYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+

Km5ldXJvcHJvdGVjdGlvbjwva2V5d29yZD48a2V5d29yZD4qc21hbGwgUk5BPC9rZXl3b3JkPjxr

ZXl3b3JkPip0aGVyYXB5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3ll

YXI+PHB1Yi1kYXRlcz48ZGF0ZT5GZWI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

NTMwLTY4NjAgKEVsZWN0cm9uaWMpJiN4RDswODkyLTY2MzggKExpbmtpbmcpPC9pc2JuPjxhY2Nl

c3Npb24tbnVtPjI4MTQ4Nzc1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy

bD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yODE0ODc3NTwvdXJsPjwvcmVs

YXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA5Ni9mai4yMDE2

MDEzMDg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPkdvZWRla2U8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNOdW0+MTA0MTwvUmVjTnVt

PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTA0MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg

YXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGlt

ZXN0YW1wPSIxNTMyODY1Njc5Ij4xMDQxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5Hb2VkZWtlLCBMZWlnaDwvYXV0aG9yPjxhdXRob3I+RmVybsOhbmRlei1IZXJuYW5k

bywgQ2FybG9zPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxl

Pm1pY3JvUk5BczogQSBjb25uZWN0aW9uIGJldHdlZW4gY2hvbGVzdGVyb2wgbWV0YWJvbGlzbSBh

bmQgbmV1cm9kZWdlbmVyYXRpb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmV1cm9iaW9sb2d5

IG9mIERpc2Vhc2U8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NDgtNTM8L3BhZ2Vz

Pjx2b2x1bWU+NzI8L3ZvbHVtZT48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48cHViLWRhdGVzPjxk

YXRlPjIwMTQvMTI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2aWVy

IEJWPC9wdWJsaXNoZXI+PGlzYm4+MDk2OS05OTYxPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2oubmJkLjIwMTQuMDUuMDM0PC91cmw+PC9y

ZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2oubmJk

LjIwMTQuMDUuMDM0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QdXR0ZWVyYWo8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFy

PjxSZWNOdW0+MTA0MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjE2NSwxNjYsNDQ3PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+

MTA0MDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTBy

eDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTMyODY1Njc5Ij4x

MDQwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+

MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5QdXR0ZWVyYWosIE1h

bmlzaDwvYXV0aG9yPjxhdXRob3I+RmFpcnV6LCBZYWhheWEgTW9oYW1hZDwvYXV0aG9yPjxhdXRo

b3I+VGVvaCwgU2VvbmcgTGluPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRs

ZXM+PHRpdGxlPk1pY3JvUk5BIER5c3JlZ3VsYXRpb24gaW4gQWx6aGVpbWVyJmFwb3M7cyBEaXNl

YXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNOUyAmYW1wOyBOZXVyb2xvZ2ljYWwgRGlzb3Jk

ZXJzIC0gRHJ1ZyBUYXJnZXRzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHZvbHVtZT4xNjwv

dm9sdW1lPjxudW1iZXI+OTwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0

ZXM+PGRhdGU+MjAxOC8wMS8xOTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxwdWJsaXNoZXI+

QmVudGhhbSBTY2llbmNlIFB1Ymxpc2hlcnMgTHRkLjwvcHVibGlzaGVyPjxpc2JuPjE4NzEtNTI3

MzwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL2R4LmRvaS5vcmcvMTAuMjE3

NC8xODcxNTI3MzE2NjY2MTcwODA3MTQyMzExPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxl

bGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4yMTc0LzE4NzE1MjczMTY2NjYxNzA4MDcxNDIzMTE8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlNh

bHRhPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48UmVjTnVtPjIxNzI8L1JlY051bT48cmVjb3Jk

PjxyZWMtbnVtYmVyPjIxNzI8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0i

MTUzNDg2NDEyMSI+MjE3Mjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy

bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+

U2FsdGEsIEUuPC9hdXRob3I+PGF1dGhvcj5EZSBTdHJvb3BlciwgQi48L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5WbGFhbXMgSW5zdGl0dXV0IHZvb3IgQmlv

dGVjaG5vbG9naWUgKFZJQikgQ2VudGVyIGZvciBCcmFpbiBhbmQgRGlzZWFzZSwgVklCLUxldXZl

biwgTGV1dmVuLCBCZWxnaXVtOyBldmdlbmlhLnNhbHRhQGNtZS52aWIta3VsZXV2ZW4uYmUuJiN4

RDtDZW50ZXIgZm9yIEh1bWFuIEdlbmV0aWNzLCBVbml2ZXJzaXRhaXJlIFppZWtlbmh1aXplbiBh

bmQgTGV1dmVuIFJlc2VhcmNoIEluc3RpdHV0ZSBmb3IgTmV1cm9zY2llbmNlIGFuZCBEaXNlYXNl

LCBLVS1MZXV2ZW4sIExldXZlbiwgQmVsZ2l1bTsgYW5kLiYjeEQ7VmxhYW1zIEluc3RpdHV1dCB2

b29yIEJpb3RlY2hub2xvZ2llIChWSUIpIENlbnRlciBmb3IgQnJhaW4gYW5kIERpc2Vhc2UsIFZJ

Qi1MZXV2ZW4sIExldXZlbiwgQmVsZ2l1bTsgYmFydC5kZXN0cm9vcGVyQGNtZS52aWIta3VsZXV2

ZW4uYmUuJiN4RDtJbnN0aXR1dGUgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IENvbGxlZ2UgTG9u

ZG9uLCBMb25kb24sIFVuaXRlZCBLaW5nZG9tLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxl

Pm1pY3JvUk5BLTEzMjogYSBrZXkgbm9uY29kaW5nIFJOQSBvcGVyYXRpbmcgaW4gdGhlIGNlbGx1

bGFyIHBoYXNlIG9mIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5GQVNFQiBKPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwt

dGl0bGU+RkFTRUIgSjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjQyNC00MzM8L3Bh

Z2VzPjx2b2x1bWU+MzE8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48ZWRpdGlvbj4yMDE3LzAy

LzA2PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qbWV0YWJv

bGlzbTwva2V5d29yZD48a2V5d29yZD5DZW50cmFsIE5lcnZvdXMgU3lzdGVtLypwaHlzaW9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPkdlbmUgRXhwcmVzc2lvbiBSZWd1bGF0aW9uLypwaHlzaW9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NaWNyb1JOQXMvZ2Vu

ZXRpY3MvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+KmFteWxvaWQvVEFVIHBhdGhvbG9n

eTwva2V5d29yZD48a2V5d29yZD4qbmV1cm9kZWdlbmVyYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+

Km5ldXJvcHJvdGVjdGlvbjwva2V5d29yZD48a2V5d29yZD4qc21hbGwgUk5BPC9rZXl3b3JkPjxr

ZXl3b3JkPip0aGVyYXB5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTc8L3ll

YXI+PHB1Yi1kYXRlcz48ZGF0ZT5GZWI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x

NTMwLTY4NjAgKEVsZWN0cm9uaWMpJiN4RDswODkyLTY2MzggKExpbmtpbmcpPC9pc2JuPjxhY2Nl

c3Npb24tbnVtPjI4MTQ4Nzc1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy

bD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yODE0ODc3NTwvdXJsPjwvcmVs

YXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA5Ni9mai4yMDE2

MDEzMDg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPkdvZWRla2U8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNOdW0+MTA0MTwvUmVjTnVt

PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTA0MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg

YXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGlt

ZXN0YW1wPSIxNTMyODY1Njc5Ij4xMDQxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5Hb2VkZWtlLCBMZWlnaDwvYXV0aG9yPjxhdXRob3I+RmVybsOhbmRlei1IZXJuYW5k

bywgQ2FybG9zPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxl

Pm1pY3JvUk5BczogQSBjb25uZWN0aW9uIGJldHdlZW4gY2hvbGVzdGVyb2wgbWV0YWJvbGlzbSBh

bmQgbmV1cm9kZWdlbmVyYXRpb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmV1cm9iaW9sb2d5

IG9mIERpc2Vhc2U8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NDgtNTM8L3BhZ2Vz

Pjx2b2x1bWU+NzI8L3ZvbHVtZT48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48cHViLWRhdGVzPjxk

YXRlPjIwMTQvMTI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48cHVibGlzaGVyPkVsc2V2aWVy

IEJWPC9wdWJsaXNoZXI+PGlzYm4+MDk2OS05OTYxPC9pc2JuPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vZHguZG9pLm9yZy8xMC4xMDE2L2oubmJkLjIwMTQuMDUuMDM0PC91cmw+PC9y

ZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2oubmJk

LjIwMTQuMDUuMDM0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPgB=

ADDIN EN.CITE.DATA 165,166,447. Also, recent works have discovered miR exosomes mediating neuron-astrocyte communication ADDIN EN.CITE <EndNote><Cite><Author>Chaudhuri</Author><Year>2018</Year><RecNum>2506</RecNum><DisplayText><style face="superscript">448</style></DisplayText><record><rec-number>2506</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535026755">2506</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chaudhuri, A. D.</author><author>Dastgheyb, R. M.</author><author>Yoo, S. W.</author><author>Trout, A.</author><author>Talbot, C. C., Jr.</author><author>Hao, H.</author><author>Witwer, K. W.</author><author>Haughey, N. J.</author></authors></contributors><auth-address>Department of Neurology, Richard T Johnson Division of Neuroimmunology and Neurological Infections, Johns Hopkins University School of Medicine, Baltimore, MD, USA.&#xD;Institute of Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.&#xD;Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.&#xD;Department of Neurology, Richard T Johnson Division of Neuroimmunology and Neurological Infections, Johns Hopkins University School of Medicine, Baltimore, MD, USA. nhaughe1@jhmi.edu.</auth-address><titles><title>TNFalpha and IL-1beta modify the miRNA cargo of astrocyte shed extracellular vesicles to regulate neurotrophic signaling in neurons</title><secondary-title>Cell Death Dis</secondary-title></titles><periodical><full-title>Cell Death Dis</full-title></periodical><pages>363</pages><volume>9</volume><number>3</number><dates><year>2018</year><pub-dates><date>Mar 5</date></pub-dates></dates><isbn>2041-4889 (Electronic)</isbn><accession-num>29507357</accession-num><urls><related-urls><url> and network-specific glial functions PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJ0aW48L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS

ZWNOdW0+MjUwNzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjQ0OTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI1MDc8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTAyODY5NiI+MjUwNzwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWFydGluLCBSLjwvYXV0aG9yPjxhdXRo

b3I+QmFqby1HcmFuZXJhcywgUi48L2F1dGhvcj48YXV0aG9yPk1vcmF0YWxsYSwgUi48L2F1dGhv

cj48YXV0aG9yPlBlcmVhLCBHLjwvYXV0aG9yPjxhdXRob3I+QXJhcXVlLCBBLjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkluc3RpdHV0byBDYWphbCwgQ29u

c2VqbyBTdXBlcmlvciBkZSBJbnZlc3RpZ2FjaW9uZXMgQ2llbnRpZmljYXMsIDI4MDAyIE1hZHJp

ZCwgU3BhaW4uJiN4RDtJbnN0aXR1dG8gQ2FqYWwsIENvbnNlam8gU3VwZXJpb3IgZGUgSW52ZXN0

aWdhY2lvbmVzIENpZW50aWZpY2FzLCAyODAwMiBNYWRyaWQsIFNwYWluLiBDZW50cm8gZGUgSW52

ZXN0aWdhY2lvbiBCaW9tZWRpY2EgZW4gUmVkIEVuZmVybWVkYWRlcyBOZXVyb2RlZ2VuZXJhdGl2

YXMsIEluc3RpdHV0byBkZSBTYWx1ZCBDYXJsb3MgSUlJLCAyODAyOSBNYWRyaWQsIFNwYWluLiYj

eEQ7RGVwYXJ0bWVudCBvZiBOZXVyb3NjaWVuY2UsIFVuaXZlcnNpdHkgb2YgTWlubmVzb3RhLCBN

aW5uZWFwb2xpcywgTU4gNTU0NTUsIFVTQS4gYXJhcXVlQHVtbi5lZHUuPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+Q2lyY3VpdC1zcGVjaWZpYyBzaWduYWxpbmcgaW4gYXN0cm9jeXRlLW5l

dXJvbiBuZXR3b3JrcyBpbiBiYXNhbCBnYW5nbGlhIHBhdGh3YXlzPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPlNjaWVuY2U8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVs

bC10aXRsZT5TY2llbmNlPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NzMwLTQ8L3Bh

Z2VzPjx2b2x1bWU+MzQ5PC92b2x1bWU+PG51bWJlcj42MjQ5PC9udW1iZXI+PGtleXdvcmRzPjxr

ZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0cm9jeXRlcy8qcGh5c2lvbG9neTwv

a2V5d29yZD48a2V5d29yZD5CYXNhbCBHYW5nbGlhL2N5dG9sb2d5LypwaHlzaW9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPkNlbGwgQ29tbXVuaWNhdGlvbjwva2V5d29yZD48a2V5d29yZD5HbHV0YW1h

dGVzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+

TWljZSwgSW5icmVkIEM1N0JMPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIFRyYW5zZ2VuaWM8L2tl

eXdvcmQ+PGtleXdvcmQ+TmVydmUgTmV0L3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TmV1

cm9ucy8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5SZWNlcHRvcnMsIE1ldGFib3Ryb3Bp

YyBHbHV0YW1hdGUvYWdvbmlzdHMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5SZWNlcHRv

cnMsIE4tTWV0aHlsLUQtQXNwYXJ0YXRlL2Fnb25pc3RzL21ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+U2lnbmFsIFRyYW5zZHVjdGlvbjwva2V5d29yZD48a2V5d29yZD5TeW5hcHNlcy8qcGh5

c2lvbG9neTwva2V5d29yZD48a2V5d29yZD4qU3luYXB0aWMgVHJhbnNtaXNzaW9uPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWcg

MTQ8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMDk1LTkyMDMgKEVsZWN0cm9uaWMp

JiN4RDswMDM2LTgwNzUgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2MjczMDU0PC9h

Y2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5s

bS5uaWguZ292L3B1Ym1lZC8yNjI3MzA1NDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTEyNi9zY2llbmNlLmFhYTc5NDU8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJ0aW48L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS

ZWNOdW0+MjUwNzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjQ0OTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI1MDc8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTAyODY5NiI+MjUwNzwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWFydGluLCBSLjwvYXV0aG9yPjxhdXRo

b3I+QmFqby1HcmFuZXJhcywgUi48L2F1dGhvcj48YXV0aG9yPk1vcmF0YWxsYSwgUi48L2F1dGhv

cj48YXV0aG9yPlBlcmVhLCBHLjwvYXV0aG9yPjxhdXRob3I+QXJhcXVlLCBBLjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkluc3RpdHV0byBDYWphbCwgQ29u

c2VqbyBTdXBlcmlvciBkZSBJbnZlc3RpZ2FjaW9uZXMgQ2llbnRpZmljYXMsIDI4MDAyIE1hZHJp

ZCwgU3BhaW4uJiN4RDtJbnN0aXR1dG8gQ2FqYWwsIENvbnNlam8gU3VwZXJpb3IgZGUgSW52ZXN0

aWdhY2lvbmVzIENpZW50aWZpY2FzLCAyODAwMiBNYWRyaWQsIFNwYWluLiBDZW50cm8gZGUgSW52

ZXN0aWdhY2lvbiBCaW9tZWRpY2EgZW4gUmVkIEVuZmVybWVkYWRlcyBOZXVyb2RlZ2VuZXJhdGl2

YXMsIEluc3RpdHV0byBkZSBTYWx1ZCBDYXJsb3MgSUlJLCAyODAyOSBNYWRyaWQsIFNwYWluLiYj

eEQ7RGVwYXJ0bWVudCBvZiBOZXVyb3NjaWVuY2UsIFVuaXZlcnNpdHkgb2YgTWlubmVzb3RhLCBN

aW5uZWFwb2xpcywgTU4gNTU0NTUsIFVTQS4gYXJhcXVlQHVtbi5lZHUuPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+Q2lyY3VpdC1zcGVjaWZpYyBzaWduYWxpbmcgaW4gYXN0cm9jeXRlLW5l

dXJvbiBuZXR3b3JrcyBpbiBiYXNhbCBnYW5nbGlhIHBhdGh3YXlzPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPlNjaWVuY2U8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVs

bC10aXRsZT5TY2llbmNlPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NzMwLTQ8L3Bh

Z2VzPjx2b2x1bWU+MzQ5PC92b2x1bWU+PG51bWJlcj42MjQ5PC9udW1iZXI+PGtleXdvcmRzPjxr

ZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0cm9jeXRlcy8qcGh5c2lvbG9neTwv

a2V5d29yZD48a2V5d29yZD5CYXNhbCBHYW5nbGlhL2N5dG9sb2d5LypwaHlzaW9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPkNlbGwgQ29tbXVuaWNhdGlvbjwva2V5d29yZD48a2V5d29yZD5HbHV0YW1h

dGVzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+

TWljZSwgSW5icmVkIEM1N0JMPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIFRyYW5zZ2VuaWM8L2tl

eXdvcmQ+PGtleXdvcmQ+TmVydmUgTmV0L3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TmV1

cm9ucy8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5SZWNlcHRvcnMsIE1ldGFib3Ryb3Bp

YyBHbHV0YW1hdGUvYWdvbmlzdHMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5SZWNlcHRv

cnMsIE4tTWV0aHlsLUQtQXNwYXJ0YXRlL2Fnb25pc3RzL21ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+U2lnbmFsIFRyYW5zZHVjdGlvbjwva2V5d29yZD48a2V5d29yZD5TeW5hcHNlcy8qcGh5

c2lvbG9neTwva2V5d29yZD48a2V5d29yZD4qU3luYXB0aWMgVHJhbnNtaXNzaW9uPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWcg

MTQ8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMDk1LTkyMDMgKEVsZWN0cm9uaWMp

JiN4RDswMDM2LTgwNzUgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2MjczMDU0PC9h

Y2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5s

bS5uaWguZ292L3B1Ym1lZC8yNjI3MzA1NDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTEyNi9zY2llbmNlLmFhYTc5NDU8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 449, whose role in neurodegeneration remains completely unexplored. New ventures in research from systems biology and omics approaches aims to uncover master regulators of disease-specific genes as novel targets for AD therapeutics PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXJpa3NoYWs8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFy

PjxSZWNOdW0+MjUwODwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjQ1MCw0NTE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yNTA4

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzUwMjg5NjgiPjI1MDg8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlBhcmlrc2hhaywgTi4gTi48

L2F1dGhvcj48YXV0aG9yPkdhbmRhbCwgTS4gSi48L2F1dGhvcj48YXV0aG9yPkdlc2Nod2luZCwg

RC4gSC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz4xXSBQ

cm9ncmFtIGluIE5ldXJvYmVoYXZpb3JhbCBHZW5ldGljcywgU2VtZWwgSW5zdGl0dXRlLCBhbmQg

UHJvZ3JhbSBpbiBOZXVyb2dlbmV0aWNzLCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgRGF2aWQg

R2VmZmVuIFNjaG9vbCBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBDYWxpZm9ybmlhLCBMb3Mg

QW5nZWxlcywgQ2FsaWZvcm5pYSA5MDA5NSwgVVNBLiBbMl0gSW50ZXJkZXBhcnRtZW50YWwgUHJv

Z3JhbSBpbiBOZXVyb3NjaWVuY2UsIFVuaXZlcnNpdHkgb2YgQ2FsaWZvcm5pYSwgTG9zIEFuZ2Vs

ZXMsIENhbGlmb3JuaWEgOTAwOTUsIFVTQS4mI3hEOzFdIFByb2dyYW0gaW4gTmV1cm9iZWhhdmlv

cmFsIEdlbmV0aWNzLCBTZW1lbCBJbnN0aXR1dGUsIGFuZCBQcm9ncmFtIGluIE5ldXJvZ2VuZXRp

Y3MsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBEYXZpZCBHZWZmZW4gU2Nob29sIG9mIE1lZGlj

aW5lLCBVbml2ZXJzaXR5IG9mIENhbGlmb3JuaWEsIExvcyBBbmdlbGVzLCBDYWxpZm9ybmlhIDkw

MDk1LCBVU0EuIFsyXSBDZW50ZXIgZm9yIEF1dGlzbSBUcmVhdG1lbnQgYW5kIFJlc2VhcmNoLCBT

ZW1lbCBJbnN0aXR1dGUsIERhdmlkIEdlZmZlbiBTY2hvb2wgb2YgTWVkaWNpbmUsIFVuaXZlcnNp

dHkgb2YgQ2FsaWZvcm5pYSwgTG9zIEFuZ2VsZXMsIENhbGlmb3JuaWEgOTAwOTUsIFVTQS4mI3hE

OzFdIFByb2dyYW0gaW4gTmV1cm9iZWhhdmlvcmFsIEdlbmV0aWNzLCBTZW1lbCBJbnN0aXR1dGUs

IGFuZCBQcm9ncmFtIGluIE5ldXJvZ2VuZXRpY3MsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBE

YXZpZCBHZWZmZW4gU2Nob29sIG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIENhbGlmb3JuaWEs

IExvcyBBbmdlbGVzLCBDYWxpZm9ybmlhIDkwMDk1LCBVU0EuIFsyXSBJbnRlcmRlcGFydG1lbnRh

bCBQcm9ncmFtIGluIE5ldXJvc2NpZW5jZSwgVW5pdmVyc2l0eSBvZiBDYWxpZm9ybmlhLCBMb3Mg

QW5nZWxlcywgQ2FsaWZvcm5pYSA5MDA5NSwgVVNBLiBbM10gQ2VudGVyIGZvciBBdXRpc20gVHJl

YXRtZW50IGFuZCBSZXNlYXJjaCwgU2VtZWwgSW5zdGl0dXRlLCBEYXZpZCBHZWZmZW4gU2Nob29s

IG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIENhbGlmb3JuaWEsIExvcyBBbmdlbGVzLCBDYWxp

Zm9ybmlhIDkwMDk1LCBVU0EuIFs0XSBEZXBhcnRtZW50IG9mIEh1bWFuIEdlbmV0aWNzLCBEYXZp

ZCBHZWZmZW4gU2Nob29sIG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIENhbGlmb3JuaWEsIExv

cyBBbmdlbGVzLCBDYWxpZm9ybmlhIDkwMDk1LCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48

dGl0bGU+U3lzdGVtcyBiaW9sb2d5IGFuZCBnZW5lIG5ldHdvcmtzIGluIG5ldXJvZGV2ZWxvcG1l

bnRhbCBhbmQgbmV1cm9kZWdlbmVyYXRpdmUgZGlzb3JkZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPk5hdCBSZXYgR2VuZXQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5OYXQgUmV2IEdlbmV0PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+

NDQxLTU4PC9wYWdlcz48dm9sdW1lPjE2PC92b2x1bWU+PG51bWJlcj44PC9udW1iZXI+PGtleXdv

cmRzPjxrZXl3b3JkPkJyYWluL2N5dG9sb2d5LyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

PkRldmVsb3BtZW50YWwgRGlzYWJpbGl0aWVzLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5H

ZW5lIEV4cHJlc3Npb24gUHJvZmlsaW5nLyptZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmUg

UmVndWxhdG9yeSBOZXR3b3Jrcy8qZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+SGlnaC1UaHJv

dWdocHV0IFNjcmVlbmluZyBBc3NheXMvKm1ldGhvZHMvdHJlbmRzPC9rZXl3b3JkPjxrZXl3b3Jk

Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD4qTW9kZWxzLCBOZXVyb2xvZ2ljYWw8L2tleXdvcmQ+

PGtleXdvcmQ+TmV1cm9iaW9sb2d5LyptZXRob2RzL3RyZW5kczwva2V5d29yZD48a2V5d29yZD5O

ZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcy8qZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+U3lz

dGVtcyBCaW9sb2d5L21ldGhvZHMvdHJlbmRzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5

ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4xNDcxLTAwNjQgKEVsZWN0cm9uaWMpJiN4RDsxNDcxLTAwNTYgKExpbmtpbmcp

PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2MTQ5NzEzPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh

dGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjE0OTcx

MzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0Njk5MzE2PC9jdXN0b20y

PjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDM4L25yZzM5MzQ8L2VsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkNvbG9ubmE8L0F1dGhvcj48

WWVhcj4yMDE2PC9ZZWFyPjxSZWNOdW0+MjUwOTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+

MjUwOTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTBy

eDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1MDI5NTEzIj4y

NTA5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+

MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db2xvbm5hLCBNLjwv

YXV0aG9yPjxhdXRob3I+V2FuZywgWS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+

PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIFBhdGhvbG9neSBhbmQgSW1tdW5vbG9neSwgV2Fz

aGluZ3RvbiBVbml2ZXJzaXR5IFNjaG9vbCBvZiBNZWRpY2luZSwgU3QgTG91aXMsIE1pc3NvdXJp

IDYzMTA4LCBVU0EuJiN4RDtFbGkgTGlsbHkgYW5kIENvbXBhbnksIExpbGx5IENvcnBvcmF0ZSBD

ZW50ZXIsIEluZGlhbmFwb2xpcywgSW5kaWFuYSA0NjI4NSwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPlRSRU0yIHZhcmlhbnRzOiBuZXcga2V5cyB0byBkZWNpcGhlciBBbHpoZWlt

ZXIgZGlzZWFzZSBwYXRob2dlbmVzaXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0IFJldiBO

ZXVyb3NjaTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4yMDEtNzwvcGFnZXM+PHZv

bHVtZT4xNzwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpo

ZWltZXIgRGlzZWFzZS8qZ2VuZXRpY3MvKnBhdGhvbG9neS9waHlzaW9wYXRob2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CcmFpbi9tZXRhYm9saXNtL3Bh

dGhvbG9neTwva2V5d29yZD48a2V5d29yZD5HZW5ldGljIFZhcmlhdGlvbi8qZ2VuZXRpY3M8L2tl

eXdvcmQ+PGtleXdvcmQ+R2Vub21lLVdpZGUgQXNzb2NpYXRpb24gU3R1ZHk8L2tleXdvcmQ+PGtl

eXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk1lbWJyYW5lIEdseWNvcHJvdGVpbnMvKmdl

bmV0aWNzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UmVjZXB0b3JzLCBJbW11bm9sb2dp

Yy8qZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5TaWduYWwgVHJhbnNkdWN0

aW9uL2dlbmV0aWNzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5BcHI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDcx

LTAwNDggKEVsZWN0cm9uaWMpJiN4RDsxNDcxLTAwM1ggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI2OTExNDM1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjkxMTQzNTwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9ucm4uMjAxNi43

PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXJpa3NoYWs8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFy

PjxSZWNOdW0+MjUwODwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp

cHQiPjQ1MCw0NTE8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yNTA4

PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJw

dzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzUwMjg5NjgiPjI1MDg8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlBhcmlrc2hhaywgTi4gTi48

L2F1dGhvcj48YXV0aG9yPkdhbmRhbCwgTS4gSi48L2F1dGhvcj48YXV0aG9yPkdlc2Nod2luZCwg

RC4gSC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz4xXSBQ

cm9ncmFtIGluIE5ldXJvYmVoYXZpb3JhbCBHZW5ldGljcywgU2VtZWwgSW5zdGl0dXRlLCBhbmQg

UHJvZ3JhbSBpbiBOZXVyb2dlbmV0aWNzLCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgRGF2aWQg

R2VmZmVuIFNjaG9vbCBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBDYWxpZm9ybmlhLCBMb3Mg

QW5nZWxlcywgQ2FsaWZvcm5pYSA5MDA5NSwgVVNBLiBbMl0gSW50ZXJkZXBhcnRtZW50YWwgUHJv

Z3JhbSBpbiBOZXVyb3NjaWVuY2UsIFVuaXZlcnNpdHkgb2YgQ2FsaWZvcm5pYSwgTG9zIEFuZ2Vs

ZXMsIENhbGlmb3JuaWEgOTAwOTUsIFVTQS4mI3hEOzFdIFByb2dyYW0gaW4gTmV1cm9iZWhhdmlv

cmFsIEdlbmV0aWNzLCBTZW1lbCBJbnN0aXR1dGUsIGFuZCBQcm9ncmFtIGluIE5ldXJvZ2VuZXRp

Y3MsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBEYXZpZCBHZWZmZW4gU2Nob29sIG9mIE1lZGlj

aW5lLCBVbml2ZXJzaXR5IG9mIENhbGlmb3JuaWEsIExvcyBBbmdlbGVzLCBDYWxpZm9ybmlhIDkw

MDk1LCBVU0EuIFsyXSBDZW50ZXIgZm9yIEF1dGlzbSBUcmVhdG1lbnQgYW5kIFJlc2VhcmNoLCBT

ZW1lbCBJbnN0aXR1dGUsIERhdmlkIEdlZmZlbiBTY2hvb2wgb2YgTWVkaWNpbmUsIFVuaXZlcnNp

dHkgb2YgQ2FsaWZvcm5pYSwgTG9zIEFuZ2VsZXMsIENhbGlmb3JuaWEgOTAwOTUsIFVTQS4mI3hE

OzFdIFByb2dyYW0gaW4gTmV1cm9iZWhhdmlvcmFsIEdlbmV0aWNzLCBTZW1lbCBJbnN0aXR1dGUs

IGFuZCBQcm9ncmFtIGluIE5ldXJvZ2VuZXRpY3MsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBE

YXZpZCBHZWZmZW4gU2Nob29sIG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIENhbGlmb3JuaWEs

IExvcyBBbmdlbGVzLCBDYWxpZm9ybmlhIDkwMDk1LCBVU0EuIFsyXSBJbnRlcmRlcGFydG1lbnRh

bCBQcm9ncmFtIGluIE5ldXJvc2NpZW5jZSwgVW5pdmVyc2l0eSBvZiBDYWxpZm9ybmlhLCBMb3Mg

QW5nZWxlcywgQ2FsaWZvcm5pYSA5MDA5NSwgVVNBLiBbM10gQ2VudGVyIGZvciBBdXRpc20gVHJl

YXRtZW50IGFuZCBSZXNlYXJjaCwgU2VtZWwgSW5zdGl0dXRlLCBEYXZpZCBHZWZmZW4gU2Nob29s

IG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIENhbGlmb3JuaWEsIExvcyBBbmdlbGVzLCBDYWxp

Zm9ybmlhIDkwMDk1LCBVU0EuIFs0XSBEZXBhcnRtZW50IG9mIEh1bWFuIEdlbmV0aWNzLCBEYXZp

ZCBHZWZmZW4gU2Nob29sIG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIENhbGlmb3JuaWEsIExv

cyBBbmdlbGVzLCBDYWxpZm9ybmlhIDkwMDk1LCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48

dGl0bGU+U3lzdGVtcyBiaW9sb2d5IGFuZCBnZW5lIG5ldHdvcmtzIGluIG5ldXJvZGV2ZWxvcG1l

bnRhbCBhbmQgbmV1cm9kZWdlbmVyYXRpdmUgZGlzb3JkZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPk5hdCBSZXYgR2VuZXQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5OYXQgUmV2IEdlbmV0PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+

NDQxLTU4PC9wYWdlcz48dm9sdW1lPjE2PC92b2x1bWU+PG51bWJlcj44PC9udW1iZXI+PGtleXdv

cmRzPjxrZXl3b3JkPkJyYWluL2N5dG9sb2d5LyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

PkRldmVsb3BtZW50YWwgRGlzYWJpbGl0aWVzLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5H

ZW5lIEV4cHJlc3Npb24gUHJvZmlsaW5nLyptZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmUg

UmVndWxhdG9yeSBOZXR3b3Jrcy8qZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+SGlnaC1UaHJv

dWdocHV0IFNjcmVlbmluZyBBc3NheXMvKm1ldGhvZHMvdHJlbmRzPC9rZXl3b3JkPjxrZXl3b3Jk

Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD4qTW9kZWxzLCBOZXVyb2xvZ2ljYWw8L2tleXdvcmQ+

PGtleXdvcmQ+TmV1cm9iaW9sb2d5LyptZXRob2RzL3RyZW5kczwva2V5d29yZD48a2V5d29yZD5O

ZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcy8qZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+U3lz

dGVtcyBCaW9sb2d5L21ldGhvZHMvdHJlbmRzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5

ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4xNDcxLTAwNjQgKEVsZWN0cm9uaWMpJiN4RDsxNDcxLTAwNTYgKExpbmtpbmcp

PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2MTQ5NzEzPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh

dGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjE0OTcx

MzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0Njk5MzE2PC9jdXN0b20y

PjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDM4L25yZzM5MzQ8L2VsZWN0cm9uaWMtcmVz

b3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkNvbG9ubmE8L0F1dGhvcj48

WWVhcj4yMDE2PC9ZZWFyPjxSZWNOdW0+MjUwOTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+

MjUwOTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTBy

eDUycHc5YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1MDI5NTEzIj4y

NTA5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+

MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Db2xvbm5hLCBNLjwv

YXV0aG9yPjxhdXRob3I+V2FuZywgWS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+

PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIFBhdGhvbG9neSBhbmQgSW1tdW5vbG9neSwgV2Fz

aGluZ3RvbiBVbml2ZXJzaXR5IFNjaG9vbCBvZiBNZWRpY2luZSwgU3QgTG91aXMsIE1pc3NvdXJp

IDYzMTA4LCBVU0EuJiN4RDtFbGkgTGlsbHkgYW5kIENvbXBhbnksIExpbGx5IENvcnBvcmF0ZSBD

ZW50ZXIsIEluZGlhbmFwb2xpcywgSW5kaWFuYSA0NjI4NSwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPlRSRU0yIHZhcmlhbnRzOiBuZXcga2V5cyB0byBkZWNpcGhlciBBbHpoZWlt

ZXIgZGlzZWFzZSBwYXRob2dlbmVzaXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0IFJldiBO

ZXVyb3NjaTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4yMDEtNzwvcGFnZXM+PHZv

bHVtZT4xNzwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbHpo

ZWltZXIgRGlzZWFzZS8qZ2VuZXRpY3MvKnBhdGhvbG9neS9waHlzaW9wYXRob2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CcmFpbi9tZXRhYm9saXNtL3Bh

dGhvbG9neTwva2V5d29yZD48a2V5d29yZD5HZW5ldGljIFZhcmlhdGlvbi8qZ2VuZXRpY3M8L2tl

eXdvcmQ+PGtleXdvcmQ+R2Vub21lLVdpZGUgQXNzb2NpYXRpb24gU3R1ZHk8L2tleXdvcmQ+PGtl

eXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk1lbWJyYW5lIEdseWNvcHJvdGVpbnMvKmdl

bmV0aWNzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UmVjZXB0b3JzLCBJbW11bm9sb2dp

Yy8qZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5TaWduYWwgVHJhbnNkdWN0

aW9uL2dlbmV0aWNzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5BcHI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDcx

LTAwNDggKEVsZWN0cm9uaWMpJiN4RDsxNDcxLTAwM1ggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI2OTExNDM1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjkxMTQzNTwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9ucm4uMjAxNi43

PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 450,451. In this way, some of these targets will also help to uncover previously unknown pathways of disease and can connect previously unrelated cascades underlying neurodegeneration, similar to what happened between inflammation, diabetes and obesity ADDIN EN.CITE <EndNote><Cite><Author>Donath</Author><Year>2013</Year><RecNum>2552</RecNum><DisplayText><style face="superscript">452</style></DisplayText><record><rec-number>2552</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535030738">2552</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Donath, M. Y.</author><author>Dalmas, E.</author><author>Sauter, N. S.</author><author>Boni-Schnetzler, M.</author></authors></contributors><auth-address>Endocrinology, Diabetes, and Metabolism and Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland. marc.donath@usb.ch</auth-address><titles><title>Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity</title><secondary-title>Cell Metab</secondary-title></titles><pages>860-72</pages><volume>17</volume><number>6</number><keywords><keyword>Diabetes Mellitus, Type 2/*immunology</keyword><keyword>Humans</keyword><keyword>Immunity, Innate</keyword><keyword>Inflammation/immunology</keyword><keyword>Insulin/biosynthesis/secretion</keyword><keyword>Interleukin-1beta/metabolism</keyword><keyword>Islets of Langerhans/*immunology/metabolism</keyword><keyword>Macrophages/immunology</keyword><keyword>Obesity/*immunology</keyword></keywords><dates><year>2013</year><pub-dates><date>Jun 4</date></pub-dates></dates><isbn>1932-7420 (Electronic)&#xD;1550-4131 (Linking)</isbn><accession-num>23747245</accession-num><urls><related-urls><url>. The direct consequence of these discoveries is that future therapies are likely to involve multiple targets and/or multiple strategies to exert an effect on AD-induced neurodegeneration. Similar strategies have become the norm for other conditions such as AIDS, cancer or even infectious diseases, producing health schemes that are virtually equal to a cure in many cases PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZWVrczwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl

Y051bT4yNjA1PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDUzLDQ1NDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI2MDU8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTAzMjAxMCI+MjYwNTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RGVla3MsIFMuIEcuPC9hdXRob3I+

PGF1dGhvcj5MZXdpbiwgUy4gUi48L2F1dGhvcj48YXV0aG9yPlJvc3MsIEEuIEwuPC9hdXRob3I+

PGF1dGhvcj5BbmFud29yYW5pY2gsIEouPC9hdXRob3I+PGF1dGhvcj5CZW5raXJhbmUsIE0uPC9h

dXRob3I+PGF1dGhvcj5DYW5ub24sIFAuPC9hdXRob3I+PGF1dGhvcj5DaG9tb250LCBOLjwvYXV0

aG9yPjxhdXRob3I+RG91ZWssIEQuPC9hdXRob3I+PGF1dGhvcj5MaWZzb24sIEouIEQuPC9hdXRo

b3I+PGF1dGhvcj5MbywgWS4gUi48L2F1dGhvcj48YXV0aG9yPkt1cml0emtlcywgRC48L2F1dGhv

cj48YXV0aG9yPk1hcmdvbGlzLCBELjwvYXV0aG9yPjxhdXRob3I+TWVsbG9ycywgSi48L2F1dGhv

cj48YXV0aG9yPlBlcnNhdWQsIEQuPC9hdXRob3I+PGF1dGhvcj5UdWNrZXIsIEouIEQuPC9hdXRo

b3I+PGF1dGhvcj5CYXJyZS1TaW5vdXNzaSwgRi48L2F1dGhvcj48YXV0aG9yPkludGVybmF0aW9u

YWwsIEFpZHMgU29jaWV0eSBUb3dhcmRzIGEgQ3VyZSBXb3JraW5nIEdyb3VwPC9hdXRob3I+PGF1

dGhvcj5BbHRlciwgRy48L2F1dGhvcj48YXV0aG9yPkF1ZXJiYWNoLCBKLjwvYXV0aG9yPjxhdXRo

b3I+QXV0cmFuLCBCLjwvYXV0aG9yPjxhdXRob3I+QmFyb3VjaCwgRC4gSC48L2F1dGhvcj48YXV0

aG9yPkJlaHJlbnMsIEcuPC9hdXRob3I+PGF1dGhvcj5DYXZhenphbmEsIE0uPC9hdXRob3I+PGF1

dGhvcj5DaGVuLCBaLjwvYXV0aG9yPjxhdXRob3I+Q29oZW4sIEUuIEEuPC9hdXRob3I+PGF1dGhv

cj5Db3JiZWxsaSwgRy4gTS48L2F1dGhvcj48YXV0aG9yPkVob2xpZSwgUy48L2F1dGhvcj48YXV0

aG9yPkV5YWwsIE4uPC9hdXRob3I+PGF1dGhvcj5GaWRsZXIsIFMuPC9hdXRob3I+PGF1dGhvcj5H

YXJjaWEsIEwuPC9hdXRob3I+PGF1dGhvcj5Hcm9zc21hbiwgQy48L2F1dGhvcj48YXV0aG9yPkhl

bmRlcnNvbiwgRy48L2F1dGhvcj48YXV0aG9yPkhlbnJpY2gsIFQuIEouPC9hdXRob3I+PGF1dGhv

cj5KZWZmZXJ5cywgUi48L2F1dGhvcj48YXV0aG9yPktpZW0sIEguIFAuPC9hdXRob3I+PGF1dGhv

cj5NY0N1bmUsIEouPC9hdXRob3I+PGF1dGhvcj5Nb29kbGV5LCBLLjwvYXV0aG9yPjxhdXRob3I+

TmV3bWFuLCBQLiBBLjwvYXV0aG9yPjxhdXRob3I+TmlqaHVpcywgTS48L2F1dGhvcj48YXV0aG9y

Pk5zdWJ1Z2EsIE0uIFMuPC9hdXRob3I+PGF1dGhvcj5PdHQsIE0uPC9hdXRob3I+PGF1dGhvcj5Q

YWxtZXIsIFMuPC9hdXRob3I+PGF1dGhvcj5SaWNobWFuLCBELjwvYXV0aG9yPjxhdXRob3I+U2Fl

ei1DaXJpb24sIEEuPC9hdXRob3I+PGF1dGhvcj5TaGFycCwgTS48L2F1dGhvcj48YXV0aG9yPlNp

bGljaWFubywgSi48L2F1dGhvcj48YXV0aG9yPlNpbHZlc3RyaSwgRy48L2F1dGhvcj48YXV0aG9y

PlNpbmdoLCBKLjwvYXV0aG9yPjxhdXRob3I+U3BpcmUsIEIuPC9hdXRob3I+PGF1dGhvcj5UYXls

b3IsIEouPC9hdXRob3I+PGF1dGhvcj5Ub2xzdHJ1cCwgTS48L2F1dGhvcj48YXV0aG9yPlZhbGVu

dGUsIFMuPC9hdXRob3I+PGF1dGhvcj52YW4gTHVuemVuLCBKLjwvYXV0aG9yPjxhdXRob3I+V2Fs

ZW5za3ksIFIuPC9hdXRob3I+PGF1dGhvcj5XaWxzb24sIEkuPC9hdXRob3I+PGF1dGhvcj5aYWNr

LCBKLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFy

dG1lbnQgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQ2FsaWZvcm5pYSwgU2FuIEZyYW5jaXNj

bywgU2FuIEZyYW5jaXNjbywgQ2FsaWZvcm5pYSwgVVNBLiYjeEQ7VGhlIFBldGVyIERvaGVydHkg

SW5zdGl0dXRlIGZvciBJbmZlY3Rpb24gYW5kIEltbXVuaXR5LCBVbml2ZXJzaXR5IG9mIE1lbGJv

dXJuZSBhbmQgUm95YWwgTWVsYm91cm5lIEhvc3BpdGFsLCBNZWxib3VybmUsIEF1c3RyYWxpYS4m

I3hEO0RlcGFydG1lbnQgb2YgSW5mZWN0aW91cyBEaXNlYXNlcywgQWxmcmVkIEhvc3BpdGFsIGFu

ZCBNb25hc2ggVW5pdmVyc2l0eSwgTWVsYm91cm5lLCBBdXN0cmFsaWEuJiN4RDtJbnRlcm5hdGlv

bmFsIGFuZCBTY2llbnRpZmljIFJlbGF0aW9ucyBPZmZpY2UsIEFOUlMsIFBhcmlzLCBGcmFuY2Uu

JiN4RDtVUyBNaWxpdGFyeSBISVYgUmVzZWFyY2ggUHJvZ3JhbSwgV2FsdGVyIFJlZWQgQXJteSBJ

bnN0aXR1dGUgb2YgUmVzZWFyY2gsIFNpbHZlciBTcHJpbmcsIE1hcnlsYW5kLCBVU0EuJiN4RDtI

ZW5yeSBNLiBKYWNrc29uIEZvdW5kYXRpb24gZm9yIHRoZSBBZHZhbmNlbWVudCBvZiBNaWxpdGFy

eSBNZWRpY2luZSwgQmV0aGVzZGEsIE1hcnlsYW5kLCBVU0EuJiN4RDtNb2xlY3VsYXIgVmlyb2xv

Z3kgTGFiLCBJbnN0aXR1dGUgb2YgSHVtYW4gR2VuZXRpY3MsIENOUlMgVVBSIDExNDIsIFVuaXZl

cnNpdGUgZGUgTW9udHBlbGxpZXIsIE1vbnRwZWxsaWVyLCBGcmFuY2UuJiN4RDtLZWNrIFNjaG9v

bCBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBTb3V0aGVybiBDYWxpZm9ybmlhLCBMb3MgQW5n

ZWxlcywgQ2FsaWZvcm5pYSwgVVNBLiYjeEQ7Q1JDSFVNIGFuZCBEZXBhcnRtZW50IG9mIE1pY3Jv

YmlvbG9neSwgSW5mZWN0aW9sb2d5LCBhbmQgSW1tdW5vbG9neSwgVW5pdmVyc2l0ZSBkZSBNb250

cmVhbCwgRmFjdWx0eSBvZiBNZWRpY2luZSwgTW9udHJlYWwsIFF1ZWJlYywgQ2FuYWRhLiYjeEQ7

VmFjY2luZSBSZXNlYXJjaCBDZW50ZXIsIE5hdGlvbmFsIEluc3RpdHV0ZSBvZiBBbGxlcmd5IGFu

ZCBJbmZlY3Rpb3VzIERpc2Vhc2VzLCBOYXRpb25hbCBJbnN0aXR1dGVzIG9mIEhlYWx0aCwgQmV0

aGVzZGEsIE1hcnlsYW5kLCBVU0EuJiN4RDtBSURTIGFuZCBDYW5jZXIgVmlydXMgUHJvZ3JhbSwg

TGVpZG9zIEJpb21lZGljYWwgUmVzZWFyY2gsIEluYy4sIEZyZWRlcmljayBOYXRpb25hbCBMYWJv

cmF0b3J5LCBGcmVkZXJpY2ssIE1hcnlsYW5kLCBVU0EuJiN4RDtXb3JsZCBIZWFsdGggT3JnYW5p

emF0aW9uIFJlZ2lvbmFsIE9mZmljZSBmb3IgdGhlIFdlc3Rlcm4gUGFjaWZpYywgTWFuaWxhLCBQ

aGlsaXBwaW5lcy4mI3hEO0JyaWdoYW0gJmFtcDtXb21lbiZhcG9zO3MgSG9zcGl0YWwsIEJvc3Rv

biwgTWFzc2FjaHVzZXR0cywgVVNBLiYjeEQ7VW5pdmVyc2l0eSBvZiBOb3J0aCBDYXJvbGluYSBh

dCBDaGFwZWwgSGlsbCBTY2hvb2wgb2YgTWVkaWNpbmUsIENoYXBlbCBIaWxsLCBOb3J0aCBDYXJv

bGluYSwgVVNBLiYjeEQ7RGl2aXNpb24gb2YgSW5mZWN0aW91cyBEaXNlYXNlcywgRGVwYXJ0bWVu

dCBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBQaXR0c2J1cmdoLCBQaXR0c2J1cmdoLCBQZW5u

c3lsdmFuaWEsIFVTQS4mI3hEO0pvaG5zIEhvcGtpbnMgVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVk

aWNpbmUgJmFtcDtCbG9vbWJlcmcgU2Nob29sIG9mIFB1YmxpYyBIZWFsdGgsIEJhbHRpbW9yZSwg

TWFyeWxhbmQsIFVTQS4mI3hEO1VuaXZlcnNpdHkgb2YgTm9ydGggQ2Fyb2xpbmEtUHJvamVjdCBD

aGluYSwgR3Vhbmd6aG91LCBDaGluYS4mI3hEO0luc3RpdHV0IFBhc3RldXIsIFBhcmlzLCBGcmFu

Y2UuJiN4RDtSYWdvbiBJbnN0aXR1dGUgb2YgTUdILCBNSVQgYW5kIEhhcnZhcmQsIEJvc3Rvbiwg

TWFzc2FjaHVzZXR0cywgVVNBLiYjeEQ7U29yYm9ubmUgVW5pdmVyc2l0ZXMsIFVQTUMgVW5pdiBQ

YXJpcyAwNiwgQ0lNSS1QYXJpcywgRnJhbmNlLiYjeEQ7SW5zZXJtIFUxMTM1LCBDSU1JLVBhcmlz

LCBQYXJpcywgRnJhbmNlLiYjeEQ7QVAtSFAsIEhvcGl0YWwgUGl0aWUtU2FscGV0cmllcmUsIERl

cGFydGVtZW50IGQmYXBvcztJbW11bm9sb2dpZSwgUGFyaXMsIEZyYW5jZS4mI3hEO0JldGggSXNy

YWVsIERlYWNvbmVzcyBNZWRpY2FsIENlbnRlciwgSGFydmFyZCBNZWRpY2FsIFNjaG9vbCwgQm9z

dG9uLCBNYXNzYWNodXNldHRzLCBVU0EuJiN4RDtDbGluaWMgZm9yIEltbXVub2xvZ3kgYW5kIFJo

ZW1hdG9sb2d5LCBIYW5ub3ZlciBNZWRpY2FsIFNjaG9vbCwgSGFub3ZlciwgR2VybWFueS4mI3hE

O0NlbnRyZSBkJmFwb3M7SW52ZXN0aWdhdGlvbiBDbGluaXF1ZSBlbiBiaW90aGVyYXBpZSwgSG9w

aXRhbCBOZWNrZXItRW5mYW50cyBNYWxhZGVzLCBQYXJpcywgRnJhbmNlLiYjeEQ7QUlEUyBJbnN0

aXR1dGUsIFRoZSBVbml2ZXJzaXR5IG9mIEhvbmcgS29uZywgUG9rIEZ1IExhbSwgSG9uZyBLb25n

LiYjeEQ7SW5zdGl0dXQgZGUgUmVjaGVyY2hlcyBDbGluaXF1ZXMgZGUgTW9udHJlYWwsIFVuaXZl

cnNpdGUgZGUgTW9udHJlYWwsIE1vbnRyZWFsLCBRdWViZWMsIENhbmFkYS4mI3hEO0V1cm9wZWFu

IEFJRFMgVHJlYXRtZW50IEdyb3VwLCBJdGFseS4mI3hEO1Byb2dyYW1tZSBQQUMtQ0ksIENlbnRy

ZSBIb3NwaXRhbGllciBVbml2ZXJzaXRhaXJlIGRlIFRyZWljaHZpbGxlLCBBYmlkamFuLCBDb3Rl

IGQmYXBvcztJdm9pcmUuJiN4RDtIYXJ2YXJkIFQuIEguIENoYW4gU2Nob29sIG9mIFB1YmxpYyBI

ZWFsdGgsIERlcGFydG1lbnQgb2YgR2xvYmFsIEhlYWx0aCBhbmQgUG9wdWxhdGlvbiwgQm9zdG9u

LCBNYXNzYWNodXNldHRzLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIE1lZGljaW5lLCBJbXBlcmlh

bCBDb2xsZWdlIExvbmRvbiwgTG9uZG9uLCBVbml0ZWQgS2luZ2RvbS4mI3hEO1RoZSBCLUNoYW5n

ZSBHcm91cCwgTWFuaWxhLCBQaGlsaXBwaW5lcy4mI3hEO05hdGlvbmFsIEluc3RpdHV0ZSBvZiBN

ZW50YWwgSGVhbHRoLCBOSUgsIEJldGhlc2RhLCBNYXJ5bGFuZCwgVVNBLiYjeEQ7VHJlYXRtZW50

IEFjdGlvbiBHcm91cCwgTmV3IFlvcmssIE5ldyBZb3JrLCBVU0EuJiN4RDtDbGluaWNhbCBSZXNl

YXJjaCBEaXZpc2lvbiwgRnJlZCBIdXRjaGluc29uIENhbmNlciBSZXNlYXJjaCBDZW50ZXIsIFNl

YXR0bGUsIFdhc2hpbmd0b24sIFVTQS4mI3hEO0NlbnRyZSBmb3IgTWVkaWNhbCBFdGhpY3MgYW5k

IExhdywgRGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgU3RlbGxlbmJvc2NoIFVuaXZlcnNpdHksIFdl

c3Rlcm4gQ2FwZSwgU291dGggQWZyaWNhLiYjeEQ7RmFjdG9yLUlud2VudGFzaCBGYWN1bHR5IG9m

IFNvY2lhbCBXb3JrLCBVbml2ZXJzaXR5IG9mIFRvcm9udG8sIFRvcm9udG8sIE9udGFyaW8sIENh

bmFkYS4mI3hEO0RlcGFydG1lbnQgb2YgTWVkaWNhbCBNaWNyb2Jpb2xvZ3ksIFZpcm9sb2d5LCBV

bml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyIFV0cmVjaHQsIFV0cmVjaHQsIE5ldGhlcmxhbmRzLiYj

eEQ7Sm9pbnQgQ2xpbmljYWwgUmVzZWFyY2ggQ2VudHJlLCBLYW1wYWxhLCBVZ2FuZGEuJiN4RDtH

bGFkc3RvbmUgSW5zdGl0dXRlcywgVW5pdmVyc2l0eSBvZiBDYWxpZm9ybmlhLCBTYW4gRnJhbmNp

c2NvLCBTYW4gRnJhbmNpc2NvLCBDYWxpZm9ybmlhLCBVU0EuJiN4RDtXZXN0bWVhZCBNaWxsZW5u

aXVtIEluc3RpdHV0ZSBmb3IgTWVkaWNhbCBSZXNlYXJjaCwgVW5pdmVyc2l0eSBvZiBTeWRuZXks

IFN5ZG5leSwgQXVzdHJhbGlhLiYjeEQ7VmlyZ2luaWEgU2FuIERpZWdvIEhlYWx0aGNhcmUgU3lz

dGVtIGFuZCBVbml2ZXJzaXR5IG9mIENhbGlmb3JuaWEsIFNhbiBEaWVnbywgU2FuIERpZWdvLCBD

YWxpZm9ybmlhLCBVU0EuJiN4RDtJbmRlcGVuZGVudCBISVYgRWR1Y2F0aW9uIGFuZCBBZHZvY2Fj

eSBDb25zdWx0YW50LCBTYW4gRnJhbmNpc2NvLCBDYWxpZm9ybmlhLCBVU0EuJiN4RDtEZXBhcnRt

ZW50IG9mIE1lZGljaW5lLCBKb2hucyBIb3BraW5zIFVuaXZlcnNpdHkgU2Nob29sIG9mIE1lZGlj

aW5lLCBCYWx0aW1vcmUsIE1hcnlsYW5kLCBVU0EuJiN4RDtZZXJrZXMgTmF0aW9uYWwgUHJpbWF0

ZSBSZXNlYXJjaCBDZW50cmUsIEVtb3J5IFVuaXZlcnNpdHksIEF0bGFudGEsIEdlb3JnaWEsIFVT

QS4mI3hEO05lbHNvbiBSLiBNYW5kZWxhIFNjaG9vbCBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBv

ZiBLd2FadWx1LU5hdGFsLCBEdXJiYW4sIFNvdXRoIEFmcmljYS4mI3hEO0lOU0VSTSBVTVJfUzkx

MiwgTWFyc2VpbGxlLCBGcmFuY2UuJiN4RDtDQVJFIENvbGxhYm9yYXRvcnkgQ29tbXVuaXR5IEFk

dmlzb3J5IEJvYXJkLCBQYWxtIFNwcmluZ3MsIENhbGlmb3JuaWEsIFVTQS4mI3hEO0luc3RpdHV0

ZSBvZiBDbGluaWNhbCBNZWRpY2luZSwgQWFyaHVzIFVuaXZlcnNpdHksIEFhcmh1cywgRGVubWFy

ay4mI3hEO0RlcGFydG1lbnQgb2YgSW1tdW5vbG9neSBhbmQgTWljcm9iaWFsIFNjaWVuY2VzLCBU

aGUgU2NyaXBwcyBSZXNlYXJjaCBJbnN0aXR1dGUsIEp1cGl0ZXIsIEZsb3JpZGEsIFVTQS4mI3hE

O1ZpaVYgSGVhbHRoY2FyZSwgTG9uZG9uLCBVbml0ZWQgS2luZ2RvbS4mI3hEO01hc3NhY2h1c2V0

dHMgR2VuZXJhbCBIb3NwaXRhbCwgSGFydmFyZCBNZWRpY2FsIFNjaG9vbCwgQm9zdG9uLCBNYXNz

YWNodXNldHRzLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIEhlYWx0aCBTZXJ2aWNlcywgUG9saWN5

ICZhbXA7UHJhY3RpY2UsIEJyb3duIFVuaXZlcnNpdHkgU2Nob29sIG9mIFB1YmxpYyBIZWFsdGgs

IFByb3ZpZGVuY2UsIFJob2RlIElzbGFuZCwgVVNBLiYjeEQ7RGF2aWQgR2VmZmVuIFNjaG9vbCBv

ZiBNZWRpY2luZSBhdCBVQ0xBLCBMb3MgQW5nZWxlcywgQ2FsaWZvcm5pYSwgVVNBLjwvYXV0aC1h

ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkludGVybmF0aW9uYWwgQUlEUyBTb2NpZXR5IGdsb2JhbCBz

Y2llbnRpZmljIHN0cmF0ZWd5OiB0b3dhcmRzIGFuIEhJViBjdXJlIDIwMTY8L3RpdGxlPjxzZWNv

bmRhcnktdGl0bGU+TmF0IE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz44Mzkt

NTA8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVtYmVyPjg8L251bWJlcj48a2V5d29yZHM+

PGtleXdvcmQ+QWNxdWlyZWQgSW1tdW5vZGVmaWNpZW5jeSBTeW5kcm9tZS8qdGhlcmFweTwva2V5

d29yZD48a2V5d29yZD4qR29hbHM8L2tleXdvcmQ+PGtleXdvcmQ+SElWIEluZmVjdGlvbnMvKnRo

ZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkludGVybmF0

aW9uYWwgQ29vcGVyYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+T3JnYW5pemF0aW9uYWwgT2JqZWN0

aXZlczwva2V5d29yZD48a2V5d29yZD4qUmVzZWFyY2g8L2tleXdvcmQ+PGtleXdvcmQ+U29jaWV0

aWVzLCBNZWRpY2FsPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTQ2

LTE3MFggKEVsZWN0cm9uaWMpJiN4RDsxMDc4LTg5NTYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI3NDAwMjY0PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNzQwMDI2NDwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM1MzIyNzk3PC9jdXN0b20yPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4xMDM4L25tLjQxMDg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVj

b3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkhvZGdlPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

UmVjTnVtPjI2MDY8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjI2MDY8L3JlYy1udW1iZXI+

PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3

eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTAzMjY1MCI+MjYwNjwva2V5PjwvZm9yZWln

bi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29u

dHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SG9kZ2UsIEouIFcuPC9hdXRob3I+PGF1dGhvcj5B

cmRpYW5pLCBBLjwvYXV0aG9yPjxhdXRob3I+RmFyc2FjaSwgQi48L2F1dGhvcj48YXV0aG9yPkt3

aWxhcywgQS4gUi48L2F1dGhvcj48YXV0aG9yPkdhbWVpcm8sIFMuIFIuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+UmVjb21iaW5hbnQgVmFjY2luZSBHcm91

cCwgTGFib3JhdG9yeSBvZiBUdW1vciBJbW11bm9sb2d5IGFuZCBCaW9sb2d5LCBDZW50ZXIgZm9y

IENhbmNlciBSZXNlYXJjaCwgTmF0aW9uYWwgQ2FuY2VyIEluc3RpdHV0ZSwgTmF0aW9uYWwgSW5z

dGl0dXRlcyBvZiBIZWFsdGgsIEJldGhlc2RhLCBNRCAyMDg5MiwgVVNBLiBqaDI0MWRAbmloLmdv

djwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSB0aXBwaW5nIHBvaW50IGZvciBjb21i

aW5hdGlvbiB0aGVyYXB5OiBjYW5jZXIgdmFjY2luZXMgd2l0aCByYWRpYXRpb24sIGNoZW1vdGhl

cmFweSwgb3IgdGFyZ2V0ZWQgc21hbGwgbW9sZWN1bGUgaW5oaWJpdG9yczwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5TZW1pbiBPbmNvbDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4z

MjMtMzk8L3BhZ2VzPjx2b2x1bWU+Mzk8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48a2V5d29y

ZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BbnRpbmVvcGxhc3RpYyBBZ2Vu

dHMvKmFkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS9pbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPkNhbmNlciBWYWNjaW5lcy8qYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlL2ltbXVub2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+Q29tYmluZWQgTW9kYWxpdHkgVGhlcmFweS8qbWV0aG9kczwv

a2V5d29yZD48a2V5d29yZD5EcnVnIFRoZXJhcHkvKm1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+

SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk5lb3BsYXNtcy90aGVyYXB5PC9rZXl3b3JkPjxrZXl3

b3JkPlJhZGlvdGhlcmFweS8qbWV0aG9kczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVh

cj4yMDEyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVuPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0

ZXM+PGlzYm4+MTUzMi04NzA4IChFbGVjdHJvbmljKSYjeEQ7MDA5My03NzU0IChMaW5raW5nKTwv

aXNibj48YWNjZXNzaW9uLW51bT4yMjU5NTA1NTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRl

ZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjI1OTUwNTU8

L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMzM1Njk5NDwvY3VzdG9tMj48

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA1My9qLnNlbWlub25jb2wuMjAxMi4wMi4wMDY8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZWVrczwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl

Y051bT4yNjA1PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+

NDUzLDQ1NDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI2MDU8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEy

dmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTAzMjAxMCI+MjYwNTwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RGVla3MsIFMuIEcuPC9hdXRob3I+

PGF1dGhvcj5MZXdpbiwgUy4gUi48L2F1dGhvcj48YXV0aG9yPlJvc3MsIEEuIEwuPC9hdXRob3I+

PGF1dGhvcj5BbmFud29yYW5pY2gsIEouPC9hdXRob3I+PGF1dGhvcj5CZW5raXJhbmUsIE0uPC9h

dXRob3I+PGF1dGhvcj5DYW5ub24sIFAuPC9hdXRob3I+PGF1dGhvcj5DaG9tb250LCBOLjwvYXV0

aG9yPjxhdXRob3I+RG91ZWssIEQuPC9hdXRob3I+PGF1dGhvcj5MaWZzb24sIEouIEQuPC9hdXRo

b3I+PGF1dGhvcj5MbywgWS4gUi48L2F1dGhvcj48YXV0aG9yPkt1cml0emtlcywgRC48L2F1dGhv

cj48YXV0aG9yPk1hcmdvbGlzLCBELjwvYXV0aG9yPjxhdXRob3I+TWVsbG9ycywgSi48L2F1dGhv

cj48YXV0aG9yPlBlcnNhdWQsIEQuPC9hdXRob3I+PGF1dGhvcj5UdWNrZXIsIEouIEQuPC9hdXRo

b3I+PGF1dGhvcj5CYXJyZS1TaW5vdXNzaSwgRi48L2F1dGhvcj48YXV0aG9yPkludGVybmF0aW9u

YWwsIEFpZHMgU29jaWV0eSBUb3dhcmRzIGEgQ3VyZSBXb3JraW5nIEdyb3VwPC9hdXRob3I+PGF1

dGhvcj5BbHRlciwgRy48L2F1dGhvcj48YXV0aG9yPkF1ZXJiYWNoLCBKLjwvYXV0aG9yPjxhdXRo

b3I+QXV0cmFuLCBCLjwvYXV0aG9yPjxhdXRob3I+QmFyb3VjaCwgRC4gSC48L2F1dGhvcj48YXV0

aG9yPkJlaHJlbnMsIEcuPC9hdXRob3I+PGF1dGhvcj5DYXZhenphbmEsIE0uPC9hdXRob3I+PGF1

dGhvcj5DaGVuLCBaLjwvYXV0aG9yPjxhdXRob3I+Q29oZW4sIEUuIEEuPC9hdXRob3I+PGF1dGhv

cj5Db3JiZWxsaSwgRy4gTS48L2F1dGhvcj48YXV0aG9yPkVob2xpZSwgUy48L2F1dGhvcj48YXV0

aG9yPkV5YWwsIE4uPC9hdXRob3I+PGF1dGhvcj5GaWRsZXIsIFMuPC9hdXRob3I+PGF1dGhvcj5H

YXJjaWEsIEwuPC9hdXRob3I+PGF1dGhvcj5Hcm9zc21hbiwgQy48L2F1dGhvcj48YXV0aG9yPkhl

bmRlcnNvbiwgRy48L2F1dGhvcj48YXV0aG9yPkhlbnJpY2gsIFQuIEouPC9hdXRob3I+PGF1dGhv

cj5KZWZmZXJ5cywgUi48L2F1dGhvcj48YXV0aG9yPktpZW0sIEguIFAuPC9hdXRob3I+PGF1dGhv

cj5NY0N1bmUsIEouPC9hdXRob3I+PGF1dGhvcj5Nb29kbGV5LCBLLjwvYXV0aG9yPjxhdXRob3I+

TmV3bWFuLCBQLiBBLjwvYXV0aG9yPjxhdXRob3I+TmlqaHVpcywgTS48L2F1dGhvcj48YXV0aG9y

Pk5zdWJ1Z2EsIE0uIFMuPC9hdXRob3I+PGF1dGhvcj5PdHQsIE0uPC9hdXRob3I+PGF1dGhvcj5Q

YWxtZXIsIFMuPC9hdXRob3I+PGF1dGhvcj5SaWNobWFuLCBELjwvYXV0aG9yPjxhdXRob3I+U2Fl

ei1DaXJpb24sIEEuPC9hdXRob3I+PGF1dGhvcj5TaGFycCwgTS48L2F1dGhvcj48YXV0aG9yPlNp

bGljaWFubywgSi48L2F1dGhvcj48YXV0aG9yPlNpbHZlc3RyaSwgRy48L2F1dGhvcj48YXV0aG9y

PlNpbmdoLCBKLjwvYXV0aG9yPjxhdXRob3I+U3BpcmUsIEIuPC9hdXRob3I+PGF1dGhvcj5UYXls

b3IsIEouPC9hdXRob3I+PGF1dGhvcj5Ub2xzdHJ1cCwgTS48L2F1dGhvcj48YXV0aG9yPlZhbGVu

dGUsIFMuPC9hdXRob3I+PGF1dGhvcj52YW4gTHVuemVuLCBKLjwvYXV0aG9yPjxhdXRob3I+V2Fs

ZW5za3ksIFIuPC9hdXRob3I+PGF1dGhvcj5XaWxzb24sIEkuPC9hdXRob3I+PGF1dGhvcj5aYWNr

LCBKLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFy

dG1lbnQgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQ2FsaWZvcm5pYSwgU2FuIEZyYW5jaXNj

bywgU2FuIEZyYW5jaXNjbywgQ2FsaWZvcm5pYSwgVVNBLiYjeEQ7VGhlIFBldGVyIERvaGVydHkg

SW5zdGl0dXRlIGZvciBJbmZlY3Rpb24gYW5kIEltbXVuaXR5LCBVbml2ZXJzaXR5IG9mIE1lbGJv

dXJuZSBhbmQgUm95YWwgTWVsYm91cm5lIEhvc3BpdGFsLCBNZWxib3VybmUsIEF1c3RyYWxpYS4m

I3hEO0RlcGFydG1lbnQgb2YgSW5mZWN0aW91cyBEaXNlYXNlcywgQWxmcmVkIEhvc3BpdGFsIGFu

ZCBNb25hc2ggVW5pdmVyc2l0eSwgTWVsYm91cm5lLCBBdXN0cmFsaWEuJiN4RDtJbnRlcm5hdGlv

bmFsIGFuZCBTY2llbnRpZmljIFJlbGF0aW9ucyBPZmZpY2UsIEFOUlMsIFBhcmlzLCBGcmFuY2Uu

JiN4RDtVUyBNaWxpdGFyeSBISVYgUmVzZWFyY2ggUHJvZ3JhbSwgV2FsdGVyIFJlZWQgQXJteSBJ

bnN0aXR1dGUgb2YgUmVzZWFyY2gsIFNpbHZlciBTcHJpbmcsIE1hcnlsYW5kLCBVU0EuJiN4RDtI

ZW5yeSBNLiBKYWNrc29uIEZvdW5kYXRpb24gZm9yIHRoZSBBZHZhbmNlbWVudCBvZiBNaWxpdGFy

eSBNZWRpY2luZSwgQmV0aGVzZGEsIE1hcnlsYW5kLCBVU0EuJiN4RDtNb2xlY3VsYXIgVmlyb2xv

Z3kgTGFiLCBJbnN0aXR1dGUgb2YgSHVtYW4gR2VuZXRpY3MsIENOUlMgVVBSIDExNDIsIFVuaXZl

cnNpdGUgZGUgTW9udHBlbGxpZXIsIE1vbnRwZWxsaWVyLCBGcmFuY2UuJiN4RDtLZWNrIFNjaG9v

bCBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBTb3V0aGVybiBDYWxpZm9ybmlhLCBMb3MgQW5n

ZWxlcywgQ2FsaWZvcm5pYSwgVVNBLiYjeEQ7Q1JDSFVNIGFuZCBEZXBhcnRtZW50IG9mIE1pY3Jv

YmlvbG9neSwgSW5mZWN0aW9sb2d5LCBhbmQgSW1tdW5vbG9neSwgVW5pdmVyc2l0ZSBkZSBNb250

cmVhbCwgRmFjdWx0eSBvZiBNZWRpY2luZSwgTW9udHJlYWwsIFF1ZWJlYywgQ2FuYWRhLiYjeEQ7

VmFjY2luZSBSZXNlYXJjaCBDZW50ZXIsIE5hdGlvbmFsIEluc3RpdHV0ZSBvZiBBbGxlcmd5IGFu

ZCBJbmZlY3Rpb3VzIERpc2Vhc2VzLCBOYXRpb25hbCBJbnN0aXR1dGVzIG9mIEhlYWx0aCwgQmV0

aGVzZGEsIE1hcnlsYW5kLCBVU0EuJiN4RDtBSURTIGFuZCBDYW5jZXIgVmlydXMgUHJvZ3JhbSwg

TGVpZG9zIEJpb21lZGljYWwgUmVzZWFyY2gsIEluYy4sIEZyZWRlcmljayBOYXRpb25hbCBMYWJv

cmF0b3J5LCBGcmVkZXJpY2ssIE1hcnlsYW5kLCBVU0EuJiN4RDtXb3JsZCBIZWFsdGggT3JnYW5p

emF0aW9uIFJlZ2lvbmFsIE9mZmljZSBmb3IgdGhlIFdlc3Rlcm4gUGFjaWZpYywgTWFuaWxhLCBQ

aGlsaXBwaW5lcy4mI3hEO0JyaWdoYW0gJmFtcDtXb21lbiZhcG9zO3MgSG9zcGl0YWwsIEJvc3Rv

biwgTWFzc2FjaHVzZXR0cywgVVNBLiYjeEQ7VW5pdmVyc2l0eSBvZiBOb3J0aCBDYXJvbGluYSBh

dCBDaGFwZWwgSGlsbCBTY2hvb2wgb2YgTWVkaWNpbmUsIENoYXBlbCBIaWxsLCBOb3J0aCBDYXJv

bGluYSwgVVNBLiYjeEQ7RGl2aXNpb24gb2YgSW5mZWN0aW91cyBEaXNlYXNlcywgRGVwYXJ0bWVu

dCBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBQaXR0c2J1cmdoLCBQaXR0c2J1cmdoLCBQZW5u

c3lsdmFuaWEsIFVTQS4mI3hEO0pvaG5zIEhvcGtpbnMgVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVk

aWNpbmUgJmFtcDtCbG9vbWJlcmcgU2Nob29sIG9mIFB1YmxpYyBIZWFsdGgsIEJhbHRpbW9yZSwg

TWFyeWxhbmQsIFVTQS4mI3hEO1VuaXZlcnNpdHkgb2YgTm9ydGggQ2Fyb2xpbmEtUHJvamVjdCBD

aGluYSwgR3Vhbmd6aG91LCBDaGluYS4mI3hEO0luc3RpdHV0IFBhc3RldXIsIFBhcmlzLCBGcmFu

Y2UuJiN4RDtSYWdvbiBJbnN0aXR1dGUgb2YgTUdILCBNSVQgYW5kIEhhcnZhcmQsIEJvc3Rvbiwg

TWFzc2FjaHVzZXR0cywgVVNBLiYjeEQ7U29yYm9ubmUgVW5pdmVyc2l0ZXMsIFVQTUMgVW5pdiBQ

YXJpcyAwNiwgQ0lNSS1QYXJpcywgRnJhbmNlLiYjeEQ7SW5zZXJtIFUxMTM1LCBDSU1JLVBhcmlz

LCBQYXJpcywgRnJhbmNlLiYjeEQ7QVAtSFAsIEhvcGl0YWwgUGl0aWUtU2FscGV0cmllcmUsIERl

cGFydGVtZW50IGQmYXBvcztJbW11bm9sb2dpZSwgUGFyaXMsIEZyYW5jZS4mI3hEO0JldGggSXNy

YWVsIERlYWNvbmVzcyBNZWRpY2FsIENlbnRlciwgSGFydmFyZCBNZWRpY2FsIFNjaG9vbCwgQm9z

dG9uLCBNYXNzYWNodXNldHRzLCBVU0EuJiN4RDtDbGluaWMgZm9yIEltbXVub2xvZ3kgYW5kIFJo

ZW1hdG9sb2d5LCBIYW5ub3ZlciBNZWRpY2FsIFNjaG9vbCwgSGFub3ZlciwgR2VybWFueS4mI3hE

O0NlbnRyZSBkJmFwb3M7SW52ZXN0aWdhdGlvbiBDbGluaXF1ZSBlbiBiaW90aGVyYXBpZSwgSG9w

aXRhbCBOZWNrZXItRW5mYW50cyBNYWxhZGVzLCBQYXJpcywgRnJhbmNlLiYjeEQ7QUlEUyBJbnN0

aXR1dGUsIFRoZSBVbml2ZXJzaXR5IG9mIEhvbmcgS29uZywgUG9rIEZ1IExhbSwgSG9uZyBLb25n

LiYjeEQ7SW5zdGl0dXQgZGUgUmVjaGVyY2hlcyBDbGluaXF1ZXMgZGUgTW9udHJlYWwsIFVuaXZl

cnNpdGUgZGUgTW9udHJlYWwsIE1vbnRyZWFsLCBRdWViZWMsIENhbmFkYS4mI3hEO0V1cm9wZWFu

IEFJRFMgVHJlYXRtZW50IEdyb3VwLCBJdGFseS4mI3hEO1Byb2dyYW1tZSBQQUMtQ0ksIENlbnRy

ZSBIb3NwaXRhbGllciBVbml2ZXJzaXRhaXJlIGRlIFRyZWljaHZpbGxlLCBBYmlkamFuLCBDb3Rl

IGQmYXBvcztJdm9pcmUuJiN4RDtIYXJ2YXJkIFQuIEguIENoYW4gU2Nob29sIG9mIFB1YmxpYyBI

ZWFsdGgsIERlcGFydG1lbnQgb2YgR2xvYmFsIEhlYWx0aCBhbmQgUG9wdWxhdGlvbiwgQm9zdG9u

LCBNYXNzYWNodXNldHRzLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIE1lZGljaW5lLCBJbXBlcmlh

bCBDb2xsZWdlIExvbmRvbiwgTG9uZG9uLCBVbml0ZWQgS2luZ2RvbS4mI3hEO1RoZSBCLUNoYW5n

ZSBHcm91cCwgTWFuaWxhLCBQaGlsaXBwaW5lcy4mI3hEO05hdGlvbmFsIEluc3RpdHV0ZSBvZiBN

ZW50YWwgSGVhbHRoLCBOSUgsIEJldGhlc2RhLCBNYXJ5bGFuZCwgVVNBLiYjeEQ7VHJlYXRtZW50

IEFjdGlvbiBHcm91cCwgTmV3IFlvcmssIE5ldyBZb3JrLCBVU0EuJiN4RDtDbGluaWNhbCBSZXNl

YXJjaCBEaXZpc2lvbiwgRnJlZCBIdXRjaGluc29uIENhbmNlciBSZXNlYXJjaCBDZW50ZXIsIFNl

YXR0bGUsIFdhc2hpbmd0b24sIFVTQS4mI3hEO0NlbnRyZSBmb3IgTWVkaWNhbCBFdGhpY3MgYW5k

IExhdywgRGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgU3RlbGxlbmJvc2NoIFVuaXZlcnNpdHksIFdl

c3Rlcm4gQ2FwZSwgU291dGggQWZyaWNhLiYjeEQ7RmFjdG9yLUlud2VudGFzaCBGYWN1bHR5IG9m

IFNvY2lhbCBXb3JrLCBVbml2ZXJzaXR5IG9mIFRvcm9udG8sIFRvcm9udG8sIE9udGFyaW8sIENh

bmFkYS4mI3hEO0RlcGFydG1lbnQgb2YgTWVkaWNhbCBNaWNyb2Jpb2xvZ3ksIFZpcm9sb2d5LCBV

bml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyIFV0cmVjaHQsIFV0cmVjaHQsIE5ldGhlcmxhbmRzLiYj

eEQ7Sm9pbnQgQ2xpbmljYWwgUmVzZWFyY2ggQ2VudHJlLCBLYW1wYWxhLCBVZ2FuZGEuJiN4RDtH

bGFkc3RvbmUgSW5zdGl0dXRlcywgVW5pdmVyc2l0eSBvZiBDYWxpZm9ybmlhLCBTYW4gRnJhbmNp

c2NvLCBTYW4gRnJhbmNpc2NvLCBDYWxpZm9ybmlhLCBVU0EuJiN4RDtXZXN0bWVhZCBNaWxsZW5u

aXVtIEluc3RpdHV0ZSBmb3IgTWVkaWNhbCBSZXNlYXJjaCwgVW5pdmVyc2l0eSBvZiBTeWRuZXks

IFN5ZG5leSwgQXVzdHJhbGlhLiYjeEQ7VmlyZ2luaWEgU2FuIERpZWdvIEhlYWx0aGNhcmUgU3lz

dGVtIGFuZCBVbml2ZXJzaXR5IG9mIENhbGlmb3JuaWEsIFNhbiBEaWVnbywgU2FuIERpZWdvLCBD

YWxpZm9ybmlhLCBVU0EuJiN4RDtJbmRlcGVuZGVudCBISVYgRWR1Y2F0aW9uIGFuZCBBZHZvY2Fj

eSBDb25zdWx0YW50LCBTYW4gRnJhbmNpc2NvLCBDYWxpZm9ybmlhLCBVU0EuJiN4RDtEZXBhcnRt

ZW50IG9mIE1lZGljaW5lLCBKb2hucyBIb3BraW5zIFVuaXZlcnNpdHkgU2Nob29sIG9mIE1lZGlj

aW5lLCBCYWx0aW1vcmUsIE1hcnlsYW5kLCBVU0EuJiN4RDtZZXJrZXMgTmF0aW9uYWwgUHJpbWF0

ZSBSZXNlYXJjaCBDZW50cmUsIEVtb3J5IFVuaXZlcnNpdHksIEF0bGFudGEsIEdlb3JnaWEsIFVT

QS4mI3hEO05lbHNvbiBSLiBNYW5kZWxhIFNjaG9vbCBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBv

ZiBLd2FadWx1LU5hdGFsLCBEdXJiYW4sIFNvdXRoIEFmcmljYS4mI3hEO0lOU0VSTSBVTVJfUzkx

MiwgTWFyc2VpbGxlLCBGcmFuY2UuJiN4RDtDQVJFIENvbGxhYm9yYXRvcnkgQ29tbXVuaXR5IEFk

dmlzb3J5IEJvYXJkLCBQYWxtIFNwcmluZ3MsIENhbGlmb3JuaWEsIFVTQS4mI3hEO0luc3RpdHV0

ZSBvZiBDbGluaWNhbCBNZWRpY2luZSwgQWFyaHVzIFVuaXZlcnNpdHksIEFhcmh1cywgRGVubWFy

ay4mI3hEO0RlcGFydG1lbnQgb2YgSW1tdW5vbG9neSBhbmQgTWljcm9iaWFsIFNjaWVuY2VzLCBU

aGUgU2NyaXBwcyBSZXNlYXJjaCBJbnN0aXR1dGUsIEp1cGl0ZXIsIEZsb3JpZGEsIFVTQS4mI3hE

O1ZpaVYgSGVhbHRoY2FyZSwgTG9uZG9uLCBVbml0ZWQgS2luZ2RvbS4mI3hEO01hc3NhY2h1c2V0

dHMgR2VuZXJhbCBIb3NwaXRhbCwgSGFydmFyZCBNZWRpY2FsIFNjaG9vbCwgQm9zdG9uLCBNYXNz

YWNodXNldHRzLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIEhlYWx0aCBTZXJ2aWNlcywgUG9saWN5

ICZhbXA7UHJhY3RpY2UsIEJyb3duIFVuaXZlcnNpdHkgU2Nob29sIG9mIFB1YmxpYyBIZWFsdGgs

IFByb3ZpZGVuY2UsIFJob2RlIElzbGFuZCwgVVNBLiYjeEQ7RGF2aWQgR2VmZmVuIFNjaG9vbCBv

ZiBNZWRpY2luZSBhdCBVQ0xBLCBMb3MgQW5nZWxlcywgQ2FsaWZvcm5pYSwgVVNBLjwvYXV0aC1h

ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkludGVybmF0aW9uYWwgQUlEUyBTb2NpZXR5IGdsb2JhbCBz

Y2llbnRpZmljIHN0cmF0ZWd5OiB0b3dhcmRzIGFuIEhJViBjdXJlIDIwMTY8L3RpdGxlPjxzZWNv

bmRhcnktdGl0bGU+TmF0IE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz44Mzkt

NTA8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48bnVtYmVyPjg8L251bWJlcj48a2V5d29yZHM+

PGtleXdvcmQ+QWNxdWlyZWQgSW1tdW5vZGVmaWNpZW5jeSBTeW5kcm9tZS8qdGhlcmFweTwva2V5

d29yZD48a2V5d29yZD4qR29hbHM8L2tleXdvcmQ+PGtleXdvcmQ+SElWIEluZmVjdGlvbnMvKnRo

ZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkludGVybmF0

aW9uYWwgQ29vcGVyYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+T3JnYW5pemF0aW9uYWwgT2JqZWN0

aXZlczwva2V5d29yZD48a2V5d29yZD4qUmVzZWFyY2g8L2tleXdvcmQ+PGtleXdvcmQ+U29jaWV0

aWVzLCBNZWRpY2FsPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTQ2

LTE3MFggKEVsZWN0cm9uaWMpJiN4RDsxMDc4LTg5NTYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjI3NDAwMjY0PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNzQwMDI2NDwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM1MzIyNzk3PC9jdXN0b20yPjxlbGVjdHJvbmljLXJl

c291cmNlLW51bT4xMC4xMDM4L25tLjQxMDg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVj

b3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkhvZGdlPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

UmVjTnVtPjI2MDY8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjI2MDY8L3JlYy1udW1iZXI+

PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVwMHBocGZ3

eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNTAzMjY1MCI+MjYwNjwva2V5PjwvZm9yZWln

bi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29u

dHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SG9kZ2UsIEouIFcuPC9hdXRob3I+PGF1dGhvcj5B

cmRpYW5pLCBBLjwvYXV0aG9yPjxhdXRob3I+RmFyc2FjaSwgQi48L2F1dGhvcj48YXV0aG9yPkt3

aWxhcywgQS4gUi48L2F1dGhvcj48YXV0aG9yPkdhbWVpcm8sIFMuIFIuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+UmVjb21iaW5hbnQgVmFjY2luZSBHcm91

cCwgTGFib3JhdG9yeSBvZiBUdW1vciBJbW11bm9sb2d5IGFuZCBCaW9sb2d5LCBDZW50ZXIgZm9y

IENhbmNlciBSZXNlYXJjaCwgTmF0aW9uYWwgQ2FuY2VyIEluc3RpdHV0ZSwgTmF0aW9uYWwgSW5z

dGl0dXRlcyBvZiBIZWFsdGgsIEJldGhlc2RhLCBNRCAyMDg5MiwgVVNBLiBqaDI0MWRAbmloLmdv

djwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSB0aXBwaW5nIHBvaW50IGZvciBjb21i

aW5hdGlvbiB0aGVyYXB5OiBjYW5jZXIgdmFjY2luZXMgd2l0aCByYWRpYXRpb24sIGNoZW1vdGhl

cmFweSwgb3IgdGFyZ2V0ZWQgc21hbGwgbW9sZWN1bGUgaW5oaWJpdG9yczwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5TZW1pbiBPbmNvbDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz4z

MjMtMzk8L3BhZ2VzPjx2b2x1bWU+Mzk8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48a2V5d29y

ZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BbnRpbmVvcGxhc3RpYyBBZ2Vu

dHMvKmFkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS9pbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPkNhbmNlciBWYWNjaW5lcy8qYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlL2ltbXVub2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+Q29tYmluZWQgTW9kYWxpdHkgVGhlcmFweS8qbWV0aG9kczwv

a2V5d29yZD48a2V5d29yZD5EcnVnIFRoZXJhcHkvKm1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+

SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk5lb3BsYXNtcy90aGVyYXB5PC9rZXl3b3JkPjxrZXl3

b3JkPlJhZGlvdGhlcmFweS8qbWV0aG9kczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVh

cj4yMDEyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVuPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0

ZXM+PGlzYm4+MTUzMi04NzA4IChFbGVjdHJvbmljKSYjeEQ7MDA5My03NzU0IChMaW5raW5nKTwv

aXNibj48YWNjZXNzaW9uLW51bT4yMjU5NTA1NTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRl

ZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjI1OTUwNTU8

L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMzM1Njk5NDwvY3VzdG9tMj48

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA1My9qLnNlbWlub25jb2wuMjAxMi4wMi4wMDY8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA 453,454 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb1J1c3NvPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

UmVjTnVtPjI2MDc8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij40NTUsNDU2PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjYwNzwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1MDMyOTA5Ij4yNjA3PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Mb1J1c3NvLCBQLiBNLjwvYXV0

aG9yPjxhdXRob3I+Q2FuZXR0YSwgUi48L2F1dGhvcj48YXV0aG9yPldhZ25lciwgSi4gQS48L2F1

dGhvcj48YXV0aG9yPkJhbG9naCwgRS4gUC48L2F1dGhvcj48YXV0aG9yPk5hc3MsIFMuIEouPC9h

dXRob3I+PGF1dGhvcj5Cb2VybmVyLCBTLiBBLjwvYXV0aG9yPjxhdXRob3I+SG9obmVrZXIsIEou

PC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+S2FybWFub3Mg

Q2FuY2VyIEluc3RpdHV0ZSwgV2F5bmUgU3RhdGUgVW5pdmVyc2l0eSwgRGV0cm9pdCwgTWljaGln

YW4gNDgyMDEsIFVTQS4gbG9ydXNzb3BAa2FybWFub3Mub3JnPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+QWNjZWxlcmF0aW5nIGNhbmNlciB0aGVyYXB5IGRldmVsb3BtZW50OiB0aGUgaW1w

b3J0YW5jZSBvZiBjb21iaW5hdGlvbiBzdHJhdGVnaWVzIGFuZCBjb2xsYWJvcmF0aW9uLiBTdW1t

YXJ5IG9mIGFuIEluc3RpdHV0ZSBvZiBNZWRpY2luZSB3b3Jrc2hvcDwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5DbGluIENhbmNlciBSZXM8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9k

aWNhbD48ZnVsbC10aXRsZT5DbGluIENhbmNlciBSZXM8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz42MTAxLTk8L3BhZ2VzPjx2b2x1bWU+MTg8L3ZvbHVtZT48bnVtYmVyPjIyPC9udW1i

ZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QW50aW5lb3Bs

YXN0aWMgQ29tYmluZWQgQ2hlbW90aGVyYXB5IFByb3RvY29scy90aGVyYXBldXRpYyB1c2U8L2tl

eXdvcmQ+PGtleXdvcmQ+Q2xpbmljYWwgVHJpYWxzIGFzIFRvcGljPC9rZXl3b3JkPjxrZXl3b3Jk

PkNvbWJpbmVkIE1vZGFsaXR5IFRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+Q29vcGVyYXRpdmUg

QmVoYXZpb3I8L2tleXdvcmQ+PGtleXdvcmQ+RHJ1ZyBEaXNjb3ZlcnkvbGVnaXNsYXRpb24gJmFt

cDsganVyaXNwcnVkZW5jZTwva2V5d29yZD48a2V5d29yZD5EcnVnIFNjcmVlbmluZyBBc3NheXMs

IEFudGl0dW1vcjwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW50

ZXJkaXNjaXBsaW5hcnkgQ29tbXVuaWNhdGlvbjwva2V5d29yZD48a2V5d29yZD5OYXRpb25hbCBB

Y2FkZW1pZXMgb2YgU2NpZW5jZSwgRW5naW5lZXJpbmcsIGFuZCBNZWRpY2luZSAoVS5TLikgSGVh

bHRoIGFuZDwva2V5d29yZD48a2V5d29yZD5NZWRpY2luZSBEaXZpc2lvbjwva2V5d29yZD48a2V5

d29yZD5OZW9wbGFzbXMvKnRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+VW5pdGVkIFN0YXRlczwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEyPC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+Tm92IDE1PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA3OC0wNDMyIChQcmlu

dCkmI3hEOzEwNzgtMDQzMiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjMwNjU0Mjg8

L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmku

bmxtLm5paC5nb3YvcHVibWVkLzIzMDY1NDI4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxl

bGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTU4LzEwNzgtMDQzMi5DQ1ItMTItMjQ1NTwvZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+VHVtYmFy

ZWxsbzwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJlY051bT4yNjA4PC9SZWNOdW0+PHJlY29y

ZD48cmVjLW51bWJlcj4yNjA4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9

IjE1MzUwMzI5MDkiPjI2MDg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PlR1bWJhcmVsbG8sIE0uPC9hdXRob3I+PGF1dGhvcj5WaWFsZSwgUC48L2F1dGhvcj48YXV0aG9y

PlZpc2NvbGksIEMuPC9hdXRob3I+PGF1dGhvcj5UcmVjYXJpY2hpLCBFLiBNLjwvYXV0aG9yPjxh

dXRob3I+VHVtaWV0dG8sIEYuPC9hdXRob3I+PGF1dGhvcj5NYXJjaGVzZSwgQS48L2F1dGhvcj48

YXV0aG9yPlNwYW51LCBULjwvYXV0aG9yPjxhdXRob3I+QW1icmV0dGksIFMuPC9hdXRob3I+PGF1

dGhvcj5HaW5vY2NoaW8sIEYuPC9hdXRob3I+PGF1dGhvcj5DcmlzdGluaSwgRi48L2F1dGhvcj48

YXV0aG9yPkxvc2l0bywgQS4gUi48L2F1dGhvcj48YXV0aG9yPlRlZGVzY2hpLCBTLjwvYXV0aG9y

PjxhdXRob3I+Q2F1ZGEsIFIuPC9hdXRob3I+PGF1dGhvcj5CYXNzZXR0aSwgTS48L2F1dGhvcj48

L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5JbnN0aXR1dGUgb2YgSW5mZWN0

aW91cyBEaXNlYXNlcywgQ2F0aG9saWMgVW5pdmVyc2l0eSBvZiB0aGUgU2FjcmVkIEhlYXJ0LCBB

LiBHZW1lbGxpIEhvc3BpdGFsLCBSb21lLiB0dW1iYXJlbGxvQHJtLnVuaWNhdHQuaXQ8L2F1dGgt

YWRkcmVzcz48dGl0bGVzPjx0aXRsZT5QcmVkaWN0b3JzIG9mIG1vcnRhbGl0eSBpbiBibG9vZHN0

cmVhbSBpbmZlY3Rpb25zIGNhdXNlZCBieSBLbGVic2llbGxhIHBuZXVtb25pYWUgY2FyYmFwZW5l

bWFzZS1wcm9kdWNpbmcgSy4gcG5ldW1vbmlhZTogaW1wb3J0YW5jZSBvZiBjb21iaW5hdGlvbiB0

aGVyYXB5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNsaW4gSW5mZWN0IERpczwvc2Vjb25kYXJ5

LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz45NDMtNTA8L3BhZ2VzPjx2b2x1bWU+NTU8L3ZvbHVtZT48

bnVtYmVyPjc8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdv

cmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5

d29yZD5BbnRpLUJhY3RlcmlhbCBBZ2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3

b3JkPkJhY3RlcmVtaWEvKmRpYWdub3Npcy9taWNyb2Jpb2xvZ3kvKm1vcnRhbGl0eTwva2V5d29y

ZD48a2V5d29yZD5CYWN0ZXJpYWwgUHJvdGVpbnMvKnNlY3JldGlvbjwva2V5d29yZD48a2V5d29y

ZD5Db2hvcnQgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD4qRGVjaXNpb24gU3VwcG9ydCBUZWNo

bmlxdWVzPC9rZXl3b3JkPjxrZXl3b3JkPkRydWcgVGhlcmFweSwgQ29tYmluYXRpb24vbWV0aG9k

czwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3

b3JkPjxrZXl3b3JkPkl0YWx5PC9rZXl3b3JkPjxrZXl3b3JkPktsZWJzaWVsbGEgSW5mZWN0aW9u

cy8qZGlhZ25vc2lzL21pY3JvYmlvbG9neS8qbW9ydGFsaXR5PC9rZXl3b3JkPjxrZXl3b3JkPkts

ZWJzaWVsbGEgcG5ldW1vbmlhZS8qZW56eW1vbG9neS9pc29sYXRpb24gJmFtcDsgcHVyaWZpY2F0

aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8

L2tleXdvcmQ+PGtleXdvcmQ+UHJvZ25vc2lzPC9rZXl3b3JkPjxrZXl3b3JkPlJldHJvc3BlY3Rp

dmUgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdv

cmQ+U2V2ZXJpdHkgb2YgSWxsbmVzcyBJbmRleDwva2V5d29yZD48a2V5d29yZD5TdXJ2aXZhbCBB

bmFseXNpczwva2V5d29yZD48a2V5d29yZD5iZXRhLUxhY3RhbWFzZXMvKnNlY3JldGlvbjwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

T2N0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUzNy02NTkxIChFbGVjdHJvbmlj

KSYjeEQ7MTA1OC00ODM4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMjc1MjUxNjwv

YWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5u

bG0ubmloLmdvdi9wdWJtZWQvMjI3NTI1MTY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwOTMvY2lkL2NpczU4ODwvZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb1J1c3NvPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

UmVjTnVtPjI2MDc8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0

Ij40NTUsNDU2PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjYwNzwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImZ3YTByeDUycHc5

YTJ2ZXAwcGhwZnd4OXp0c3p6cHJwdDVhdiIgdGltZXN0YW1wPSIxNTM1MDMyOTA5Ij4yNjA3PC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Mb1J1c3NvLCBQLiBNLjwvYXV0

aG9yPjxhdXRob3I+Q2FuZXR0YSwgUi48L2F1dGhvcj48YXV0aG9yPldhZ25lciwgSi4gQS48L2F1

dGhvcj48YXV0aG9yPkJhbG9naCwgRS4gUC48L2F1dGhvcj48YXV0aG9yPk5hc3MsIFMuIEouPC9h

dXRob3I+PGF1dGhvcj5Cb2VybmVyLCBTLiBBLjwvYXV0aG9yPjxhdXRob3I+SG9obmVrZXIsIEou

PC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+S2FybWFub3Mg

Q2FuY2VyIEluc3RpdHV0ZSwgV2F5bmUgU3RhdGUgVW5pdmVyc2l0eSwgRGV0cm9pdCwgTWljaGln

YW4gNDgyMDEsIFVTQS4gbG9ydXNzb3BAa2FybWFub3Mub3JnPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+QWNjZWxlcmF0aW5nIGNhbmNlciB0aGVyYXB5IGRldmVsb3BtZW50OiB0aGUgaW1w

b3J0YW5jZSBvZiBjb21iaW5hdGlvbiBzdHJhdGVnaWVzIGFuZCBjb2xsYWJvcmF0aW9uLiBTdW1t

YXJ5IG9mIGFuIEluc3RpdHV0ZSBvZiBNZWRpY2luZSB3b3Jrc2hvcDwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5DbGluIENhbmNlciBSZXM8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9k

aWNhbD48ZnVsbC10aXRsZT5DbGluIENhbmNlciBSZXM8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz42MTAxLTk8L3BhZ2VzPjx2b2x1bWU+MTg8L3ZvbHVtZT48bnVtYmVyPjIyPC9udW1i

ZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QW50aW5lb3Bs

YXN0aWMgQ29tYmluZWQgQ2hlbW90aGVyYXB5IFByb3RvY29scy90aGVyYXBldXRpYyB1c2U8L2tl

eXdvcmQ+PGtleXdvcmQ+Q2xpbmljYWwgVHJpYWxzIGFzIFRvcGljPC9rZXl3b3JkPjxrZXl3b3Jk

PkNvbWJpbmVkIE1vZGFsaXR5IFRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+Q29vcGVyYXRpdmUg

QmVoYXZpb3I8L2tleXdvcmQ+PGtleXdvcmQ+RHJ1ZyBEaXNjb3ZlcnkvbGVnaXNsYXRpb24gJmFt

cDsganVyaXNwcnVkZW5jZTwva2V5d29yZD48a2V5d29yZD5EcnVnIFNjcmVlbmluZyBBc3NheXMs

IEFudGl0dW1vcjwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW50

ZXJkaXNjaXBsaW5hcnkgQ29tbXVuaWNhdGlvbjwva2V5d29yZD48a2V5d29yZD5OYXRpb25hbCBB

Y2FkZW1pZXMgb2YgU2NpZW5jZSwgRW5naW5lZXJpbmcsIGFuZCBNZWRpY2luZSAoVS5TLikgSGVh

bHRoIGFuZDwva2V5d29yZD48a2V5d29yZD5NZWRpY2luZSBEaXZpc2lvbjwva2V5d29yZD48a2V5

d29yZD5OZW9wbGFzbXMvKnRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+VW5pdGVkIFN0YXRlczwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEyPC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+Tm92IDE1PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA3OC0wNDMyIChQcmlu

dCkmI3hEOzEwNzgtMDQzMiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjMwNjU0Mjg8

L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmku

bmxtLm5paC5nb3YvcHVibWVkLzIzMDY1NDI4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxl

bGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTU4LzEwNzgtMDQzMi5DQ1ItMTItMjQ1NTwvZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+VHVtYmFy

ZWxsbzwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJlY051bT4yNjA4PC9SZWNOdW0+PHJlY29y

ZD48cmVjLW51bWJlcj4yNjA4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBwaHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9

IjE1MzUwMzI5MDkiPjI2MDg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PlR1bWJhcmVsbG8sIE0uPC9hdXRob3I+PGF1dGhvcj5WaWFsZSwgUC48L2F1dGhvcj48YXV0aG9y

PlZpc2NvbGksIEMuPC9hdXRob3I+PGF1dGhvcj5UcmVjYXJpY2hpLCBFLiBNLjwvYXV0aG9yPjxh

dXRob3I+VHVtaWV0dG8sIEYuPC9hdXRob3I+PGF1dGhvcj5NYXJjaGVzZSwgQS48L2F1dGhvcj48

YXV0aG9yPlNwYW51LCBULjwvYXV0aG9yPjxhdXRob3I+QW1icmV0dGksIFMuPC9hdXRob3I+PGF1

dGhvcj5HaW5vY2NoaW8sIEYuPC9hdXRob3I+PGF1dGhvcj5DcmlzdGluaSwgRi48L2F1dGhvcj48

YXV0aG9yPkxvc2l0bywgQS4gUi48L2F1dGhvcj48YXV0aG9yPlRlZGVzY2hpLCBTLjwvYXV0aG9y

PjxhdXRob3I+Q2F1ZGEsIFIuPC9hdXRob3I+PGF1dGhvcj5CYXNzZXR0aSwgTS48L2F1dGhvcj48

L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5JbnN0aXR1dGUgb2YgSW5mZWN0

aW91cyBEaXNlYXNlcywgQ2F0aG9saWMgVW5pdmVyc2l0eSBvZiB0aGUgU2FjcmVkIEhlYXJ0LCBB

LiBHZW1lbGxpIEhvc3BpdGFsLCBSb21lLiB0dW1iYXJlbGxvQHJtLnVuaWNhdHQuaXQ8L2F1dGgt

YWRkcmVzcz48dGl0bGVzPjx0aXRsZT5QcmVkaWN0b3JzIG9mIG1vcnRhbGl0eSBpbiBibG9vZHN0

cmVhbSBpbmZlY3Rpb25zIGNhdXNlZCBieSBLbGVic2llbGxhIHBuZXVtb25pYWUgY2FyYmFwZW5l

bWFzZS1wcm9kdWNpbmcgSy4gcG5ldW1vbmlhZTogaW1wb3J0YW5jZSBvZiBjb21iaW5hdGlvbiB0

aGVyYXB5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNsaW4gSW5mZWN0IERpczwvc2Vjb25kYXJ5

LXRpdGxlPjwvdGl0bGVzPjxwYWdlcz45NDMtNTA8L3BhZ2VzPjx2b2x1bWU+NTU8L3ZvbHVtZT48

bnVtYmVyPjc8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdv

cmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5

d29yZD5BbnRpLUJhY3RlcmlhbCBBZ2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3

b3JkPkJhY3RlcmVtaWEvKmRpYWdub3Npcy9taWNyb2Jpb2xvZ3kvKm1vcnRhbGl0eTwva2V5d29y

ZD48a2V5d29yZD5CYWN0ZXJpYWwgUHJvdGVpbnMvKnNlY3JldGlvbjwva2V5d29yZD48a2V5d29y

ZD5Db2hvcnQgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD4qRGVjaXNpb24gU3VwcG9ydCBUZWNo

bmlxdWVzPC9rZXl3b3JkPjxrZXl3b3JkPkRydWcgVGhlcmFweSwgQ29tYmluYXRpb24vbWV0aG9k

czwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3

b3JkPjxrZXl3b3JkPkl0YWx5PC9rZXl3b3JkPjxrZXl3b3JkPktsZWJzaWVsbGEgSW5mZWN0aW9u

cy8qZGlhZ25vc2lzL21pY3JvYmlvbG9neS8qbW9ydGFsaXR5PC9rZXl3b3JkPjxrZXl3b3JkPkts

ZWJzaWVsbGEgcG5ldW1vbmlhZS8qZW56eW1vbG9neS9pc29sYXRpb24gJmFtcDsgcHVyaWZpY2F0

aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8

L2tleXdvcmQ+PGtleXdvcmQ+UHJvZ25vc2lzPC9rZXl3b3JkPjxrZXl3b3JkPlJldHJvc3BlY3Rp

dmUgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdv

cmQ+U2V2ZXJpdHkgb2YgSWxsbmVzcyBJbmRleDwva2V5d29yZD48a2V5d29yZD5TdXJ2aXZhbCBB

bmFseXNpczwva2V5d29yZD48a2V5d29yZD5iZXRhLUxhY3RhbWFzZXMvKnNlY3JldGlvbjwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

T2N0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUzNy02NTkxIChFbGVjdHJvbmlj

KSYjeEQ7MTA1OC00ODM4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMjc1MjUxNjwv

YWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5u

bG0ubmloLmdvdi9wdWJtZWQvMjI3NTI1MTY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwOTMvY2lkL2NpczU4ODwvZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 455,456. AD therapeutics faces great challenges in terms of drug delivery, toxicity, and maintenance of cognition in patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjI3MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjQsMTk8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yNzI8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMTc3NTI3MSI+MjcyPC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XaW5ibGFkLCBCLjwvYXV0aG9yPjxhdXRo

b3I+QW1vdXllbCwgUC48L2F1dGhvcj48YXV0aG9yPkFuZHJpZXUsIFMuPC9hdXRob3I+PGF1dGhv

cj5CYWxsYXJkLCBDLjwvYXV0aG9yPjxhdXRob3I+QnJheW5lLCBDLjwvYXV0aG9yPjxhdXRob3I+

QnJvZGF0eSwgSC48L2F1dGhvcj48YXV0aG9yPkNlZGF6by1NaW5ndWV6LCBBLjwvYXV0aG9yPjxh

dXRob3I+RHVib2lzLCBCLjwvYXV0aG9yPjxhdXRob3I+RWR2YXJkc3NvbiwgRC48L2F1dGhvcj48

YXV0aG9yPkZlbGRtYW4sIEguPC9hdXRob3I+PGF1dGhvcj5GcmF0aWdsaW9uaSwgTC48L2F1dGhv

cj48YXV0aG9yPkZyaXNvbmksIEcuIEIuPC9hdXRob3I+PGF1dGhvcj5HYXV0aGllciwgUy48L2F1

dGhvcj48YXV0aG9yPkdlb3JnZXMsIEouPC9hdXRob3I+PGF1dGhvcj5HcmFmZiwgQy48L2F1dGhv

cj48YXV0aG9yPklxYmFsLCBLLjwvYXV0aG9yPjxhdXRob3I+SmVzc2VuLCBGLjwvYXV0aG9yPjxh

dXRob3I+Sm9oYW5zc29uLCBHLjwvYXV0aG9yPjxhdXRob3I+Sm9uc3NvbiwgTC48L2F1dGhvcj48

YXV0aG9yPktpdmlwZWx0bywgTS48L2F1dGhvcj48YXV0aG9yPktuYXBwLCBNLjwvYXV0aG9yPjxh

dXRob3I+TWFuZ2lhbGFzY2hlLCBGLjwvYXV0aG9yPjxhdXRob3I+TWVsaXMsIFIuPC9hdXRob3I+

PGF1dGhvcj5Ob3JkYmVyZywgQS48L2F1dGhvcj48YXV0aG9yPlJpa2tlcnQsIE0uIE8uPC9hdXRo

b3I+PGF1dGhvcj5RaXUsIEMuPC9hdXRob3I+PGF1dGhvcj5TYWttYXIsIFQuIFAuPC9hdXRob3I+

PGF1dGhvcj5TY2hlbHRlbnMsIFAuPC9hdXRob3I+PGF1dGhvcj5TY2huZWlkZXIsIEwuIFMuPC9h

dXRob3I+PGF1dGhvcj5TcGVybGluZywgUi48L2F1dGhvcj48YXV0aG9yPlRqZXJuYmVyZywgTC4g

Ty48L2F1dGhvcj48YXV0aG9yPldhbGRlbWFyLCBHLjwvYXV0aG9yPjxhdXRob3I+V2ltbywgQS48

L2F1dGhvcj48YXV0aG9yPlpldHRlcmJlcmcsIEguPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp

YnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2Np

ZW5jZXMgYW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEaXZpc2lv

biBvZiBOZXVyb2dlcmlhdHJpY3MsIEthcm9saW5za2EgSW5zdGl0dXRldCwgSHVkZGluZ2UsIFN3

ZWRlbjsgRGVwYXJ0bWVudCBvZiBHZXJpYXRyaWMgTWVkaWNpbmUsIEthcm9saW5za2EgVW5pdmVy

c2l0eSBIb3NwaXRhbCwgSHVkZGluZ2UsIFN3ZWRlbi4gRWxlY3Ryb25pYyBhZGRyZXNzOiBiZW5n

dC13aW5ibGFkLXN3ZWRpc2hicmFpbnBvd2VyQGtpLnNlLiYjeEQ7Q2VudHJlIEhvc3BpdGFsaWVy

IFJlZ2lvbmFsIFVuaXZlcnNpdGFpcmUgZGUgTGlsbGUsIEluc3RpdHV0IFBhc3RldXIgZGUgTGls

bGUsIElOU0VSTSBVMTE2NyBSSUQtQUdFLCBVbml0ZSBkJmFwb3M7RXBpZGVtaW9sb2dpZSBldCBk

ZSBTYW50ZSBQdWJsaXF1ZSwgTGFiZXggRElTVEFMWiwgTGlsbGUsIEZyYW5jZS4mI3hEO0RlcGFy

dG1lbnQgb2YgRXBpZGVtaW9sb2d5IGFuZCBQdWJsaWMgSGVhbHRoLCBGYWN1bHR5IG9mIE1lZGlj

aW5lLCBUb3Vsb3VzZSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBUb3Vsb3VzZSwgRnJhbmNlLiYjeEQ7

V29sZnNvbiBDZW50cmUgZm9yIEFnZS1SZWxhdGVkIERpc2Vhc2VzLCBLaW5nJmFwb3M7cyBDb2xs

ZWdlIExvbmRvbiwgTG9uZG9uLCBVSy4mI3hEO0NhbWJyaWRnZSBJbnN0aXR1dGUgb2YgUHVibGlj

IEhlYWx0aCwgVW5pdmVyc2l0eSBvZiBDYW1icmlkZ2UsIENhbWJyaWRnZSwgVUsuJiN4RDtDZW50

cmUgZm9yIEhlYWx0aHkgQnJhaW4gQWdlaW5nIGFuZCBEZW1lbnRpYSBDb2xsYWJvcmF0aXZlIFJl

c2VhcmNoIENlbnRyZSwgVW5pdmVyc2l0eSBvZiBOZXcgU291dGggV2FsZXMsIFN5ZG5leSwgTlNX

LCBBdXN0cmFsaWEuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNl

cyBhbmQgU29jaWV0eSwgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9m

IE5ldXJvZ2VyaWF0cmljcywgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBIdWRkaW5nZSwgU3dlZGVu

LiYjeEQ7SW5zdGl0dXQgZGUgbGEgTWVtb2lyZSBldCBkZSBsYSBNYWxhZGllIGQmYXBvcztBbHpo

ZWltZXIsIElNMkEsIElOU0VSTSwgSW5zdGl0dXQgZHUgQ2VydmVhdSBldCBkZSBsYSBNb2VsbGUg

RXBpbmllcmUsIFVNUi1TOTc1LCBHcm91cGUgSG9zcGl0YWxpZXIgUGl0aWUtU2FscGV0cmllcmUs

IFVuaXZlcnNpdGUgUGllcnJlIGV0IE1hcmllIEN1cmllLVBhcmlzIDYsIFBhcmlzLCBGcmFuY2Uu

JiN4RDtTY2hvb2wgb2YgTnVyc2luZyBhbmQgTWlkd2lmZXJ5LCBMYSBUcm9iZSBVbml2ZXJzaXR5

LCBNZWxib3VybmUsIFZJQywgQXVzdHJhbGlhOyBEZXBhcnRtZW50IG9mIE51cnNpbmcsIFVtZWEg

VW5pdmVyc2l0eSwgVW1lYSwgU3dlZGVuLiYjeEQ7RGl2aXNpb24gb2YgTmV1cm9sb2d5LCBGYWN1

bHR5IG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIEJyaXRpc2ggQ29sdW1iaWEsIFZhbmNvdXZl

ciwgQkMsIENhbmFkYS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVu

Y2VzIGFuZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgQWdpbmcgUmVz

ZWFyY2ggQ2VudGVyLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVuLiYj

eEQ7R2VuZXZhIFVuaXZlcnNpdHkgSG9zcGl0YWxzIGFuZCBVbml2ZXJzaXR5IG9mIEdlbmV2YSwg

R2VuZXZhLCBTd2l0emVybGFuZDsgSVJDQ1MgQ2VudHJvIFNhbiBHaW92YW5uaSBkaSBEaW8gRmF0

ZWJlbmVmcmF0ZWxsaSwgQnJlc2NpYSwgSXRhbHkuJiN4RDtNY0dpbGwgQ2VudGVyIGZvciBTdHVk

aWVzIGluIEFnaW5nLCBBbHpoZWltZXImYXBvcztzIERpc2Vhc2UgUmVzZWFyY2ggVW5pdCwgYW5k

IERvdWdsYXMgTWVudGFsIEhlYWx0aCBVbml2ZXJzaXR5IEluc3RpdHV0ZSwgTW9udHJlYWwsIFFD

LCBDYW5hZGEuJiN4RDtBbHpoZWltZXIgRXVyb3BlLCBMdXhlbWJvdXJnIENpdHksIEx1eGVtYm91

cmcuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29j

aWV0eSwgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIE5ldXJvZ2Vy

aWF0cmljcywgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBIdWRkaW5nZSwgU3dlZGVuOyBEZXBhcnRt

ZW50IG9mIEdlcmlhdHJpYyBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFs

LCBIdWRkaW5nZSwgU3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2NoZW1pc3RyeSwgSW5n

ZSBHcnVuZGtlLUlxYmFsIFJlc2VhcmNoIEZsb29yLCBOZXcgWW9yayBTdGF0ZSBJbnN0aXR1dGUg

Zm9yIEJhc2ljIFJlc2VhcmNoLCBTdGF0ZW4gSXNsYW5kLCBOWSwgVVNBLiYjeEQ7RGVwYXJ0bWVu

dCBvZiBQc3ljaGlhdHJ5LCBVbml2ZXJzaXR5IG9mIENvbG9nbmUsIENvbG9nbmUsIEdlcm1hbnk7

IEdlcm1hbiBDZW50ZXIgZm9yIE5ldXJvZGVnZW5lcmF0aXZlIERpc2Vhc2VzIChEWk5FKSwgQm9u

biwgR2VybWFueS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2Vz

IGFuZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2Yg

TmV1cm9nZXJpYXRyaWNzLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIEh1ZGRpbmdlLCBTd2VkZW47

IERlcGFydG1lbnQgb2YgR2VyaWF0cmljIE1lZGljaW5lLCBLYXJvbGluc2thIFVuaXZlcnNpdHkg

SG9zcGl0YWwsIEh1ZGRpbmdlLCBTd2VkZW47IERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBD

YXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwg

QWdpbmcgUmVzZWFyY2ggQ2VudGVyLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwg

U3dlZGVuLiYjeEQ7UGVyc29uYWwgU29jaWFsIFNlcnZpY2VzIFJlc2VhcmNoIFVuaXQsIExvbmRv

biBTY2hvb2wgb2YgRWNvbm9taWNzIGFuZCBQb2xpdGljYWwgU2NpZW5jZSwgTG9uZG9uLCBVSy4m

I3hEO1JhZGJvdWR1bWMgQWx6aGVpbWVyIENlbnRyZSBhbmQgRGVwYXJ0bWVudCBvZiBHZXJpYXRy

aWMgTWVkaWNpbmUsIFJhZGJvdWQgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRlciwgTmlqbWVnZW4s

IE5ldGhlcmxhbmRzLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5j

ZXMgYW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEaXZpc2lvbiBv

ZiBUcmFuc2xhdGlvbmFsIEFsemhlaW1lciBCaW9sb2d5LCBLYXJvbGluc2thIEluc3RpdHV0ZXQs

IEh1ZGRpbmdlLCBTd2VkZW47IERlcGFydG1lbnQgb2YgR2VyaWF0cmljIE1lZGljaW5lLCBLYXJv

bGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtEZXBhcnRt

ZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgQ2VudGVyIGZv

ciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0cmljcywgS2Fyb2xp

bnNrYSBJbnN0aXR1dGV0LCBIdWRkaW5nZSwgU3dlZGVuOyBMYWJvcmF0b3J5IG9mIENoZW1pY2Fs

IEJpb2xvZ3kgJmFtcDsgU2lnbmFsIFRyYW5zZHVjdGlvbiwgVGhlIFJvY2tlZmVsbGVyIFVuaXZl

cnNpdHksIE5ldyBZb3JrLCBOWSwgVVNBLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3kgYW5k

IEFsemhlaW1lciBDZW50ZXIsIFZVIFVuaXZlcnNpdHkgTWVkaWNhbCBDZW50ZXIsIE5ldXJvc2Np

ZW5jZSBDYW1wdXMsIEFtc3RlcmRhbSwgTmV0aGVybGFuZHMuJiN4RDtEZXBhcnRtZW50IG9mIFBz

eWNoaWF0cnkgYW5kIHRoZSBCZWhhdmlvcmFsIFNjaWVuY2VzIGFuZCBEZXBhcnRtZW50IG9mIE5l

dXJvbG9neSwgS2VjayBTY2hvb2wgb2YgTWVkaWNpbmUsIExlb25hcmQgRGF2aXMgU2Nob29sIG9m

IEdlcm9udG9sb2d5IG9mIHRoZSBVbml2ZXJzaXR5IG9mIFNvdXRoZXJuIENhbGlmb3JuaWEsIExv

cyBBbmdlbGVzLCBDQSwgVVNBLiYjeEQ7Q2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2ggYW5k

IFRyZWF0bWVudCwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIEJyaWdoYW0gYW5kIFdvbWVuJmFw

b3M7cyBIb3NwaXRhbCBhbmQgTWFzc2FjaHVzZXR0cyBHZW5lcmFsIEhvc3BpdGFsLCBIYXJ2YXJk

IE1lZGljYWwgU2Nob29sLCBCb3N0b24sIE1BLCBVU0EuJiN4RDtEYW5pc2ggRGVtZW50aWEgUmVz

ZWFyY2ggQ2VudHJlLCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgUmlnc2hvc3BpdGFsZXQsIFVu

aXZlcnNpdHkgb2YgQ29wZW5oYWdlbiwgQ29wZW5oYWdlbiwgRGVubWFyay4mI3hEO0NsaW5pY2Fs

IE5ldXJvY2hlbWlzdHJ5IExhYm9yYXRvcnksIERlcGFydG1lbnQgb2YgTmV1cm9zY2llbmNlIGFu

ZCBQaHlzaW9sb2d5LCBUaGUgU2FobGdyZW5za2EgQWNhZGVteSBhdCB0aGUgVW5pdmVyc2l0eSBv

ZiBHb3RoZW5idXJnLCBNb2xuZGFsLCBTd2VkZW47IFVDTCBJbnN0aXR1dGUgb2YgTmV1cm9sb2d5

LCBRdWVlbiBTcXVhcmUsIExvbmRvbiwgVUsuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+

RGVmZWF0aW5nIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZSBhbmQgb3RoZXIgZGVtZW50aWFzOiBh

IHByaW9yaXR5IGZvciBFdXJvcGVhbiBzY2llbmNlIGFuZCBzb2NpZXR5PC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPkxhbmNldCBOZXVyb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+

NDU1LTUzMjwvcGFnZXM+PHZvbHVtZT4xNTwvdm9sdW1lPjxudW1iZXI+NTwvbnVtYmVyPjxrZXl3

b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qdGhlcmFweTwva2V5d29yZD48a2V5d29y

ZD5CaW9tZWRpY2FsIFJlc2VhcmNoL2Vjb25vbWljcy8qb3JnYW5pemF0aW9uICZhbXA7IGFkbWlu

aXN0cmF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkRlbWVudGlhLyp0aGVyYXB5PC9rZXl3b3JkPjxr

ZXl3b3JkPkV1cm9wZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkFwcjwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0NzQtNDQ2NSAoRWxlY3Ryb25pYykmI3hEOzE0NzQtNDQy

MiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjY5ODc3MDE8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMjY5ODc3MDE8L3VybD48dXJsPmh0dHBzOi8vYWMuZWxzLWNkbi5jb20vUzE0NzQ0NDIyMTYw

MDA2MjQvMS1zMi4wLVMxNDc0NDQyMjE2MDAwNjI0LW1haW4ucGRmP190aWQ9MDc3ZjA4MTUtY2I1

Ni00MGM1LWFkYmYtZjhiZmFhNWJjOWE3JmFtcDthY2RuYXQ9MTUzNDQ5NTI2MF84MWYwMmEzZGZi

OGRiY2IwMWNjY2VjMTJlMjlmNmNlZTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMTQ3NC00NDIyKDE2KTAwMDYyLTQ8L2VsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkhhcmR5PC9BdXRo

b3I+PFllYXI+MjAxNzwvWWVhcj48UmVjTnVtPjIxMjU8L1JlY051bT48cmVjb3JkPjxyZWMtbnVt

YmVyPjIxMjU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJm

d2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDg2Mzcx

MSI+MjEyNTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj

bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SGFyZHksIEou

PC9hdXRob3I+PGF1dGhvcj5EZSBTdHJvb3BlciwgQi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlOiB3aGVyZSBu

ZXh0IGZvciBhbnRpLWFteWxvaWQgdGhlcmFwaWVzPzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5C

cmFpbjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkJy

YWluPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+ODUzLTg1NTwvcGFnZXM+PHZvbHVt

ZT4xNDA8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZWRpdGlvbj4yMDE3LzA0LzA1PC9lZGl0

aW9uPjxkYXRlcz48eWVhcj4yMDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXByIDE8L2RhdGU+

PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDYwLTIxNTYgKEVsZWN0cm9uaWMpJiN4RDswMDA2

LTg5NTAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI4Mzc1NDYxPC9hY2Nlc3Npb24t

bnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292

L3B1Ym1lZC8yODM3NTQ2MTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+MTAuMTA5My9icmFpbi9hd3gwNTk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5ibGFkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

UmVjTnVtPjI3MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi

PjQsMTk8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yNzI8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmd2Ewcng1MnB3OWEydmVw

MHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzMTc3NTI3MSI+MjcyPC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5XaW5ibGFkLCBCLjwvYXV0aG9yPjxhdXRo

b3I+QW1vdXllbCwgUC48L2F1dGhvcj48YXV0aG9yPkFuZHJpZXUsIFMuPC9hdXRob3I+PGF1dGhv

cj5CYWxsYXJkLCBDLjwvYXV0aG9yPjxhdXRob3I+QnJheW5lLCBDLjwvYXV0aG9yPjxhdXRob3I+

QnJvZGF0eSwgSC48L2F1dGhvcj48YXV0aG9yPkNlZGF6by1NaW5ndWV6LCBBLjwvYXV0aG9yPjxh

dXRob3I+RHVib2lzLCBCLjwvYXV0aG9yPjxhdXRob3I+RWR2YXJkc3NvbiwgRC48L2F1dGhvcj48

YXV0aG9yPkZlbGRtYW4sIEguPC9hdXRob3I+PGF1dGhvcj5GcmF0aWdsaW9uaSwgTC48L2F1dGhv

cj48YXV0aG9yPkZyaXNvbmksIEcuIEIuPC9hdXRob3I+PGF1dGhvcj5HYXV0aGllciwgUy48L2F1

dGhvcj48YXV0aG9yPkdlb3JnZXMsIEouPC9hdXRob3I+PGF1dGhvcj5HcmFmZiwgQy48L2F1dGhv

cj48YXV0aG9yPklxYmFsLCBLLjwvYXV0aG9yPjxhdXRob3I+SmVzc2VuLCBGLjwvYXV0aG9yPjxh

dXRob3I+Sm9oYW5zc29uLCBHLjwvYXV0aG9yPjxhdXRob3I+Sm9uc3NvbiwgTC48L2F1dGhvcj48

YXV0aG9yPktpdmlwZWx0bywgTS48L2F1dGhvcj48YXV0aG9yPktuYXBwLCBNLjwvYXV0aG9yPjxh

dXRob3I+TWFuZ2lhbGFzY2hlLCBGLjwvYXV0aG9yPjxhdXRob3I+TWVsaXMsIFIuPC9hdXRob3I+

PGF1dGhvcj5Ob3JkYmVyZywgQS48L2F1dGhvcj48YXV0aG9yPlJpa2tlcnQsIE0uIE8uPC9hdXRo

b3I+PGF1dGhvcj5RaXUsIEMuPC9hdXRob3I+PGF1dGhvcj5TYWttYXIsIFQuIFAuPC9hdXRob3I+

PGF1dGhvcj5TY2hlbHRlbnMsIFAuPC9hdXRob3I+PGF1dGhvcj5TY2huZWlkZXIsIEwuIFMuPC9h

dXRob3I+PGF1dGhvcj5TcGVybGluZywgUi48L2F1dGhvcj48YXV0aG9yPlRqZXJuYmVyZywgTC4g

Ty48L2F1dGhvcj48YXV0aG9yPldhbGRlbWFyLCBHLjwvYXV0aG9yPjxhdXRob3I+V2ltbywgQS48

L2F1dGhvcj48YXV0aG9yPlpldHRlcmJlcmcsIEguPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp

YnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2Np

ZW5jZXMgYW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEaXZpc2lv

biBvZiBOZXVyb2dlcmlhdHJpY3MsIEthcm9saW5za2EgSW5zdGl0dXRldCwgSHVkZGluZ2UsIFN3

ZWRlbjsgRGVwYXJ0bWVudCBvZiBHZXJpYXRyaWMgTWVkaWNpbmUsIEthcm9saW5za2EgVW5pdmVy

c2l0eSBIb3NwaXRhbCwgSHVkZGluZ2UsIFN3ZWRlbi4gRWxlY3Ryb25pYyBhZGRyZXNzOiBiZW5n

dC13aW5ibGFkLXN3ZWRpc2hicmFpbnBvd2VyQGtpLnNlLiYjeEQ7Q2VudHJlIEhvc3BpdGFsaWVy

IFJlZ2lvbmFsIFVuaXZlcnNpdGFpcmUgZGUgTGlsbGUsIEluc3RpdHV0IFBhc3RldXIgZGUgTGls

bGUsIElOU0VSTSBVMTE2NyBSSUQtQUdFLCBVbml0ZSBkJmFwb3M7RXBpZGVtaW9sb2dpZSBldCBk

ZSBTYW50ZSBQdWJsaXF1ZSwgTGFiZXggRElTVEFMWiwgTGlsbGUsIEZyYW5jZS4mI3hEO0RlcGFy

dG1lbnQgb2YgRXBpZGVtaW9sb2d5IGFuZCBQdWJsaWMgSGVhbHRoLCBGYWN1bHR5IG9mIE1lZGlj

aW5lLCBUb3Vsb3VzZSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBUb3Vsb3VzZSwgRnJhbmNlLiYjeEQ7

V29sZnNvbiBDZW50cmUgZm9yIEFnZS1SZWxhdGVkIERpc2Vhc2VzLCBLaW5nJmFwb3M7cyBDb2xs

ZWdlIExvbmRvbiwgTG9uZG9uLCBVSy4mI3hEO0NhbWJyaWRnZSBJbnN0aXR1dGUgb2YgUHVibGlj

IEhlYWx0aCwgVW5pdmVyc2l0eSBvZiBDYW1icmlkZ2UsIENhbWJyaWRnZSwgVUsuJiN4RDtDZW50

cmUgZm9yIEhlYWx0aHkgQnJhaW4gQWdlaW5nIGFuZCBEZW1lbnRpYSBDb2xsYWJvcmF0aXZlIFJl

c2VhcmNoIENlbnRyZSwgVW5pdmVyc2l0eSBvZiBOZXcgU291dGggV2FsZXMsIFN5ZG5leSwgTlNX

LCBBdXN0cmFsaWEuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNl

cyBhbmQgU29jaWV0eSwgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9m

IE5ldXJvZ2VyaWF0cmljcywgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBIdWRkaW5nZSwgU3dlZGVu

LiYjeEQ7SW5zdGl0dXQgZGUgbGEgTWVtb2lyZSBldCBkZSBsYSBNYWxhZGllIGQmYXBvcztBbHpo

ZWltZXIsIElNMkEsIElOU0VSTSwgSW5zdGl0dXQgZHUgQ2VydmVhdSBldCBkZSBsYSBNb2VsbGUg

RXBpbmllcmUsIFVNUi1TOTc1LCBHcm91cGUgSG9zcGl0YWxpZXIgUGl0aWUtU2FscGV0cmllcmUs

IFVuaXZlcnNpdGUgUGllcnJlIGV0IE1hcmllIEN1cmllLVBhcmlzIDYsIFBhcmlzLCBGcmFuY2Uu

JiN4RDtTY2hvb2wgb2YgTnVyc2luZyBhbmQgTWlkd2lmZXJ5LCBMYSBUcm9iZSBVbml2ZXJzaXR5

LCBNZWxib3VybmUsIFZJQywgQXVzdHJhbGlhOyBEZXBhcnRtZW50IG9mIE51cnNpbmcsIFVtZWEg

VW5pdmVyc2l0eSwgVW1lYSwgU3dlZGVuLiYjeEQ7RGl2aXNpb24gb2YgTmV1cm9sb2d5LCBGYWN1

bHR5IG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIEJyaXRpc2ggQ29sdW1iaWEsIFZhbmNvdXZl

ciwgQkMsIENhbmFkYS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVu

Y2VzIGFuZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgQWdpbmcgUmVz

ZWFyY2ggQ2VudGVyLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwgU3dlZGVuLiYj

eEQ7R2VuZXZhIFVuaXZlcnNpdHkgSG9zcGl0YWxzIGFuZCBVbml2ZXJzaXR5IG9mIEdlbmV2YSwg

R2VuZXZhLCBTd2l0emVybGFuZDsgSVJDQ1MgQ2VudHJvIFNhbiBHaW92YW5uaSBkaSBEaW8gRmF0

ZWJlbmVmcmF0ZWxsaSwgQnJlc2NpYSwgSXRhbHkuJiN4RDtNY0dpbGwgQ2VudGVyIGZvciBTdHVk

aWVzIGluIEFnaW5nLCBBbHpoZWltZXImYXBvcztzIERpc2Vhc2UgUmVzZWFyY2ggVW5pdCwgYW5k

IERvdWdsYXMgTWVudGFsIEhlYWx0aCBVbml2ZXJzaXR5IEluc3RpdHV0ZSwgTW9udHJlYWwsIFFD

LCBDYW5hZGEuJiN4RDtBbHpoZWltZXIgRXVyb3BlLCBMdXhlbWJvdXJnIENpdHksIEx1eGVtYm91

cmcuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29j

aWV0eSwgQ2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIE5ldXJvZ2Vy

aWF0cmljcywgS2Fyb2xpbnNrYSBJbnN0aXR1dGV0LCBIdWRkaW5nZSwgU3dlZGVuOyBEZXBhcnRt

ZW50IG9mIEdlcmlhdHJpYyBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFs

LCBIdWRkaW5nZSwgU3dlZGVuLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2NoZW1pc3RyeSwgSW5n

ZSBHcnVuZGtlLUlxYmFsIFJlc2VhcmNoIEZsb29yLCBOZXcgWW9yayBTdGF0ZSBJbnN0aXR1dGUg

Zm9yIEJhc2ljIFJlc2VhcmNoLCBTdGF0ZW4gSXNsYW5kLCBOWSwgVVNBLiYjeEQ7RGVwYXJ0bWVu

dCBvZiBQc3ljaGlhdHJ5LCBVbml2ZXJzaXR5IG9mIENvbG9nbmUsIENvbG9nbmUsIEdlcm1hbnk7

IEdlcm1hbiBDZW50ZXIgZm9yIE5ldXJvZGVnZW5lcmF0aXZlIERpc2Vhc2VzIChEWk5FKSwgQm9u

biwgR2VybWFueS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBDYXJlIFNjaWVuY2Vz

IGFuZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwgRGl2aXNpb24gb2Yg

TmV1cm9nZXJpYXRyaWNzLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIEh1ZGRpbmdlLCBTd2VkZW47

IERlcGFydG1lbnQgb2YgR2VyaWF0cmljIE1lZGljaW5lLCBLYXJvbGluc2thIFVuaXZlcnNpdHkg

SG9zcGl0YWwsIEh1ZGRpbmdlLCBTd2VkZW47IERlcGFydG1lbnQgb2YgTmV1cm9iaW9sb2d5LCBD

YXJlIFNjaWVuY2VzIGFuZCBTb2NpZXR5LCBDZW50ZXIgZm9yIEFsemhlaW1lciBSZXNlYXJjaCwg

QWdpbmcgUmVzZWFyY2ggQ2VudGVyLCBLYXJvbGluc2thIEluc3RpdHV0ZXQsIFN0b2NraG9sbSwg

U3dlZGVuLiYjeEQ7UGVyc29uYWwgU29jaWFsIFNlcnZpY2VzIFJlc2VhcmNoIFVuaXQsIExvbmRv

biBTY2hvb2wgb2YgRWNvbm9taWNzIGFuZCBQb2xpdGljYWwgU2NpZW5jZSwgTG9uZG9uLCBVSy4m

I3hEO1JhZGJvdWR1bWMgQWx6aGVpbWVyIENlbnRyZSBhbmQgRGVwYXJ0bWVudCBvZiBHZXJpYXRy

aWMgTWVkaWNpbmUsIFJhZGJvdWQgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRlciwgTmlqbWVnZW4s

IE5ldGhlcmxhbmRzLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2Jpb2xvZ3ksIENhcmUgU2NpZW5j

ZXMgYW5kIFNvY2lldHksIENlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoLCBEaXZpc2lvbiBv

ZiBUcmFuc2xhdGlvbmFsIEFsemhlaW1lciBCaW9sb2d5LCBLYXJvbGluc2thIEluc3RpdHV0ZXQs

IEh1ZGRpbmdlLCBTd2VkZW47IERlcGFydG1lbnQgb2YgR2VyaWF0cmljIE1lZGljaW5lLCBLYXJv

bGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEh1ZGRpbmdlLCBTd2VkZW4uJiN4RDtEZXBhcnRt

ZW50IG9mIE5ldXJvYmlvbG9neSwgQ2FyZSBTY2llbmNlcyBhbmQgU29jaWV0eSwgQ2VudGVyIGZv

ciBBbHpoZWltZXIgUmVzZWFyY2gsIERpdmlzaW9uIG9mIE5ldXJvZ2VyaWF0cmljcywgS2Fyb2xp

bnNrYSBJbnN0aXR1dGV0LCBIdWRkaW5nZSwgU3dlZGVuOyBMYWJvcmF0b3J5IG9mIENoZW1pY2Fs

IEJpb2xvZ3kgJmFtcDsgU2lnbmFsIFRyYW5zZHVjdGlvbiwgVGhlIFJvY2tlZmVsbGVyIFVuaXZl

cnNpdHksIE5ldyBZb3JrLCBOWSwgVVNBLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3kgYW5k

IEFsemhlaW1lciBDZW50ZXIsIFZVIFVuaXZlcnNpdHkgTWVkaWNhbCBDZW50ZXIsIE5ldXJvc2Np

ZW5jZSBDYW1wdXMsIEFtc3RlcmRhbSwgTmV0aGVybGFuZHMuJiN4RDtEZXBhcnRtZW50IG9mIFBz

eWNoaWF0cnkgYW5kIHRoZSBCZWhhdmlvcmFsIFNjaWVuY2VzIGFuZCBEZXBhcnRtZW50IG9mIE5l

dXJvbG9neSwgS2VjayBTY2hvb2wgb2YgTWVkaWNpbmUsIExlb25hcmQgRGF2aXMgU2Nob29sIG9m

IEdlcm9udG9sb2d5IG9mIHRoZSBVbml2ZXJzaXR5IG9mIFNvdXRoZXJuIENhbGlmb3JuaWEsIExv

cyBBbmdlbGVzLCBDQSwgVVNBLiYjeEQ7Q2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2ggYW5k

IFRyZWF0bWVudCwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIEJyaWdoYW0gYW5kIFdvbWVuJmFw

b3M7cyBIb3NwaXRhbCBhbmQgTWFzc2FjaHVzZXR0cyBHZW5lcmFsIEhvc3BpdGFsLCBIYXJ2YXJk

IE1lZGljYWwgU2Nob29sLCBCb3N0b24sIE1BLCBVU0EuJiN4RDtEYW5pc2ggRGVtZW50aWEgUmVz

ZWFyY2ggQ2VudHJlLCBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgUmlnc2hvc3BpdGFsZXQsIFVu

aXZlcnNpdHkgb2YgQ29wZW5oYWdlbiwgQ29wZW5oYWdlbiwgRGVubWFyay4mI3hEO0NsaW5pY2Fs

IE5ldXJvY2hlbWlzdHJ5IExhYm9yYXRvcnksIERlcGFydG1lbnQgb2YgTmV1cm9zY2llbmNlIGFu

ZCBQaHlzaW9sb2d5LCBUaGUgU2FobGdyZW5za2EgQWNhZGVteSBhdCB0aGUgVW5pdmVyc2l0eSBv

ZiBHb3RoZW5idXJnLCBNb2xuZGFsLCBTd2VkZW47IFVDTCBJbnN0aXR1dGUgb2YgTmV1cm9sb2d5

LCBRdWVlbiBTcXVhcmUsIExvbmRvbiwgVUsuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+

RGVmZWF0aW5nIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZSBhbmQgb3RoZXIgZGVtZW50aWFzOiBh

IHByaW9yaXR5IGZvciBFdXJvcGVhbiBzY2llbmNlIGFuZCBzb2NpZXR5PC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPkxhbmNldCBOZXVyb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+

NDU1LTUzMjwvcGFnZXM+PHZvbHVtZT4xNTwvdm9sdW1lPjxudW1iZXI+NTwvbnVtYmVyPjxrZXl3

b3Jkcz48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qdGhlcmFweTwva2V5d29yZD48a2V5d29y

ZD5CaW9tZWRpY2FsIFJlc2VhcmNoL2Vjb25vbWljcy8qb3JnYW5pemF0aW9uICZhbXA7IGFkbWlu

aXN0cmF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkRlbWVudGlhLyp0aGVyYXB5PC9rZXl3b3JkPjxr

ZXl3b3JkPkV1cm9wZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkFwcjwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0NzQtNDQ2NSAoRWxlY3Ryb25pYykmI3hEOzE0NzQtNDQy

MiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjY5ODc3MDE8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMjY5ODc3MDE8L3VybD48dXJsPmh0dHBzOi8vYWMuZWxzLWNkbi5jb20vUzE0NzQ0NDIyMTYw

MDA2MjQvMS1zMi4wLVMxNDc0NDQyMjE2MDAwNjI0LW1haW4ucGRmP190aWQ9MDc3ZjA4MTUtY2I1

Ni00MGM1LWFkYmYtZjhiZmFhNWJjOWE3JmFtcDthY2RuYXQ9MTUzNDQ5NTI2MF84MWYwMmEzZGZi

OGRiY2IwMWNjY2VjMTJlMjlmNmNlZTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMTQ3NC00NDIyKDE2KTAwMDYyLTQ8L2VsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkhhcmR5PC9BdXRo

b3I+PFllYXI+MjAxNzwvWWVhcj48UmVjTnVtPjIxMjU8L1JlY051bT48cmVjb3JkPjxyZWMtbnVt

YmVyPjIxMjU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJm

d2Ewcng1MnB3OWEydmVwMHBocGZ3eDl6dHN6enBycHQ1YXYiIHRpbWVzdGFtcD0iMTUzNDg2Mzcx

MSI+MjEyNTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj

bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SGFyZHksIEou

PC9hdXRob3I+PGF1dGhvcj5EZSBTdHJvb3BlciwgQi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlOiB3aGVyZSBu

ZXh0IGZvciBhbnRpLWFteWxvaWQgdGhlcmFwaWVzPzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5C

cmFpbjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkJy

YWluPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+ODUzLTg1NTwvcGFnZXM+PHZvbHVt

ZT4xNDA8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZWRpdGlvbj4yMDE3LzA0LzA1PC9lZGl0

aW9uPjxkYXRlcz48eWVhcj4yMDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXByIDE8L2RhdGU+

PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDYwLTIxNTYgKEVsZWN0cm9uaWMpJiN4RDswMDA2

LTg5NTAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI4Mzc1NDYxPC9hY2Nlc3Npb24t

bnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292

L3B1Ym1lZC8yODM3NTQ2MTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1y

ZXNvdXJjZS1udW0+MTAuMTA5My9icmFpbi9hd3gwNTk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVt

PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 4,19. These topics will lead the future of AD basic research in the long term. In the short term, the most important strategies to improve the chances for treating AD are the targeting of factors increasing the risk of developing AD. We must underline that many risk factors for AD are modifiable ADDIN EN.CITE <EndNote><Cite><Author>Barnes</Author><Year>2011</Year><RecNum>2610</RecNum><DisplayText><style face="superscript">457</style></DisplayText><record><rec-number>2610</rec-number><foreign-keys><key app="EN" db-id="fwa0rx52pw9a2vep0phpfwx9ztszzprpt5av" timestamp="1535033323">2610</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Barnes, D. E.</author><author>Yaffe, K.</author></authors></contributors><auth-address>Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94121, USA. deborah.barnes@ucsf.edu</auth-address><titles><title>The projected effect of risk factor reduction on Alzheimer&apos;s disease prevalence</title><secondary-title>Lancet Neurol</secondary-title></titles><pages>819-28</pages><volume>10</volume><number>9</number><keywords><keyword>Alzheimer Disease/*epidemiology/etiology/*prevention &amp; control</keyword><keyword>Depression/complications/epidemiology/prevention &amp; control</keyword><keyword>Diabetes Mellitus/epidemiology/prevention &amp; control</keyword><keyword>Humans</keyword><keyword>Hypertension/complications/epidemiology/prevention &amp; control</keyword><keyword>*Life Style</keyword><keyword>Motor Activity</keyword><keyword>Obesity/complications/epidemiology/prevention &amp; control</keyword><keyword>Prevalence</keyword><keyword>Risk Factors</keyword><keyword>Smoking/adverse effects</keyword><keyword>Smoking Prevention</keyword></keywords><dates><year>2011</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1474-4465 (Electronic)&#xD;1474-4422 (Linking)</isbn><accession-num>21775213</accession-num><urls><related-urls><url>(11)70072-2</electronic-resource-num></record></Cite></EndNote>457. In this work, we have described clinical trials and strategies involving already approved drugs to alter specific pathways in the brain. Some of these studies have reported improvement in cognition of patients and have a solid molecular and biochemical background behind them. This evidence call for larger studies, more thorough stratification of cohorts, and in-depth research into the mechanisms behind the risk factors involved. Some of these pathways can tremendously increase the possibilities for treatment. For example, vascular dynamics in the brain are susceptible to regulation from an “out of the BBB” approach PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaW5rPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVj

TnVtPjI2MTE8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij40

NTg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yNjExPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzUzNTYzMjkiPjI2MTE8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNpbmssIEsuIE0uPC9hdXRob3I+PGF1dGhv

cj5MZW5nLCBYLjwvYXV0aG9yPjxhdXRob3I+V2lsbGlhbXNvbiwgSi48L2F1dGhvcj48YXV0aG9y

PktyaXRjaGV2c2t5LCBTLiBCLjwvYXV0aG9yPjxhdXRob3I+WWFmZmUsIEsuPC9hdXRob3I+PGF1

dGhvcj5LdWxsZXIsIEwuPC9hdXRob3I+PGF1dGhvcj5ZYXNhciwgUy48L2F1dGhvcj48YXV0aG9y

PkF0a2luc29uLCBILjwvYXV0aG9yPjxhdXRob3I+Um9iYmlucywgTS48L2F1dGhvcj48YXV0aG9y

PlBzYXR5LCBCLjwvYXV0aG9yPjxhdXRob3I+R29mZiwgRC4gQy4sIEpyLjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlN0aWNodCBDZW50ZXIgb24gQWdpbmcs

IFdha2UgRm9yZXN0IFVuaXZlcnNpdHksIFdpbnN0b24tU2FsZW0sIE5vcnRoIENhcm9saW5hIDI3

MTU3LCBVU0EuIGttc2lua0B3ZnVibWMuZWR1PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+

QW5naW90ZW5zaW4tY29udmVydGluZyBlbnp5bWUgaW5oaWJpdG9ycyBhbmQgY29nbml0aXZlIGRl

Y2xpbmUgaW4gb2xkZXIgYWR1bHRzIHdpdGggaHlwZXJ0ZW5zaW9uOiByZXN1bHRzIGZyb20gdGhl

IENhcmRpb3Zhc2N1bGFyIEhlYWx0aCBTdHVkeTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BcmNo

IEludGVybiBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTE5NS0yMDI8L3Bh

Z2VzPjx2b2x1bWU+MTY5PC92b2x1bWU+PG51bWJlcj4xMzwvbnVtYmVyPjxlZGl0aW9uPjIwMDkv

MDcvMTU8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+

QW5naW90ZW5zaW4tQ29udmVydGluZyBFbnp5bWUgSW5oaWJpdG9ycy9waGFybWFjb2tpbmV0aWNz

Lyp0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+Qmxvb2QtQnJhaW4gQmFycmllci9w

aHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbi8qZHJ1ZyBlZmZlY3RzPC9rZXl3

b3JkPjxrZXl3b3JkPkRlbWVudGlhL2VwaWRlbWlvbG9neS9ldGlvbG9neS8qcHJldmVudGlvbiAm

YW1wOyBjb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5G

b2xsb3ctVXAgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdv

cmQ+SHlwZXJ0ZW5zaW9uL2NvbXBsaWNhdGlvbnMvKmRydWcgdGhlcmFweS9tZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPkluY2lkZW5jZTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3Jk

PjxrZXl3b3JkPlByb3NwZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+UmlzayBGYWN0

b3JzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDk8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT5KdWwgMTM8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTM4LTM2Nzkg

KEVsZWN0cm9uaWMpJiN4RDswMDAzLTk5MjYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVt

PjE5NTk3MDY4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczov

L3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xOTU5NzA2ODwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48Y3VzdG9tMj5QTUMyODgxNjg2PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNl

LW51bT4xMC4xMDAxL2FyY2hpbnRlcm5tZWQuMjAwOS4xNzU8L2VsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaW5rPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVj

TnVtPjI2MTE8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij40

NTg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yNjExPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZndhMHJ4NTJwdzlhMnZlcDBw

aHBmd3g5enRzenpwcnB0NWF2IiB0aW1lc3RhbXA9IjE1MzUzNTYzMjkiPjI2MTE8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNpbmssIEsuIE0uPC9hdXRob3I+PGF1dGhv

cj5MZW5nLCBYLjwvYXV0aG9yPjxhdXRob3I+V2lsbGlhbXNvbiwgSi48L2F1dGhvcj48YXV0aG9y

PktyaXRjaGV2c2t5LCBTLiBCLjwvYXV0aG9yPjxhdXRob3I+WWFmZmUsIEsuPC9hdXRob3I+PGF1

dGhvcj5LdWxsZXIsIEwuPC9hdXRob3I+PGF1dGhvcj5ZYXNhciwgUy48L2F1dGhvcj48YXV0aG9y

PkF0a2luc29uLCBILjwvYXV0aG9yPjxhdXRob3I+Um9iYmlucywgTS48L2F1dGhvcj48YXV0aG9y

PlBzYXR5LCBCLjwvYXV0aG9yPjxhdXRob3I+R29mZiwgRC4gQy4sIEpyLjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlN0aWNodCBDZW50ZXIgb24gQWdpbmcs

IFdha2UgRm9yZXN0IFVuaXZlcnNpdHksIFdpbnN0b24tU2FsZW0sIE5vcnRoIENhcm9saW5hIDI3

MTU3LCBVU0EuIGttc2lua0B3ZnVibWMuZWR1PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+

QW5naW90ZW5zaW4tY29udmVydGluZyBlbnp5bWUgaW5oaWJpdG9ycyBhbmQgY29nbml0aXZlIGRl

Y2xpbmUgaW4gb2xkZXIgYWR1bHRzIHdpdGggaHlwZXJ0ZW5zaW9uOiByZXN1bHRzIGZyb20gdGhl

IENhcmRpb3Zhc2N1bGFyIEhlYWx0aCBTdHVkeTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BcmNo

IEludGVybiBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTE5NS0yMDI8L3Bh

Z2VzPjx2b2x1bWU+MTY5PC92b2x1bWU+PG51bWJlcj4xMzwvbnVtYmVyPjxlZGl0aW9uPjIwMDkv

MDcvMTU8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+

QW5naW90ZW5zaW4tQ29udmVydGluZyBFbnp5bWUgSW5oaWJpdG9ycy9waGFybWFjb2tpbmV0aWNz

Lyp0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+Qmxvb2QtQnJhaW4gQmFycmllci9w

aHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbi8qZHJ1ZyBlZmZlY3RzPC9rZXl3

b3JkPjxrZXl3b3JkPkRlbWVudGlhL2VwaWRlbWlvbG9neS9ldGlvbG9neS8qcHJldmVudGlvbiAm

YW1wOyBjb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5G

b2xsb3ctVXAgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdv

cmQ+SHlwZXJ0ZW5zaW9uL2NvbXBsaWNhdGlvbnMvKmRydWcgdGhlcmFweS9tZXRhYm9saXNtPC9r

ZXl3b3JkPjxrZXl3b3JkPkluY2lkZW5jZTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3Jk

PjxrZXl3b3JkPlByb3NwZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+UmlzayBGYWN0

b3JzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDk8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT5KdWwgMTM8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTM4LTM2Nzkg

KEVsZWN0cm9uaWMpJiN4RDswMDAzLTk5MjYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVt

PjE5NTk3MDY4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczov

L3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xOTU5NzA2ODwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48Y3VzdG9tMj5QTUMyODgxNjg2PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNl

LW51bT4xMC4xMDAxL2FyY2hpbnRlcm5tZWQuMjAwOS4xNzU8L2VsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA 458 and could improve parallel dysfunctions such as insulin/glucose availability or amyloid clearing consequently. As pointed out by leading experts in AD, researchers should learn from the previous experiences in therapeutics and keep developing knowledge about this disease. Only then, we will crystalize the possibility for treating AD in our lifetime. AcknowledgmentsFunded by European funds from FEDER, via Programa Operacional Factores de Competitividade – COMPETE 2020; by Portuguese funds from FCT - Funda??o para a Ciência e a Tecnologia (PTDC/SAU-TOX/117481/2010 and Strategic Project POCI-01-0145-FEDER-007440), and by European Social Fund (Fellowship SFRH/BPD/84473/2012 to A. I. Duarte).ACM, BW and RLV were financially supported by Margaretha af Ugglas foundation. ACM and RLV were also partially funded by Olle Enqvist Foundation grant no. 2014/778 and Lindhés Advokatbyr? Foundation.REFERENCES ADDIN EN.REFLIST 1.Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer's disease. Alzheimers Dement 2007;3:186-91.2.Brookmeyer R, Evans DA, Hebert L, et al. National estimates of the prevalence of Alzheimer's disease in the United States. Alzheimers Dement 2011;7:61-73.3.Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366:2112-7.4.Winblad B, Amouyel P, Andrieu S, et al. Defeating Alzheimer's disease and other dementias: a priority for European science and society. Lancet Neurol 2016;15:455-532.5.Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006;367:1747-57.6.Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 1997;278:1349-56.7.Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement 2013;9:63-75 e2.8.Wimo A, Guerchet M, Ali GC, et al. The worldwide costs of dementia 2015 and comparisons with 2010. Alzheimers Dement 2017;13:1-7.9.Prince M, Ali GC, Guerchet M, Prina AM, Albanese E, Wu YT. Recent global trends in the prevalence and incidence of dementia, and survival with dementia. Alzheimers Res Ther 2016;8:23.10.Wimo A, Jonsson L, Bond J, Prince M, Winblad B, Alzheimer Disease I. The worldwide economic impact of dementia 2010. Alzheimers Dement 2013;9:1-11 e3.11.Clark BF. Healthy human ageing. N Biotechnol 2008;25:13-5.12.Daskalopoulou C, Stubbs B, Kralj C, Koukounari A, Prince M, Prina AM. Associations of smoking and alcohol consumption with healthy ageing: a systematic review and meta-analysis of longitudinal studies. BMJ Open 2018;8:e019540.13.Schneider LS, Mangialasche F, Andreasen N, et al. Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014. J Intern Med 2014;275:251-83.14.Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M. Alzheimer's disease: clinical trials and drug development. Lancet Neurol 2010;9:702-16.15.Hardy JA, Higgins GA. Alzheimer's disease: the amyloid cascade hypothesis. Science 1992;256:184-5.16.Karran E, De Strooper B. The amyloid cascade hypothesis: are we poised for success or failure? J Neurochem 2016;139 Suppl 2:237-52.17.Novak P, Schmidt R, Kontsekova E, et al. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neurol 2017;16:123-34.18.Jobke B, McBride T, Nevin L, et al. Setbacks in Alzheimer research demand new strategies, not surrender. PLoS Med 2018;15:e1002518.19.Hardy J, De Strooper B. Alzheimer's disease: where next for anti-amyloid therapies? Brain 2017;140:853-5.20.Pugazhenthi S. Metabolic Syndrome and the Cellular Phase of Alzheimer's Disease. Prog Mol Biol Transl Sci 2017;146:243-58.21.De Strooper B, Karran E. The Cellular Phase of Alzheimer's Disease. Cell 2016;164:603-15.22.McGeer PL, McGeer EG. The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol 2013;126:479-97.23.Sarazin M, Dorothee G, de Souza LC, Aucouturier P. Immunotherapy in Alzheimer's disease: do we have all the pieces of the puzzle? Biol Psychiatry 2013;74:329-32.24.Loera-Valencia R, Piras A, Ismail MAM, et al. Targeting Alzheimer's disease with gene and cell therapies. J Intern Med 2018;284:2-36.25.Kemppainen N, Johansson J, Teuho J, et al. Brain amyloid load and its associations with cognition and vascular risk factors in FINGER Study. Neurology 2018;90:e206-e13.26.Worker A, Dima D, Combes A, et al. Test-retest reliability and longitudinal analysis of automated hippocampal subregion volumes in healthy ageing and Alzheimer's disease populations. Hum Brain Mapp 2018;39:1743-54.27.Fraser MA, Shaw ME, Cherbuin N. A systematic review and meta-analysis of longitudinal hippocampal atrophy in healthy human ageing. Neuroimage 2015;112:364-74.28.Vos SJB, Gordon BA, Su Y, et al. NIA-AA staging of preclinical Alzheimer disease: discordance and concordance of CSF and imaging biomarkers. Neurobiol Aging 2016;44:1-8.29.LaFerla FM, Troncoso JC, Strickland DK, Kawas CH, Jay G. Neuronal cell death in Alzheimer's disease correlates with apoE uptake and intracellular Abeta stabilization. J Clin Invest 1997;100:310-20.30.Cummings BJ, Cotman CW. Image analysis of beta-amyloid load in Alzheimer's disease and relation to dementia severity. Lancet 1995;346:1524-8.31.Kalaria RN, Cohen DL, Greenberg BD, et al. Abundance of the longer A beta 42 in neocortical and cerebrovascular amyloid beta deposits in Swedish familial Alzheimer's disease and Down's syndrome. Neuroreport 1996;7:1377-81.32.Mattsson N, Zetterberg H, Hansson O, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 2009;302:385-93.33.Eckman CB, Mehta ND, Crook R, et al. A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A beta 42(43). Hum Mol Genet 1997;6:2087-9.34.Sandebring A, Welander H, Winblad B, Graff C, Tjernberg LO. The pathogenic abeta43 is enriched in familial and sporadic Alzheimer disease. PLoS One 2013;8:e55847.35.Sturchler-Pierrat C, Abramowski D, Duke M, et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A 1997;94:13287-92.36.Holcomb L, Gordon MN, McGowan E, et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 1998;4:97-100.37.Games D, Adams D, Alessandrini R, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 1995;373:523-7.38.Oddo S, Caccamo A, Shepherd JD, et al. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 2003;39:409-21.39.Golde TE, Dickson D, Hutton M. Filling the gaps in the abeta cascade hypothesis of Alzheimer's disease. Curr Alzheimer Res 2006;3:421-30.40.Saito T, Matsuba Y, Yamazaki N, Hashimoto S, Saido TC. Calpain Activation in Alzheimer's Model Mice Is an Artifact of APP and Presenilin Overexpression. J Neurosci 2016;36:9933-6.41.Saito T, Matsuba Y, Mihira N, et al. Single App knock-in mouse models of Alzheimer's disease. Nat Neurosci 2014;17:661-3.42.Geula C, Nagykery N, Wu CK. Amyloid-beta deposits in the cerebral cortex of the aged common marmoset (Callithrix jacchus): incidence and chemical composition. Acta Neuropathol 2002;103:48-58.43.Sasaguri H, Nilsson P, Hashimoto S, et al. APP mouse models for Alzheimer's disease preclinical studies. EMBO J 2017;36:2473-87.44.Jones L, Holmans PA, Hamshere ML, et al. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. PLoS One 2010;5:e13950.45.Castellano JM, Kim J, Stewart FR, et al. Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med 2011;3:89ra57.46.Hardy J, Bogdanovic N, Winblad B, et al. Pathways to Alzheimer's disease. J Intern Med 2014;275:296-303.47.Hardy J. Alzheimer's disease: the amyloid cascade hypothesis: an update and reappraisal. J Alzheimers Dis 2006;9:151-3.48.Harold D, Abraham R, Hollingworth P, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet 2009;41:1088-93.49.Jones B. Alzheimer disease: TREM2 linked to late-onset AD. Nature reviews Neurology 2013;9:5.50.Forsberg A, Almkvist O, Engler H, Wall A, Langstrom B, Nordberg A. High PIB retention in Alzheimer's disease is an early event with complex relationship with CSF biomarkers and functional parameters. Curr Alzheimer Res 2010;7:56-66.51.Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol 2004;55:306-19.52.Rodriguez-Vieitez E, Saint-Aubert L, Carter SF, et al. Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease. Brain 2016;139:922-36.53.Aisen PS, Petersen RC, Donohue M, Weiner MW, Alzheimer's Disease Neuroimaging I. Alzheimer's Disease Neuroimaging Initiative 2 Clinical Core: Progress and plans. Alzheimers Dement 2015;11:734-9.54.Aisen PS, Petersen RC, Donohue MC, et al. Clinical Core of the Alzheimer's Disease Neuroimaging Initiative: progress and plans. Alzheimers Dement 2010;6:239-46.55.Jack CR, Jr., Bennett DA, Blennow K, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement 2018;14:535-62.56.Forsberg A, Engler H, Almkvist O, et al. PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol Aging 2008;29:1456-65.57.Budd Haeberlein S, O'Gorman J, Chiao P, et al. Clinical Development of Aducanumab, an Anti-Abeta Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer's Disease. J Prev Alzheimers Dis 2017;4:255-63.58.Honig LS, Vellas B, Woodward M, et al. Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease. N Engl J Med 2018;378:321-30.59.Egan MF, Kost J, Tariot PN, et al. Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease. N Engl J Med 2018;378:1691-703.60.Gulisano W, Maugeri D, Baltrons MA, et al. Role of Amyloid-beta and Tau Proteins in Alzheimer's Disease: Confuting the Amyloid Cascade. J Alzheimers Dis 2018;64:S611-S31.61.Gold M. Phase II clinical trials of anti-amyloid beta antibodies: When is enough, enough? Alzheimers Dement (N Y) 2017;3:402-9.62.Wisniewski T. Active immunotherapy for Alzheimer's disease. Lancet Neurol 2012;11:571-2.63.Dodel RC, Hampel H, Du Y. Immunotherapy for Alzheimer's disease. Lancet Neurol 2003;2:215-20.64.Sigurdsson EM, Scholtzova H, Mehta PD, Frangione B, Wisniewski T. Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer's disease-associated pathology in transgenic mice. Am J Pathol 2001;159:439-47.65.Morgan D. Immunotherapy for Alzheimer's disease. J Intern Med 2011;269:54-63.66.Novak P, Schmidt R, Kontsekova E, et al. FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer's disease. Alzheimers Res Ther 2018;10:108.67.Logovinsky V, Satlin A, Lai R, et al. Safety and tolerability of BAN2401--a clinical study in Alzheimer's disease with a protofibril selective Abeta antibody. Alzheimers Res Ther 2016;8:14.68.Bard F, Barbour R, Cannon C, et al. Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer's disease-like neuropathology. Proc Natl Acad Sci U S A 2003;100:2023-8.69.Lemere CA. Immunotherapy for Alzheimer's disease: hoops and hurdles. Mol Neurodegener 2013;8:36.70.Panza F, Frisardi V, Imbimbo BP, Seripa D, Solfrizzi V, Pilotto A. Monoclonal antibodies against beta-amyloid (Abeta) for the treatment of Alzheimer's disease: the Abeta target at a crossroads. Expert Opin Biol Ther 2011;11:679-86.71.Pfeifer M, Boncristiano S, Bondolfi L, et al. Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science 2002;298:1379.72.Crane A, Brubaker WD, Johansson JU, et al. Peripheral complement interactions with amyloid beta peptide in Alzheimer's disease: 2. Relationship to amyloid beta immunotherapy. Alzheimers Dement 2018;14:243-52.73.Cehlar O, Skrabana R, Revajova V, Novak M. Structural aspects of Alzheimer's disease immunotherapy targeted against amyloid-beta peptide. Bratisl Lek Listy 2018;119:201-4.74.Lannfelt L, Moller C, Basun H, et al. Perspectives on future Alzheimer therapies: amyloid-beta protofibrils - a new target for immunotherapy with BAN2401 in Alzheimer's disease. Alzheimers Res Ther 2014;6:16.75.Bittar A, Sengupta U, Kayed R. Prospects for strain-specific immunotherapy in Alzheimer's disease and tauopathies. NPJ Vaccines 2018;3:9.76.Wilcock DM, Rojiani A, Rosenthal A, et al. Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflammation 2004;1:24.77.Vandenberghe R, Riviere ME, Caputo A, et al. Active Abeta immunotherapy CAD106 in Alzheimer's disease: A phase 2b study. Alzheimers Dement (N Y) 2017;3:10-22.ogozo JM, Gilman S, Dartigues JF, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 2003;61:46-54.79.Morgan D. Modulation of microglial activation state following passive immunization in amyloid depositing transgenic mice. Neurochem Int 2006;49:190-4.80.Lemere CA, Masliah E. Can Alzheimer disease be prevented by amyloid-beta immunotherapy? Nat Rev Neurol 2010;6:108-19.81.Farlow MR, Andreasen N, Riviere ME, et al. Long-term treatment with active Abeta immunotherapy with CAD106 in mild Alzheimer's disease. Alzheimers Res Ther 2015;7:23.82.Winblad B, Andreasen N, Minthon L, et al. Safety, tolerability, and antibody response of active Abeta immunotherapy with CAD106 in patients with Alzheimer's disease: randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol 2012;11:597-604.83.Winblad B, Graf A, Riviere ME, Andreasen N, Ryan JM. Active immunotherapy options for Alzheimer's disease. Alzheimers Res Ther 2014;6:7.84.Menendez-Gonzalez M, Perez-Pinera P, Martinez-Rivera M, Muniz AL, Vega JA. Immunotherapy for Alzheimer's disease: rational basis in ongoing clinical trials. Curr Pharm Des 2011;17:508-20.85.Wiessner C, Wiederhold KH, Tissot AC, et al. The second-generation active Abeta immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects. J Neurosci 2011;31:9323-31.86.Sevigny J, Chiao P, Bussiere T, et al. The antibody aducanumab reduces Abeta plaques in Alzheimer's disease. Nature 2016;537:50-6.87.Sevigny J, Chiao P, Bussiere T, et al. Addendum: The antibody aducanumab reduces Abeta plaques in Alzheimer's disease. Nature 2017;546:564.88.Piazza F. Reader response: A phase 3 trial of IV immunoglobulin for Alzheimer disease. Neurology 2018;90:144-5.89.Relkin NR, Thomas RG, Rissman RA, et al. A phase 3 trial of IV immunoglobulin for Alzheimer disease. Neurology 2017;88:1768-75.90.BioArctic announces positive topline results of BAN2401 Phase 2b at 18 months in early Alzheimer’s Disease. BioArctic, 2018. (Accessed July 6, 2018, 2018, at .)91.Nilsson P, Loganathan K, Sekiguchi M, et al. Abeta secretion and plaque formation depend on autophagy. Cell Rep 2013;5:61-9.92.Caspersen C, Wang N, Yao J, et al. Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease. FASEB J 2005;19:2040-1.93.Sanchez-Pulido L, Devos D, Valencia A. BRICHOS: a conserved domain in proteins associated with dementia, respiratory distress and cancer. Trends Biochem Sci 2002;27:329-32.94.Hermansson E, Schultz S, Crowther D, et al. The chaperone domain BRICHOS prevents CNS toxicity of amyloid-beta peptide in Drosophila melanogaster. Dis Model Mech 2014;7:659-65.95.Kim J, Chakrabarty P, Hanna A, et al. Normal cognition in transgenic BRI2-Abeta mice. Mol Neurodegener 2013;8:15.96.Willander H, Askarieh G, Landreh M, et al. High-resolution structure of a BRICHOS domain and its implications for anti-amyloid chaperone activity on lung surfactant protein C. Proc Natl Acad Sci U S A 2012;109:2325-9.97.Walther FJ, Hernandez-Juviel JM, Waring AJ. Aerosol delivery of synthetic lung surfactant. PeerJ 2014;2:e403.98.Leinenga G, Gotz J. Scanning ultrasound removes amyloid-beta and restores memory in an Alzheimer's disease mouse model. Sci Transl Med 2015;7:278ra33.99.Bray N. Biologics: Transferrin' bispecific antibodies across the blood-brain barrier. Nat Rev Drug Discov 2015;14:14-5.100.Friden PM, Walus LR, Musso GF, Taylor MA, Malfroy B, Starzyk RM. Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood-brain barrier. Proc Natl Acad Sci U S A 1991;88:4771-5.101.Okun I, Tkachenko SE, Khvat A, Mitkin O, Kazey V, Ivachtchenko AV. From anti-allergic to anti-Alzheimer's: Molecular pharmacology of Dimebon. Curr Alzheimer Res 2010;7:97-112.102.Doody RS, Gavrilova SI, Sano M, et al. Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study. Lancet 2008;372:207-15.103.Grigorev VV, Dranyi OA, Bachurin SO. Comparative study of action mechanisms of dimebon and memantine on AMPA- and NMDA-subtypes glutamate receptors in rat cerebral neurons. Bull Exp Biol Med 2003;136:474-7.104.DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 2001;98:8850-5.105.He Z, Guo JL, McBride JD, et al. Amyloid-beta plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med 2018;24:29-38.106.Ando K, Brion JP, Stygelbout V, et al. Clathrin adaptor CALM/PICALM is associated with neurofibrillary tangles and is cleaved in Alzheimer's brains. Acta Neuropathol 2013;125:861-78.107.Chapuis J, Hansmannel F, Gistelinck M, et al. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. Mol Psychiatry 2013;18:1225-34.108.Dourlen P, Fernandez-Gomez FJ, Dupont C, et al. Functional screening of Alzheimer risk loci identifies PTK2B as an in vivo modulator and early marker of Tau pathology. Mol Psychiatry 2017;22:874-83.109.Moreau K, Fleming A, Imarisio S, et al. PICALM modulates autophagy activity and tau accumulation. Nat Commun 2014;5:4998.110.Goedert M, Spillantini MG, Cairns NJ, Crowther RA. Tau proteins of alzheimer paired helical filaments: Abnormal phosphorylation of all six brain isoforms. Neuron 1992;8:159-68.111.Tolnay M, Sergeant N, Ghestem A, et al. Argyrophilic grain disease and Alzheimer's disease are distinguished by their different distribution of tau protein isoforms. Acta Neuropathol 2002;104:425-34.112.Hof PR, Delacourte A, Bouras C. Distribution of cortical neurofibrillary tangles in progressive supranuclear palsy: A quantitative analysis of six cases. Acta Neuropathologica 1992;84:45-51.113.Hof PR, Knabe R, Bovier P, Bouras C. Neuropathological observations in a case of autism presenting with self-injury behavior. Acta Neuropathologica 1991;82:321-6.114.Schmidt ML, Zhukareva V, Newell KL, Lee VM, Trojanowski JQ. Tau isoform profile and phosphorylation state in dementia pugilistica recapitulate Alzheimer's disease. Acta Neuropathol 2001;101:518-24.115.Buée-Scherrer V, Buée L, Leveugle B, et al. Pathological τ proteins in postencephalitic parkinsonism: Comparison with Alzheimer's disease and other neurodegenerative disorders. Annals of Neurology 1997;42:356-9.116.Ikeda K, Akiyama H, Kondo H, et al. Thorn-shaped astrocytes: possibly secondarily induced tau-positive glial fibrillary tangles. Acta Neuropathol 1995;90:620-5.117.Caparros E. [Avant-propos]. Revue générale de droit 2002;32:205.118.Caparros-Lefebvre D, Golbe LI, Deramecourt V, et al. A geographical cluster of progressive supranuclear palsy in northern France. Neurology 2015;85:1293-300.119.Buée-Scherrer V, Buée L, Hof PR, et al. Tau Variants in Aging and Neurodegenerative Disorders. Alzheimer’s Disease: Lessons from Cell Biology: Springer Berlin Heidelberg; 1995:132-49.120.Buée-Scherrer V, Hof PR, Buée L, et al. Hyperphosphorylated tau proteins differentiate corticobasal degeneration and Pick's disease. Acta Neuropathologica 1996;91:351-9.121.Mailliot C, Sergeant N, Bussière T, Caillet-Boudin M-L, Delacourte A, Buée L. Phosphorylation of specific sets of tau isoforms reflects different neurofibrillary degeneration processes. FEBS Letters 1998;433:201-4.122.Delacourte A, Robitaille Y, Sergeant N, et al. Specific Pathological Tau Protein Variants Characterize Pick?s Disease. Journal of Neuropathology and Experimental Neurology 1996;55:159-68.123.Delacourte A, Sergeant N, Wattez A, Gauvreau D, Robitaille Y. Vulnerable neuronal subsets in Alzheimer's and Pick's disease are distinguished by their ? isoform distribution and phosphorylation. Annals of Neurology 1998;43:193-204.124.Love S, Bridges LR, Case CP. Neurofibrillary tangles in Niemann—Pick disease type C. Brain 1995;118:119-29.125.Spillantini MG, Tolnay M, Love S, Goedert M. Microtubule-associated protein tau, heparan sulphate and alpha-synuclein in several neurodegenerative diseases with dementia. Acta Neuropathol 1999;97:585-94.126.Sergeant N, Sablonniere B, Schraen-Maschke S, et al. Dysregulation of human brain microtubule-associated tau mRNA maturation in myotonic dystrophy type 1. Hum Mol Genet 2001;10:2143-55.127.Vermersch P, Sergeant N, Ruchoux MM, et al. Specific tau variants in the brains of patients with myotonic dystrophy. Neurology 1996;47:711-7.128.Goedert M, Ghetti B, Spillantini MG. Frontotemporal dementia: implications for understanding Alzheimer disease. Cold Spring Harb Perspect Med 2012;2:a006254.129.Smith PY, Delay C, Girard J, et al. MicroRNA-132 loss is associated with tau exon 10 inclusion in progressive supranuclear palsy. Hum Mol Genet 2011;20:4016-24.130.Baker M, Litvan I, Houlden H, et al. Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet 1999;8:711-5.131.Jucker M, Walker LC. Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann Neurol 2011;70:532-40.132.Kuchibhotla KV, Wegmann S, Kopeikina KJ, et al. Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo. Proc Natl Acad Sci U S A 2014;111:510-4.133.Ahmed T, Van der Jeugd A, Blum D, et al. Cognition and hippocampal synaptic plasticity in mice with a homozygous tau deletion. Neurobiol Aging 2014;35:2474-8.134.Santacruz K, Lewis J, Spires T, et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 2005;309:476-81.135.Sydow A, Van der Jeugd A, Zheng F, et al. Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic Tau mutant. J Neurosci 2011;31:2511-25.136.Pooler AM, Usardi A, Evans CJ, Philpott KL, Noble W, Hanger DP. Dynamic association of tau with neuronal membranes is regulated by phosphorylation. Neurobiol Aging 2012;33:431 e27-38.137.Marciniak E, Leboucher A, Caron E, et al. Tau deletion promotes brain insulin resistance. J Exp Med 2017;214:2257-69.138.Frost B, Hemberg M, Lewis J, Feany MB. Tau promotes neurodegeneration through global chromatin relaxation. Nat Neurosci 2014;17:357-66.139.Reynolds CH, Garwood CJ, Wray S, et al. Phosphorylation regulates tau interactions with Src homology 3 domains of phosphatidylinositol 3-kinase, phospholipase Cgamma1, Grb2, and Src family kinases. J Biol Chem 2008;283:18177-86.140.Ittner LM, Ke YD, Delerue F, et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell 2010;142:387-97.141.Braak H, Braak E. Development of Alzheimer-related neurofibrillary changes in the neocortex inversely recapitulates cortical myelogenesis. Acta Neuropathologica 1996;92:197-201.142.Scheff SW, Price DA, Schmitt FA, Mufson EJ. Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment. Neurobiol Aging 2006;27:1372-84.143.Klein WL. Synaptic targeting by Aβ oligomers (ADDLS) as a basis for memory loss in early Alzheimer’s disease. Alzheimer's & Dementia 2006;2:43-55.144.Lacor PN, Buniel MC, Furlow PW, et al. A? Oligomer-Induced Aberrations in Synapse Composition, Shape, and Density Provide a Molecular Basis for Loss of Connectivity in Alzheimer's Disease. Journal of Neuroscience 2007;27:796-807.145.Wang H-W, Pasternak JF, Kuo H, et al. Soluble oligomers of β amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Research 2002;924:133-40.146.Blazquez E, Velazquez E, Hurtado-Carneiro V, Ruiz-Albusac JM. Insulin in the brain: its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer's disease. Front Endocrinol (Lausanne) 2014;5:161.147.Dyer AH, Vahdatpour C, Sanfeliu A, Tropea D. The role of Insulin-Like Growth Factor 1 (IGF-1) in brain development, maturation and neuroplasticity. Neuroscience 2016;325:89-99.148.Rodriguez-Rodriguez P, Sandebring-Matton A, Merino-Serrais P, et al. Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons. Brain 2017;140:3269-85.149.Esteves?da?Silva M, Adrian M, Sch?tzle P, et al. Positioning of AMPA Receptor-Containing Endosomes Regulates Synapse Architecture. Cell Reports 2015;13:933-43.150.Angelo M, Plattner F, Giese KP. Cyclin-dependent kinase 5 in synaptic plasticity, learning and memory. Journal of Neurochemistry 2006;99:353-70.151.Brami-Cherrier K, Roze E, Girault J-A, Betuing S, Caboche J. Role of the ERK/MSK1 signalling pathway in chromatin remodelling and brain responses to drugs of abuse. Journal of Neurochemistry 2009;108:1323-35.152.Leshchyns’ka I, Sytnyk V. Synaptic Cell Adhesion Molecules in Alzheimer’s Disease. Neural Plasticity 2016;2016:1-9.153.Eyjolfsdottir H, Eriksdotter M, Linderoth B, et al. Targeted delivery of nerve growth factor to the cholinergic basal forebrain of Alzheimer's disease patients: application of a second-generation encapsulated cell biodelivery device. Alzheimers Res Ther 2016;8:30.154.Bothwell M. NGF, BDNF, NT3, and NT4. Neurotrophic Factors: Springer Berlin Heidelberg; 2014:3-15.155.Miyamoto A, Wake H, Ishikawa AW, et al. Microglia contact induces synapse formation in developing somatosensory cortex. Nature Communications 2016;7:12540.156.Haraguchi S, Sasahara K, Shikimi H, Honda S-i, Harada N, Tsutsui K. Estradiol Promotes Purkinje Dendritic Growth, Spinogenesis, and Synaptogenesis During Neonatal Life by Inducing the Expression of BDNF. The Cerebellum 2011;11:416-7.157.Dave KA, Platel J-C, Huang F, Tian D, Stamboulian-Platel S, Bordey A. Prostaglandin E2 induces glutamate release from subventricular zone astrocytes. Neuron Glia Biology 2010;6:201-7.158.Batti L, O'Connor JJ. Tumor necrosis factor-α impairs the recovery of synaptic transmission from hypoxia in rat hippocampal slices. Journal of Neuroimmunology 2010;218:21-7.159.Dupont C, Armant D, Brenner C. Epigenetics: Definition, Mechanisms and Clinical Perspective. Seminars in Reproductive Medicine 2009;27:351-7.160.Rogers J, Mastroeni D, Grover A, Delvaux E, Whiteside C, Coleman PD. The epigenetics of Alzheimer's disease — additional considerations. Neurobiology of Aging 2011;32:1196-7.161.Neal M, Richardson JR. Epigenetic regulation of astrocyte function in neuroinflammation and neurodegeneration. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2018;1864:432-43.162.Feligioni M, Nisticò R. SUMO: a (Oxidative) Stressed Protein. NeuroMolecular Medicine 2013;15:707-19.163.Li T, Santockyte R, Shen R-F, et al. Expression of SUMO-2/3 Induced Senescence through p53- and pRB-mediated Pathways. Journal of Biological Chemistry 2006;281:36221-7.164.Fiore R, Khudayberdiev S, Saba R, Schratt G. MicroRNA Function in the Nervous System. Progress in Molecular Biology and Translational Science: Elsevier; 2011:47-100.165.Putteeraj M, Fairuz YM, Teoh SL. MicroRNA Dysregulation in Alzheimer's Disease. CNS & Neurological Disorders - Drug Targets 2018;16.166.Goedeke L, Fernández-Hernando C. microRNAs: A connection between cholesterol metabolism and neurodegeneration. Neurobiology of Disease 2014;72:48-53.167.Heneka MT, Carson MJ, Khoury JE, et al. Neuroinflammation in Alzheimer's disease. The Lancet Neurology 2015;14:388-405.168.Obermeier B, Verma A, Ransohoff RM. The blood–brain barrier. Handbook of Clinical Neurology: Elsevier; 2016:39-59.169.Daneman R, Prat A. The Blood–Brain Barrier. Cold Spring Harbor Perspectives in Biology 2015;7:a020412.170.Sweeney MD, Ayyadurai S, Zlokovic BV. Pericytes of the neurovascular unit: key functions and signaling pathways. Nature Neuroscience 2016;19:771-83.171.Cheslow L, Alvarez JI. Glial-endothelial crosstalk regulates blood–brain barrier function. Current Opinion in Pharmacology 2016;26:39-46.172.Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV. Establishment and Dysfunction of the Blood-Brain Barrier. Cell 2015;163:1064-78.173.Mahringer A, Fricker G. ABC transporters at the blood–brain barrier. Expert Opinion on Drug Metabolism & Toxicology 2016;12:499-508.174.Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nature Reviews Neuroscience 2011;12:723-38.175.Vanlandewijck M, He L, Mae MA, et al. A molecular atlas of cell types and zonation in the brain vasculature. Nature 2018;554:475-80.176.Erd? F, Denes L, de Lange E. Age-associated physiological and pathological changes at the blood–brain barrier: A review. Journal of Cerebral Blood Flow & Metabolism 2016;37:4-24.177.Montagne A, Nation DA, Pa J, Sweeney MD, Toga AW, Zlokovic BV. Brain imaging of neurovascular dysfunction in Alzheimer’s disease. Acta Neuropathologica 2016;131:687-707.178.van de Haar HJ, Burgmans S, Jansen JFA, et al. Blood-Brain Barrier Leakage in Patients with Early Alzheimer Disease. Radiology 2016;281:527-35.179.Sweeney MD, Sagare AP, Zlokovic BV. Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nature Reviews Neurology 2018;14:133-50.180.Poliakova T, Levin O, Arablinskiy A, Vasenina E, Zerr I. Cerebral microbleeds in early Alzheimer’s disease. Journal of Neurology 2016;263:1961-8.181.Deo AK, Borson S, Link JM, et al. Activity of P-Glycoprotein, a ?-Amyloid Transporter at the Blood-Brain Barrier, Is Compromised in Patients with Mild Alzheimer Disease. Journal of Nuclear Medicine 2014;55:1106-11.182.Bailey TL, Rivara CB, Rocher AB, Hof PR. The nature and effects of cortical microvascular pathology in aging and Alzheimer's disease. Neurological Research 2004;26:573-8.183.Lepelletier FX, Mann DMA, Robinson AC, Pinteaux E, Boutin H. Early changes in extracellular matrix in Alzheimer's disease. Neuropathology and Applied Neurobiology 2015;43:167-82.184.Halliday MR, Rege SV, Ma Q, et al. Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease. Journal of Cerebral Blood Flow & Metabolism 2015;36:216-27.185.Nelson AR, Sweeney MD, Sagare AP, Zlokovic BV. Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2016;1862:887-900.186.Rogers J, Luber-Narod J, Styren SD, Civin WH. Expression of immune system-associated antigens by cells of the human central nervous system: Relationship to the pathology of Alzheimer's disease. Neurobiology of Aging 1988;9:339-49.187.Togo T, Akiyama H, Iseki E, et al. Occurrence of T cells in the brain of Alzheimer's disease and other neurological diseases. Journal of Neuroimmunology 2002;124:83-92.188.Mietelska-Porowska A, Wojda U. T Lymphocytes and Inflammatory Mediators in the Interplay between Brain and Blood in Alzheimer’s Disease: Potential Pools of New Biomarkers. Journal of Immunology Research 2017;2017:1-17.189.Baruch K, Schwartz M. CNS-specific T cells shape brain function via the choroid plexus. Brain, Behavior, and Immunity 2013;34:11-6.190.Lueg G, Gross CC, Lohmann H, et al. Clinical relevance of specific T-cell activation in the blood and cerebrospinal fluid of patients with mild Alzheimer's disease. Neurobiology of Aging 2015;36:81-9.191.McManus RM, Mills KHG, Lynch MA. T Cells—Protective or Pathogenic in Alzheimer’s Disease? Journal of Neuroimmune Pharmacology 2015;10:547-60.192.Bryson KJ, Lynch MA. Linking T cells to Alzheimer's disease: from neurodegeneration to neurorepair. Current Opinion in Pharmacology 2016;26:67-73.193.Schenk D. Amyloid-β immunotherapy for Alzheimer's disease: the end of the beginning. Nature Reviews Neuroscience 2002;3:824-8.194.Laurent C, Dorothée G, Hunot S, et al. Hippocampal T cell infiltration promotes neuroinflammation and cognitive decline in a mouse model of tauopathy. Brain 2016;140:184-200.195.Xing X, Sha S, Li Y, Zong L, Jiang T, Cao Y. Immunization with a new DNA vaccine for Alzheimer's disease elicited Th2 immune response in BALB/c mice by in vivo electroporation. Journal of the Neurological Sciences 2012;313:17-21.196.Simard AR, Soulet D, Gowing G, Julien J-P, Rivest S. Bone Marrow-Derived Microglia Play a Critical Role in Restricting Senile Plaque Formation in Alzheimer's Disease. Neuron 2006;49:489-502.197.Fisher Y, Nemirovsky A, Baron R, Monsonego A. T Cells Specifically Targeted to Amyloid Plaques Enhance Plaque Clearance in a Mouse Model of Alzheimer's Disease. PLoS ONE 2010;5:e10830.198.Dansokho C, Ait Ahmed D, Aid S, et al. Regulatory T cells delay disease progression in Alzheimer-like pathology. Brain 2016;139:1237-51.199.Paouri E, Tzara O, Kartalou G-I, Zenelak S, Georgopoulos S. Peripheral Tumor Necrosis Factor-Alpha (TNF-α) Modulates Amyloid Pathology by Regulating Blood-Derived Immune Cells and Glial Response in the Brain of AD/TNF Transgenic Mice. The Journal of Neuroscience 2017;37:5155-71.200.Middeldorp J, Lehallier B, Villeda SA, et al. Preclinical Assessment of Young Blood Plasma for Alzheimer Disease. JAMA Neurology 2016;73:1325.201.Bu XL, Xiang Y, Jin WS, et al. Blood-derived amyloid-β protein induces Alzheimer’s disease pathologies. Molecular Psychiatry 2017.202.Walker KA, Hoogeveen RC, Folsom AR, et al. Midlife systemic inflammatory markers are associated with late-life brain volume. Neurology 2017;89:2262-70.203.Bagyinszky E, Giau VV, Shim K, Suk K, An SSA, Kim S. Role of inflammatory molecules in the Alzheimer's disease progression and diagnosis. Journal of the Neurological Sciences 2017;376:242-54.204.Krauthausen M, Kummer MP, Zimmermann J, et al. CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer’s disease model. Journal of Clinical Investigation 2014;125:365-78.205.Torres KCL, Santos RR, de Lima GSF, et al. Decreased Expression of CCL3 in Monocytes and CCR5 in Lymphocytes From Frontotemporal Dementia as Compared With Alzheimer’s Disease Patients. The Journal of Neuropsychiatry and Clinical Neurosciences 2012;24:E11-E2.206.Zhu M, Allard JS, Zhang Y, et al. Age-Related Brain Expression and Regulation of the Chemokine CCL4/MIP-1β in APP/PS1 Double-Transgenic Mice. Journal of Neuropathology & Experimental Neurology 2014;73:362-74.207.Franciosi S, Choi HB, Kim SU, McLarnon JG. IL-8 enhancement of amyloid-beta (Aβ1-42)-induced expression and production of pro-inflammatory cytokines and COX-2 in cultured human microglia. Journal of Neuroimmunology 2005;159:66-74.208.Fuhrmann M, Bittner T, Jung CKE, et al. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease. Nature Neuroscience 2010;13:411-3.209.Tripathy D, Thirumangalakudi L, Grammas P. RANTES upregulation in the Alzheimer's disease brain: A possible neuroprotective role. Neurobiology of Aging 2010;31:8-16.210.Lee JK, Schuchman EH, Jin HK, Bae J-S. Soluble CCL5 Derived from Bone Marrow-Derived Mesenchymal Stem Cells and Activated by Amyloid β Ameliorates Alzheimer's Disease in Mice by Recruiting Bone Marrow-Induced Microglia Immune Responses. STEM CELLS 2012;30:1544-55.211.Naert G, Rivest S. CC Chemokine Receptor 2 Deficiency Aggravates Cognitive Impairments and Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease. Journal of Neuroscience 2011;31:6208-20.212.Kiyota T, Yamamoto M, Xiong H, et al. CCL2 Accelerates Microglia-Mediated Aβ Oligomer Formation and Progression of Neurocognitive Dysfunction. PLoS ONE 2009;4:e6197.213.Yamamoto M, Horiba M, Buescher JL, et al. Overexpression of Monocyte Chemotactic Protein-1/CCL2 in β-Amyloid Precursor Protein Transgenic Mice Show Accelerated Diffuse β-Amyloid Deposition. The American Journal of Pathology 2005;166:1475-85.214.Verite J, Janet T, Julian A, Chassaing D, Page G, Paccalin M. Peripheral Blood Mononuclear Cells of Alzheimer's Disease Patients Control CCL4 and CXCL10 Levels in a Human Blood Brain Barrier Model. Current Alzheimer Research 2017;14.215.Verite J, Janet T, Chassaing D, Fauconneau B, Rabeony H, Page G. Longitudinal chemokine profile expression in a blood-brain barrier model from Alzheimer transgenic versus wild-type mice. J Neuroinflammation 2018;15:182.216.Gorelick PB, Scuteri A, Black SE, et al. Vascular Contributions to Cognitive Impairment and Dementia: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2011;42:2672-713.217.Maillard P, Seshadri S, Beiser A, et al. Effects of systolic blood pressure on white-matter integrity in young adults in the Framingham Heart Study: a cross-sectional study. The Lancet Neurology 2012;11:1039-47.218.Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol 2013;12:483-97.219.Yoshino H, Sakurai T, Oizumi XS, et al. Dilation of perforating arteries in rat brain in response to systemic hypotension is more sensitive and pronounced than that of pial arterioles: simultaneous visualization of perforating and cortical vessels by in-vivo microangiography. Microvasc Res 2009;77:230-3.220.Hainsworth AH, Markus HS. Do in vivo Experimental Models Reflect Human Cerebral Small Vessel Disease? a Systematic Review. Journal of Cerebral Blood Flow & Metabolism 2008;28:1877-91.221.Schreiber S, Bueche CZ, Garz C, et al. Kidney pathology precedes and predicts the pathological cascade of cerebrovascular lesions in stroke prone rats. PLoS One 2011;6:e26287.222.Schreiber S, Bueche CZ, Garz C, et al. The pathologic cascade of cerebrovascular lesions in SHRSP: is erythrocyte accumulation an early phase? J Cereb Blood Flow Metab 2012;32:278-90.223.Bailey EL, Wardlaw JM, Graham D, Dominiczak AF, Sudlow CLM, Smith C. Cerebral small vessel endothelial structural changes predate hypertension in stroke-prone spontaneously hypertensive rats: a blinded, controlled immunohistochemical study of 5- to 21-week-old rats. Neuropathology and Applied Neurobiology 2011;37:711-26.224.Kaiser D, Weise G, M?ller K, et al. Spontaneous white matter damage, cognitive decline and neuroinflammation in middle-aged hypertensive rats: an animal model of early-stage cerebral small vessel disease. Acta Neuropathologica Communications 2014;2.225.Ennaceur A, Delacour J. A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behavioural Brain Research 1988;31:47-59.226.den Heijer T, Launer LJ, Prins ND, et al. Association between blood pressure, white matter lesions, and atrophy of the medial temporal lobe. Neurology 2005;64:263-7.227.Sabbatini M, Catalani A, Consoli C, Marletta N, Tomassoni D, Avola R. The hippocampus in spontaneously hypertensive rats: an animal model of vascular dementia? Mech Ageing Dev 2002;123:547-59.228.Leeuw FE, Kleine M, Frijns CJM, Fijnheer R, Gijn J, Kappelle LJ. Endothelial Cell Activation Is Associated with Cerebral White Matter Lesions in Patients with Cerebrovascular Disease. Annals of the New York Academy of Sciences 2002;977:306-14.229.Schiffrin EL. Immune mechanisms in hypertension and vascular injury. Clin Sci (Lond) 2014;126:267-74.230.Moller K, Posel C, Kranz A, et al. Arterial Hypertension Aggravates Innate Immune Responses after Experimental Stroke. Front Cell Neurosci 2015;9:461.231.Tummala PE, Chen XL, Sundell CL, et al. Angiotensin II induces vascular cell adhesion molecule-1 expression in rat vasculature: A potential link between the renin-angiotensin system and atherosclerosis. Circulation 1999;100:1223-9.232.Rouhl RP, Damoiseaux JG, Lodder J, et al. Vascular inflammation in cerebral small vessel disease. Neurobiol Aging 2012;33:1800-6.233.Harrison DG, Marvar PJ, Titze JM. Vascular Inflammatory Cells in Hypertension. Frontiers in Physiology 2012;3.234.Derecki NC, Cardani AN, Yang CH, et al. Regulation of learning and memory by meningeal immunity: a key role for IL-4. The Journal of Experimental Medicine 2010;207:1067-80.235.van Weel V, Toes RE, Seghers L, et al. Natural killer cells and CD4+ T-cells modulate collateral artery development. Arterioscler Thromb Vasc Biol 2007;27:2310-8.236.Rosenberg A, Ngandu T, Rusanen M, et al. Multidomain lifestyle intervention benefits a large elderly population at risk for cognitive decline and dementia regardless of baseline characteristics: The FINGER trial. Alzheimers Dement 2018;14:263-70.237.Martinez-Ramirez S, Greenberg SM, Viswanathan A. Cerebral microbleeds: overview and implications in cognitive impairment. Alzheimers Res Ther 2014;6:33.238.Ding J, Sigur?sson S, Jónsson PV, et al. Space and location of cerebral microbleeds, cognitive decline, and dementia in the community. Neurology 2017;88:2089-97.239.Matsuyama H, Ii Y, Maeda M, et al. Background and distribution of lobar microbleeds in cognitive dysfunction. Brain Behav 2017;7:e00856.240.Hilal S, Akoudad S, van Duijn CM, et al. Plasma Amyloid-β Levels, Cerebral Small Vessel Disease, and Cognition: The Rotterdam Study. Journal of Alzheimer's Disease 2017;60:977-87.241.Stehling C, Wersching H, Kloska SP, et al. Detection of asymptomatic cerebral microbleeds: a comparative study at 1.5 and 3.0 T. Acad Radiol 2008;15:895-900.242.Vernooij MW, van der Lugt A, Ikram MA, et al. Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurology 2008;70:1208-14.243.Kumar P, Yadav AK, Misra S, Kumar A, Chakravarty K, Prasad K. Prediction of upper extremity motor recovery after subacute intracerebral hemorrhage through diffusion tensor imaging: a systematic review and meta-analysis. Neuroradiology 2016;58:1043-50.244.Karuppagounder SS, Alim I, Khim SJ, et al. Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models. Science Translational Medicine 2016;8:328ra29-ra29.245.Zille M, Karuppagounder SS, Chen Y, et al. Neuronal Death After Hemorrhagic Stroke In Vitro and In Vivo Shares Features of Ferroptosis and Necroptosis. Stroke 2017;48:1033-43.246.Raff MC, Whitmore AV, Finn JT. Axonal self-destruction and neurodegeneration. Science 2002;296:868-71.247.Sagot Y, Dubois-Dauphin M, Tan SA, et al. Bcl-2 overexpression prevents motoneuron cell body loss but not axonal degeneration in a mouse model of a neurodegenerative disease. J Neurosci 1995;15:7727-33.248.Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 2009;457:981-9.249.Heppner FL, Ransohoff RM, Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci 2015;16:358-72.250.Zotova E, Nicoll JA, Kalaria R, Holmes C, Boche D. Inflammation in Alzheimer's disease: relevance to pathogenesis and therapy. Alzheimers Res Ther 2010;2:1.251.Sommer F, Backhed F. The gut microbiota--masters of host development and physiology. Nat Rev Microbiol 2013;11:227-38.252.Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012;489:242-9.253.Claesson MJ, Jeffery IB, Conde S, et al. Gut microbiota composition correlates with diet and health in the elderly. Nature 2012;488:178-84.254.Mulak A, Bonaz B. Brain-gut-microbiota axis in Parkinson's disease. World J Gastroenterol 2015;21:10609-20.255.Miyake S, Kim S, Suda W, et al. Dysbiosis in the Gut Microbiota of Patients with Multiple Sclerosis, with a Striking Depletion of Species Belonging to Clostridia XIVa and IV Clusters. PLoS One 2015;10:e0137429.256.D'Mello C, Ronaghan N, Zaheer R, et al. Probiotics Improve Inflammation-Associated Sickness Behavior by Altering Communication between the Peripheral Immune System and the Brain. J Neurosci 2015;35:10821-30.257.Naseribafrouei A, Hestad K, Avershina E, et al. Correlation between the human fecal microbiota and depression. Neurogastroenterol Motil 2014;26:1155-62.258.Kang DW, Park JG, Ilhan ZE, et al. Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS One 2013;8:e68322.259.De Angelis M, Piccolo M, Vannini L, et al. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS One 2013;8:e76993.260.Soscia SJ, Kirby JE, Washicosky KJ, et al. The Alzheimer's disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One 2010;5:e9505.261.Kumar DK, Choi SH, Washicosky KJ, et al. Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer's disease. Sci Transl Med 2016;8:340ra72.262.Pisa D, Alonso R, Rabano A, Rodal I, Carrasco L. Different Brain Regions are Infected with Fungi in Alzheimer's Disease. Sci Rep 2015;5:15015.263.Harach T, Marungruang N, Duthilleul N, et al. Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep 2017;7:41802.264.Cattaneo A, Cattane N, Galluzzi S, et al. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol Aging 2017;49:60-8.265.Kamer AR, Craig RG, Dasanayake AP, Brys M, Glodzik-Sobanska L, de Leon MJ. Inflammation and Alzheimer's disease: possible role of periodontal diseases. Alzheimers Dement 2008;4:242-50.266.Franzosa EA, Huang K, Meadow JF, et al. Identifying personal microbiomes using metagenomic codes. Proc Natl Acad Sci U S A 2015;112:E2930-8.267.Akbari E, Asemi Z, Daneshvar Kakhaki R, et al. Effect of Probiotic Supplementation on Cognitive Function and Metabolic Status in Alzheimer's Disease: A Randomized, Double-Blind and Controlled Trial. Front Aging Neurosci 2016;8:256.268.Jarosz-Griffiths HH, Noble E, Rushworth JV, Hooper NM. Amyloid-β Receptors: The Good, the Bad, and the Prion Protein. Journal of Biological Chemistry 2015;291:3174-83.269.Miklossy J, Qing H, Radenovic A, et al. Beta amyloid and hyperphosphorylated tau deposits in the pancreas in type 2 diabetes. Neurobiology of Aging 2010;31:1503-15.270.Roher AE, Cribbs DH, Kim RC, et al. Bapineuzumab alters abeta composition: implications for the amyloid cascade hypothesis and anti-amyloid immunotherapy. PloS one 2013;8:e59735.271.Yang Y, Wu Y, Zhang S, Song W. High Glucose Promotes Aβ Production by Inhibiting APP Degradation. PLoS ONE 2013;8:e69824.272.Takeda S, Sato N, Uchio-Yamada K, et al. Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Abeta deposition in an Alzheimer mouse model with diabetes. Proc Natl Acad Sci U S A 2010;107:7036-41.273.Bharadwaj P, Solomon T, Malajczuk CJ, et al. Role of the cell membrane interface in modulating production and uptake of Alzheimer's beta amyloid protein. Biochimica et biophysica acta 2018.274.Balczon R. The identification, purification, and characterization of a pancreatic beta-cell form of the microtubule adenosine triphosphatase kinesin. Endocrinology 1992;131:331-6.275.Alvim RO, Cheuhen MR, Machado SR, Sousa AGP, Santos PCJL. General aspects of muscle glucose uptake. Anais da Academia Brasileira de Ciências 2015;87:351-68.276.Emoto M, Langille SE, Czech MP. A Role for Kinesin in Insulin-stimulated GLUT4 Glucose Transporter Translocation in 3T3-L1 Adipocytes. Journal of Biological Chemistry 2001;276:10677-82.277.Olson AL, Trumbly AR, Gibson GV. Insulin-mediated GLUT4 Translocation Is Dependent on the Microtubule Network. Journal of Biological Chemistry 2001;276:10706-14.278.Porte D, Baskin DG, Schwartz MW. Insulin Signaling in the Central Nervous System: A Critical Role in Metabolic Homeostasis and Disease From C. elegans to Humans. Diabetes 2005;54:1264-76.279.Yin F, Yao J, Sancheti H, et al. The perimenopausal aging transition in the female rat brain: decline in bioenergetic systems and synaptic plasticity. Neurobiology of Aging 2015;36:2282-95.280.Moreira PI, Santos MS, Sena C, Seica R, Oliveira CR. Insulin protects against amyloid beta-peptide toxicity in brain mitochondria of diabetic rats. Neurobiol Dis 2005;18:628-37.281.Duarte AI, Proenca T, Oliveira CR, Santos MS, Rego AC. Insulin Restores Metabolic Function in Cultured Cortical Neurons Subjected to Oxidative Stress. Diabetes 2006;55:2863-70.282.Santos RX, Correia SC, Alves MG, et al. Insulin therapy modulates mitochondrial dynamics and biogenesis, autophagy and tau protein phosphorylation in the brain of type 1 diabetic rats. Biochim Biophys Acta 2014;1842:1154-66.283.Duarte AI, Santos MS, Oliveira CR, Rego AC. Insulin neuroprotection against oxidative stress in cortical neurons--involvement of uric acid and glutathione antioxidant defenses. Free Radic Biol Med 2005;39:876-89.284.Duarte AI, Santos P, Oliveira CR, Santos MS, Rego AC. Insulin neuroprotection against oxidative stress is mediated by Akt and GSK-3beta signaling pathways and changes in protein expression. Biochim Biophys Acta 2008;1783:994-1002.285.Duarte AI, Santos MS, Seica R, Oliveira CR. Oxidative Stress Affects Synaptosomal ?-Aminobutyric Acid and Glutamate Transport in Diabetic Rats: The Role of Insulin. Diabetes 2004;53:2110-6.286.Duarte AI, Santos MS, Sei?a R, Oliveira CRd. Insulin affects synaptosomal GABA and glutamate transport under oxidative stress conditions. Brain Research 2003;977:23-30.287.De Felice FG, Benedict C. A Key Role of Insulin Receptors in Memory: Figure 1. Diabetes 2015;64:3653-5.288.Rodriguez-Rodriguez P, Sandebring-Matton A, Merino-Serrais P, et al. Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons. Brain 2017;140:3269-85.289.Kullmann S, Heni M, Hallschmid M, Fritsche A, Preissl H, H?ring H-U. Brain Insulin Resistance at the Crossroads of Metabolic and Cognitive Disorders in Humans. Physiological Reviews 2016;96:1169-209.290.Zhao L, Mao Z, Woody SK, Brinton RD. Sex differences in metabolic aging of the brain: insights into female susceptibility to Alzheimer's disease. Neurobiology of Aging 2016;42:69-79.291.Brinton RD, Yao J, Yin F, Mack WJ, Cadenas E. Perimenopause as a neurological transition state. Nature Reviews Endocrinology 2015;11:393-405.292.Swerdlow RH, Burns JM, Khan SM. The Alzheimer's disease mitochondrial cascade hypothesis: Progress and perspectives. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2014;1842:1219-31.293.Kandimalla R, Thirumala V, Reddy PH. Is Alzheimer's disease a Type 3 Diabetes? A critical appraisal. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2017;1863:1078-89.294.Winblad B, Qiu C, Ballard C, Johansson G. Evidence-based prevention and treatment of dementia – Authors' reply. The Lancet Neurology 2016;15:1007-8.295.Pearson-Leary J, Jahagirdar V, Sage J, McNay EC. Insulin modulates hippocampally-mediated spatial working memory via glucose transporter-4. Behavioural Brain Research 2018;338:32-9.296.Winkler EA, Nishida Y, Sagare AP, et al. GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration. Nature Neuroscience 2015;18:521-30.297.Kapogiannis D, Mattson MP. Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease. The Lancet Neurology 2011;10:187-98.298.Cunnane S, Nugent S, Roy M, et al. Brain fuel metabolism, aging, and Alzheimer's disease. Nutrition 2011;27:3-20.299.Calkins MJ, Manczak M, Mao P, Shirendeb U, Reddy PH. Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease. Hum Mol Genet 2011;20:4515-29.300.Bubber P, Haroutunian V, Fisch G, Blass JP, Gibson GE. Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann Neurol 2005;57:695-703.301.Melo JB, Agostinho P, Oliveira CR. Amyloid beta-peptide 25-35 reduces [3H]acetylcholine release in retinal neurons. Involvement of metabolic dysfunction. Amyloid 2002;9:221-8.302.Onyango IG, Dennis J, Khan SM. Mitochondrial Dysfunction in Alzheimer's Disease and the Rationale for Bioenergetics Based Therapies. Aging Dis 2016;7:201-14.303.Yao J, Zhao L, Mao Z, et al. Potentiation of brain mitochondrial function by S-equol and R/S-equol estrogen receptor beta-selective phytoSERM treatments. Brain Res 2013;1514:128-41.304.Fang D, Wang Y, Zhang Z, et al. Increased neuronal PreP activity reduces Abeta accumulation, attenuates neuroinflammation and improves mitochondrial and synaptic function in Alzheimer disease's mouse model. Hum Mol Genet 2015;24:5198-210.305.Yao J, Irwin R, Chen S, Hamilton R, Cadenas E, Brinton RD. Ovarian hormone loss induces bioenergetic deficits and mitochondrial beta-amyloid. Neurobiol Aging 2012;33:1507-21.306.Mosconi L, de Leon M, Murray J, et al. Reduced mitochondria cytochrome oxidase activity in adult children of mothers with Alzheimer's disease. J Alzheimers Dis 2011;27:483-90.307.Swerdlow RH. Mitochondria and cell bioenergetics: increasingly recognized components and a possible etiologic cause of Alzheimer's disease. Antioxid Redox Signal 2012;16:1434-55.308.Yu Q, Du F, Douglas JT, Yu H, Yan SS, Yan SF. Mitochondrial Dysfunction Triggers Synaptic Deficits via Activation of p38 MAP Kinase Signaling in Differentiated Alzheimer's Disease Trans-Mitochondrial Cybrid Cells. J Alzheimers Dis 2017;59:223-39.309.Amorim JA, Canas PM, Tome AR, et al. Mitochondria in Excitatory and Inhibitory Synapses have Similar Susceptibility to Amyloid-beta Peptides Modeling Alzheimer's Disease. J Alzheimers Dis 2017;60:525-36.310.Fang D, Yan S, Yu Q, Chen D, Yan SS. Mfn2 is Required for Mitochondrial Development and Synapse Formation in Human Induced Pluripotent Stem Cells/hiPSC Derived Cortical Neurons. Sci Rep 2016;6:31462.311.Gan X, Huang S, Wu L, et al. Inhibition of ERK-DLP1 signaling and mitochondrial division alleviates mitochondrial dysfunction in Alzheimer's disease cybrid cell. Biochim Biophys Acta 2014;1842:220-31.312.Du H, Guo L, Yan S, Sosunov AA, McKhann GM, Yan SS. Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model. Proc Natl Acad Sci U S A 2010;107:18670-5.313.Tortelli R, Lozupone M, Guerra V, et al. Midlife Metabolic Profile and the Risk of Late-Life Cognitive Decline. J Alzheimers Dis 2017;59:121-30.314.Mosconi L, Murray J, Tsui WH, et al. Brain imaging of cognitively normal individuals with 2 parents affected by late-onset AD. Neurology 2014;82:752-60.315.Verdile G, Fuller SJ, Martins RN. The role of type 2 diabetes in neurodegeneration. Neurobiol Dis 2015;84:22-38.316.Verdile G, Laws SM, Henley D, et al. Associations between gonadotropins, testosterone and beta amyloid in men at risk of Alzheimer's disease. Mol Psychiatry 2014;19:69-75.317.Duarte AI, Santos MS, Oliveira CR, Moreira PI. Brain insulin signalling, glucose metabolism and females' reproductive aging: A dangerous triad in Alzheimer's disease. Neuropharmacology 2018;136:223-42.318.Ankarcrona M, Winblad B, Monteiro C, et al. Current and future treatment of amyloid diseases. J Intern Med 2016;280:177-202.319.Wisniewski T, Goni F. Immunotherapeutic approaches for Alzheimer's disease. Neuron 2015;85:1162-76.320.Medina M, Avila J. Glycogen synthase kinase-3 (GSK-3) inhibitors for the treatment of Alzheimer's disease. Curr Pharm Des 2010;16:2790-8.321.Medina M, Avila J. New perspectives on the role of tau in Alzheimer's disease. Implications for therapy. Biochem Pharmacol 2014;88:540-7.322.Shaikh S, Rizvi SM, Shakil S, Riyaz S, Biswas D, Jahan R. Forxiga (dapagliflozin): Plausible role in the treatment of diabetes-associated neurological disorders. Biotechnol Appl Biochem 2016;63:145-50.323.Corbett A, Ballard C. Is a potential Alzheimer's therapy already in use for other conditions? Can medications for hypertension, diabetes and acne help with the symptoms? Expert Opin Investig Drugs 2013;22:941-3.324.Sandhir R, Gupta S. Molecular and biochemical trajectories from diabetes to Alzheimer's disease: A critical appraisal. World J Diabetes 2015;6:1223-42.325.Sebastiao I, Candeias E, Santos MS, de Oliveira CR, Moreira PI, Duarte AI. Insulin as a Bridge between Type 2 Diabetes and Alzheimer Disease - How Anti-Diabetics Could be a Solution for Dementia. Front Endocrinol (Lausanne) 2014;5:110.326.Ahmed S, Mahmood Z, Javed A, et al. Effect of Metformin on Adult Hippocampal Neurogenesis: Comparison with Donepezil and Links to Cognition. Journal of Molecular Neuroscience 2017;62:88-98.327.Li J, Deng J, Sheng W, Zuo Z. Metformin attenuates Alzheimer's disease-like neuropathology in obese, leptin-resistant mice. Pharmacology Biochemistry and Behavior 2012;101:564-74.328.Carvalho C, Correia S, Santos MS, Sei?a R, Oliveira CR, Moreira PI. Metformin promotes isolated rat liver mitochondria impairment. Molecular and Cellular Biochemistry 2007;308:75-83.329.Hsu CC, Wahlqvist ML, Lee MS, Tsai HN. Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. J Alzheimers Dis 2011;24:485-93.330.Cai Z, Ratka A. Opioid System and Alzheimer’s Disease. NeuroMolecular Medicine 2012;14:91-111.331.Moore EM, Mander AG, Ames D, et al. Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care 2013;36:2981-7.332.Kickstein E, Krauss S, Thornhill P, et al. Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proc Natl Acad Sci U S A 2010;107:21830-5.333.Tahrani AA, Barnett AH, Bailey CJ. Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus. Nat Rev Endocrinol 2016;12:566-92.334.Carvalho C, Correia S, Santos MS, Seica R, Oliveira CR, Moreira PI. Metformin promotes isolated rat liver mitochondria impairment. Mol Cell Biochem 2008;308:75-83.335.Cignarelli A, Giorgino F, Vettor R. Pharmacologic agents for type 2 diabetes therapy and regulation of adipogenesis. Arch Physiol Biochem 2013;119:139-50.336.Exalto LG, Whitmer RA, Kappele LJ, Biessels GJ. An update on type 2 diabetes, vascular dementia and Alzheimer's disease. Exp Gerontol 2012;47:858-64.337.Gradman TJ, Laws A, Thompson LW, Reaven GM. Verbal learning and/or memory improves with glycemic control in older subjects with non-insulin-dependent diabetes mellitus. J Am Geriatr Soc 1993;41:1305-12.338.Osborne C, West E, Nolan W, McHale-Owen H, Williams A, Bate C. Glimepiride protects neurons against amyloid-beta-induced synapse damage. Neuropharmacology 2016;101:225-36.339.Khanfar MA, AbuKhader MM, Alqtaishat S, Taha MO. Pharmacophore modeling, homology modeling, and in silico screening reveal mammalian target of rapamycin inhibitory activities for sotalol, glyburide, metipranolol, sulfamethizole, glipizide, and pioglitazone. J Mol Graph Model 2013;42:39-49.340.Lamkanfi M, Mueller JL, Vitari AC, et al. Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. J Cell Biol 2009;187:61-70.341.Imfeld P, Bodmer M, Jick SS, Meier CR. Metformin, Other Antidiabetic Drugs, and Risk of Alzheimer's Disease: A Population-Based Case-Control Study. Journal of the American Geriatrics Society 2012;60:916-21.342.Gavin JR, 3rd, Stolar MW, Freeman JS, Spellman CW. Improving outcomes in patients with type 2 diabetes mellitus: practical solutions for clinical challenges. J Am Osteopath Assoc 2010;110:S2-14; quiz S5-6.343.Tureyen K, Kapadia R, Bowen KK, et al. Peroxisome proliferator-activated receptor-gamma agonists induce neuroprotection following transient focal ischemia in normotensive, normoglycemic as well as hypertensive and type-2 diabetic rodents. J Neurochem 2007;101:41-56.344.Peymani M, Ghoochani A, Ghaedi K, et al. Dual effects of peroxisome proliferator-activated receptor γ on embryonic stem cell self-renewal in presence and absence of leukemia inhibitory factor. European Journal of Cell Biology 2013;92:160-8.345.Risner ME, Saunders AM, Altman JFB, et al. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. The Pharmacogenomics Journal 2006;6:246-54.346.Gold M, Alderton C, Zvartau-Hind M, et al. Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord 2010;30:131-46.347.Morsink LM, Smits MM, Diamant M. Advances in Pharmacologic Therapies for Type 2 Diabetes. Current Atherosclerosis Reports 2013;15.348.Craft S. Insulin and Alzheimer Disease—Reply. Archives of Neurology 2012;69:670.349.Naia L, Ferreira IL, Cunha-Oliveira T, et al. Activation of IGF-1 and Insulin Signaling Pathways Ameliorate Mitochondrial Function and Energy Metabolism in Huntington’s Disease Human Lymphoblasts. Molecular Neurobiology 2014;51:331-48.350.Naia L, Ribeiro M, Rodrigues J, et al. Insulin and IGF-1 regularize energy metabolites in neural cells expressing full-length mutant huntingtin. Neuropeptides 2016;58:73-81.351.Lopes C, Ribeiro M, Duarte AI, et al. IGF-1 Intranasal Administration Rescues Huntington's Disease Phenotypes in YAC128 Mice. Molecular Neurobiology 2013;49:1126-42.352.Duarte AI, Petit GH, Ranganathan S, et al. IGF-1 protects against diabetic features in an in vivo model of Huntington's disease. Experimental Neurology 2011;231:314-9.353.Pandini G, Pace V, Copani A, Squatrito S, Milardi D, Vigneri R. Insulin Has Multiple Antiamyloidogenic Effects on Human Neuronal Cells. Endocrinology 2013;154:375-87.354.De Felice FG, Lourenco MV, Ferreira ST. How does brain insulin resistance develop in Alzheimer's disease? Alzheimers Dement 2014;10:S26-32.355.De Felice FG, Vieira MN, Bomfim TR, et al. Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci U S A 2009;106:1971-6.356.Cardoso S, Santos RX, Correia SC, et al. Insulin-induced recurrent hypoglycemia exacerbates diabetic brain mitochondrial dysfunction and oxidative imbalance. Neurobiol Dis 2013;49:1-12.357.Cardoso S, Carvalho C, Santos R, et al. Impact of STZ-induced hyperglycemia and insulin-induced hypoglycemia in plasma amino acids and cortical synaptosomal neurotransmitters. Synapse 2010;65:457-66.358.Maimaiti S, Frazier HN, Anderson KL, et al. Novel calcium-related targets of insulin in hippocampal neurons. Neuroscience 2017;364:130-42.359.Craft S, Claxton A, Baker LD, et al. Effects of Regular and Long-Acting Insulin on Cognition and Alzheimer's Disease Biomarkers: A Pilot Clinical Trial. J Alzheimers Dis 2017;57:1325-34.360.Reger MA, Watson GS, Green PS, et al. Intranasal insulin improves cognition and modulates ?-amyloid in early AD. Neurology 2007;70:440-8.361.Ghasemi R, Dargahi L, Haeri A, Moosavi M, Mohamed Z, Ahmadiani A. Brain Insulin Dysregulation: Implication for Neurological and Neuropsychiatric Disorders. Molecular Neurobiology 2013;47:1045-65.362.Candeias EM. Gut-brain connection: The neuroprotective effects of the anti-diabetic drug liraglutide. World Journal of Diabetes 2015;6:807.363.Stolar MW, Grimm M, Chen S. Comparison of extended release GLP-1 receptor agonist therapy versus sitagliptin in the management of type 2 diabetes. Diabetes Metab Syndr Obes 2013;6:435-44.364.Montanya E. A comparison of currently available GLP-1 receptor agonists for the treatment of type 2 diabetes. Expert Opinion on Pharmacotherapy 2012;13:1451-67.365.Hamilton A, Patterson S, Porter D, Gault VA, Holscher C. Novel GLP-1 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain. Journal of Neuroscience Research 2011;89:481-9.366.D'Amico M, Di Filippo C, Marfella R, et al. Corrigendum to “LONG-TERM inhibition of dipeptidyl peptidase-4 in Alzheimer's prone mice” [Exp. Gerontol. (2010) 202–207]. Experimental Gerontology 2013;48:1002.367.Beeri MS, Schmeidler J, Silverman JM, et al. Insulin in combination with other diabetes medication is associated with less Alzheimer neuropathology. Neurology 2008;71:750-7.368.Pintana H, Apaijai N, Chattipakorn N, Chattipakorn SC. DPP-4 inhibitors improve cognition and brain mitochondrial function of insulin-resistant rats. Journal of Endocrinology 2013;218:1-11.369.Darsalia V, Klein T, Nystrom T, Patrone C. Glucagon-like receptor 1 agonists and DPP-4 inhibitors: Anti-diabetic drugs with anti-stroke potential. Neuropharmacology 2018;136:280-6.370.Kosaraju J, Murthy V, Khatwal RB, et al. Vildagliptin: an anti-diabetes agent ameliorates cognitive deficits and pathology observed in streptozotocin-induced Alzheimer's disease. Journal of Pharmacy and Pharmacology 2013;65:1773-84.371.Bae C, Song J. The Role of Glucagon-Like Peptide 1 (GLP1) in Type 3 Diabetes: GLP-1 Controls Insulin Resistance, Neuroinflammation and Neurogenesis in the Brain. International Journal of Molecular Sciences 2017;18:2493.372.Li Z, Ni C-L, Yao Z, Chen L-M, Niu W-Y. Liraglutide enhances glucose transporter 4 translocation via regulation of AMP-activated protein kinase signaling pathways in mouse skeletal muscle cells. Metabolism 2014;63:1022-30.373.Li Y, Li L, Holscher C. Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases. Rev Neurosci 2016;27:689-711.374.Muscogiuri G, DeFronzo RA, Gastaldelli A, Holst JJ. Glucagon-like Peptide-1 and the Central/Peripheral Nervous System: Crosstalk in Diabetes. Trends Endocrinol Metab 2017;28:88-103.375.Majewski C, Bakris GL. Blood Pressure Reduction: An Added Benefit of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes: Table 1. Diabetes Care 2015;38:429-30.376.Solini A. Extra-glycaemic properties of empagliflozin. Diabetes/Metabolism Research and Reviews 2015;32:230-7.377.Cai HY, Wang ZJ, Holscher C, et al. Lixisenatide attenuates the detrimental effects of amyloid beta protein on spatial working memory and hippocampal neurons in rats. Behav Brain Res 2017;318:28-35.378.Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 2014;124:499-508.379.Solini A. Extra-glycaemic properties of empagliflozin. Diabetes Metab Res Rev 2016;32:230-7.380.Vickers SP, Cheetham SC, Headland KR, et al. Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body-weight reduction and glucose homeostasis of obese rats fed a cafeteria diet. Diabetes Metab Syndr Obes 2014;7:265-75.381.Chilton R, Tikkanen I, Crowe S, et al. Empagliflozin Reduces Systolic Blood Pressure in Dipper and Non-Dipper Patients with Type 2 Diabetes and Hypertension. Am Heart Assoc; 2014.382.Tikkanen I, Chilton R, Johansen OE. Potential role of sodium glucose cotransporter 2 inhibitors in the treatment of hypertension. Current Opinion in Nephrology and Hypertension 2016;25:81-6.383.Ott C, Jumar A, Striepe K, et al. A randomised study of the impact of the SGLT2 inhibitor dapagliflozin on microvascular and macrovascular circulation. Cardiovasc Diabetol 2017;16:26.384.Lin B, Koibuchi N, Hasegawa Y, et al. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol 2014;13:148.385.Millar P, Pathak N, Parthsarathy V, et al. Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice. J Endocrinol 2017;234:255-67.386.Di Paolo G, Kim TW. Linking lipids to Alzheimer's disease: cholesterol and beyond. Nat Rev Neurosci 2011;12:284-96.387.Karasinska JM, Hayden MR. Cholesterol metabolism in Huntington disease. Nat Rev Neurol 2011;7:561-72.388.Zissimopoulos JM, Barthold D, Brinton RD, Joyce G. Sex and Race Differences in the Association Between Statin Use and the Incidence of Alzheimer Disease. JAMA Neurol 2017;74:225-32.389.Petek B, Villa-Lopez M, Loera-Valencia R, et al. Connecting the brain cholesterol and renin-angiotensin systems: potential role of statins and RAS-modifying medications in dementia. J Intern Med 2018;284:620-42.390.Bjorkhem I, Meaney S. Brain cholesterol: long secret life behind a barrier. Arterioscler Thromb Vasc Biol 2004;24:806-15.391.Lund EG, Guileyardo JM, Russell DW. cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain. Proc Natl Acad Sci U S A 1999;96:7238-43.392.Bjorkhem I, Diczfalusy U. 24(S),25-epoxycholesterol--a potential friend. Arterioscler Thromb Vasc Biol 2004;24:2209-10.393.Sodero AO, Trovo L, Iannilli F, Van Veldhoven P, Dotti CG, Martin MG. Regulation of tyrosine kinase B activity by the Cyp46/cholesterol loss pathway in mature hippocampal neurons: relevance for neuronal survival under stress and in aging. J Neurochem 2011;116:747-55.394.Lutjohann D, Breuer O, Ahlborg G, et al. Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation. Proceedings of the National Academy of Sciences of the United States of America 1996;93:9799-804.395.Burlot MA, Braudeau J, Michaelsen-Preusse K, et al. Cholesterol 24-hydroxylase defect is implicated in memory impairments associated with Alzheimer-like Tau pathology. Hum Mol Genet 2015;24:5965-76.396.Djelti F, Braudeau J, Hudry E, et al. CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer's disease. Brain 2015;138:2383-98.397.Hudry E, Van Dam D, Kulik W, et al. Adeno-associated virus gene therapy with cholesterol 24-hydroxylase reduces the amyloid pathology before or after the onset of amyloid plaques in mouse models of Alzheimer's disease. Mol Ther 2010;18:44-53.398.Boussicault L, Alves S, Lamaziere A, et al. CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntington's disease. Brain 2016;139:953-70.399.Piguet F, Alves S, Cartier N. Clinical Gene Therapy for Neurodegenerative Diseases: Past, Present, and Future. Hum Gene Ther 2017;28:988-1003.400.Kivipelto M, Rovio S, Ngandu T, et al. Apolipoprotein E epsilon4 magnifies lifestyle risks for dementia: a population-based study. J Cell Mol Med 2008;12:2762-71.401.Marengoni A, Rizzuto D, Fratiglioni L, et al. The Effect of a 2-Year Intervention Consisting of Diet, Physical Exercise, Cognitive Training, and Monitoring of Vascular Risk on Chronic Morbidity-the FINGER Randomized Controlled Trial. J Am Med Dir Assoc 2018;19:355-60 e1.402.Ngandu T, Lehtisalo J, Solomon A, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet 2015;385:2255-63.403.Medina M, Khachaturian ZS, Rossor M, Avila J, Cedazo-Minguez A. Toward common mechanisms for risk factors in Alzheimer's syndrome. Alzheimers Dement (N Y) 2017;3:571-8.404.Kivipelto M, Mangialasche F. Alzheimer disease: To what extent can Alzheimer disease be prevented? Nat Rev Neurol 2014;10:552-3.405.Solomon A, Akenine U, Andreasen N, et al. Practical lessons from amyloid immunotherapy trials in Alzheimer disease. Curr Alzheimer Res 2012;9:1126-34.406.Jucker M. The benefits and limitations of animal models for translational research in neurodegenerative diseases. Nat Med 2010;16:1210-4.407.Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7:280-92.408.Vellas B, Carrillo MC, Sampaio C, et al. Designing drug trials for Alzheimer's disease: what we have learned from the release of the phase III antibody trials: a report from the EU/US/CTAD Task Force. Alzheimers Dement 2013;9:438-44.409.Vellas B, Andrieu S, Sampaio C, Wilcock G, European Task Force g. Disease-modifying trials in Alzheimer's disease: a European task force consensus. Lancet Neurol 2007;6:56-62.410.Orth M, Bellosta S. Cholesterol: its regulation and role in central nervous system disorders. Cholesterol 2012;2012:292598.411.Cedazo-Minguez A, Ismail MA, Mateos L. Plasma cholesterol and risk for late-onset Alzheimer's disease. Expert Rev Neurother 2011;11:495-8.412.Kivipelto M, Ngandu T, Fratiglioni L, et al. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol 2005;62:1556-60.413.Kivipelto M, Helkala EL, Laakso MP, et al. Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med 2002;137:149-55.414.Cedazo-Minguez A, Cowburn RF. Apolipoprotein E: a major piece in the Alzheimer's disease puzzle. J Cell Mol Med 2001;5:254-66.415.Bjorkhem I, Cedazo-Minguez A, Leoni V, Meaney S. Oxysterols and neurodegenerative diseases. Mol Aspects Med 2009;30:171-9.416.Bjorkhem I. Crossing the barrier: oxysterols as cholesterol transporters and metabolic modulators in the brain. J Intern Med 2006;260:493-508.417.Lutjohann D, Bjorkhem I, Locatelli S, et al. Cholesterol dynamics in the foetal and neonatal brain as reflected by circulatory levels of 24S-hydroxycholesterol. Acta Paediatr 2001;90:652-7.418.Meaney S, Hassan M, Sakinis A, et al. Evidence that the major oxysterols in human circulation originate from distinct pools of cholesterol: a stable isotope study. J Lipid Res 2001;42:70-8.419.Meaney S, Lutjohann D, Diczfalusy U, Bjorkhem I. Formation of oxysterols from different pools of cholesterol as studied by stable isotope technique: cerebral origin of most circulating 24S-hydroxycholesterol in rats, but not in mice. Biochimica et biophysica acta 2000;1486:293-8.420.Vaya J, Schipper HM. Oxysterols, cholesterol homeostasis, and Alzheimer disease. J Neurochem 2007;102:1727-37.421.Lathe R, Sapronova A, Kotelevtsev Y. Atherosclerosis and Alzheimer--diseases with a common cause? Inflammation, oxysterols, vasculature. BMC Geriatr 2014;14:36.422.Marwarha G, Rhen T, Schommer T, Ghribi O. The oxysterol 27-hydroxycholesterol regulates alpha-synuclein and tyrosine hydroxylase expression levels in human neuroblastoma cells through modulation of liver X receptors and estrogen receptors--relevance to Parkinson's disease. J Neurochem 2011;119:1119-36.423.Bjorkhem I, Lovgren-Sandblom A, Leoni V, et al. Oxysterols and Parkinson's disease: evidence that levels of 24S-hydroxycholesterol in cerebrospinal fluid correlates with the duration of the disease. Neurosci Lett 2013;555:102-5.424.Teunissen CE, Dijkstra C, Polman C. Biological markers in CSF and blood for axonal degeneration in multiple sclerosis. Lancet Neurol 2005;4:32-41.425.Baek AE, Yu YA, He S, et al. The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells. Nat Commun 2017;8:864.426.Siam A, Brancale A, Simons C. Comparative modeling of 25-hydroxycholesterol-7alpha-hydroxylase (CYP7B1): ligand binding and analysis of hereditary spastic paraplegia type 5 CYP7B1 mutations. J Mol Model 2012;18:441-53.427.Schols L, Rattay TW, Martus P, et al. Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial. Brain 2017;140:3112-27.428.Ismail MA, Mateos L, Maioli S, et al. 27-Hydroxycholesterol impairs neuronal glucose uptake through an IRAP/GLUT4 system dysregulation. J Exp Med 2017;214:699-717.429.Mateos L, Akterin S, Gil-Bea FJ, et al. Activity-regulated cytoskeleton-associated protein in rodent brain is down-regulated by high fat diet in vivo and by 27-hydroxycholesterol in vitro. Brain Pathol 2009;19:69-80.430.Heverin M, Maioli S, Pham T, et al. 27-hydroxycholesterol mediates negative effects of dietary cholesterol on cognition in mice. Behav Brain Res 2015;278:356-9.431.Mateos L, Ismail M-A-M, Gil-Bea F-J, et al. Side Chain-oxidized Oxysterols Regulate the Brain Renin-Angiotensin System through a Liver X Receptor-dependent Mechanism. Journal of Biological Chemistry 2011;286:25574-85.432.Mateos L, Ismail MA, Gil-Bea FJ, et al. Upregulation of brain renin angiotensin system by 27-hydroxycholesterol in Alzheimer's disease. J Alzheimers Dis 2011;24:669-79.433.Meir K, Kitsberg D, Alkalay I, et al. Human sterol 27-hydroxylase (CYP27) overexpressor transgenic mouse model. Evidence against 27-hydroxycholesterol as a critical regulator of cholesterol homeostasis. J Biol Chem 2002;277:34036-41.434.Albiston AL, McDowall SG, Matsacos D, et al. Evidence that the angiotensin IV (AT(4)) receptor is the enzyme insulin-regulated aminopeptidase. J Biol Chem 2001;276:48623-6.435.Spolcova A, Mikulaskova B, Krskova K, et al. Deficient hippocampal insulin signaling and augmented Tau phosphorylation is related to obesity- and age-induced peripheral insulin resistance: a study in Zucker rats. BMC Neurosci 2014;15:111.436.Marwarha G, Dasari B, Prasanthi JR, Schommer J, Ghribi O. Leptin reduces the accumulation of Abeta and phosphorylated tau induced by 27-hydroxycholesterol in rabbit organotypic slices. Journal of Alzheimer's disease : JAD 2010;19:1007-19.437.Rahman A, Akterin S, Flores-Morales A, et al. High cholesterol diet induces tau hyperphosphorylation in apolipoprotein E deficient mice. FEBS Lett 2005;579:6411-6.438.Vanitallie TB. Preclinical sporadic Alzheimer's disease: target for personalized diagnosis and preventive intervention. Metabolism 2013;62 Suppl 1:S30-3.439.Silvestre FJ, Lauritano D, Carinci F, Silvestre-Rangil J, Martinez-Herrera M, Del Olmo A. Neuroinflammation, Alzheimers disease and periodontal disease: is there an association between the two processes? J Biol Regul Homeost Agents 2017;31:189-96.440.Rafii MS, Tuszynski MH, Thomas RG, et al. Adeno-Associated Viral Vector (Serotype 2)-Nerve Growth Factor for Patients With Alzheimer Disease: A Randomized Clinical Trial. JAMA Neurol 2018;75:834-41.441.Khachaturian AS, Hayden KM, Mielke MM, et al. Future prospects and challenges for Alzheimer's disease drug development in the era of the NIA-AA Research Framework. Alzheimers Dement 2018;14:532-4.442.Kodamullil AT, Zekri F, Sood M, et al. Trial watch: Tracing investment in drug development for Alzheimer disease. Nat Rev Drug Discov 2017;16:819.443.Khachaturian ZS, Mesulam MM, Khachaturian AS, Mohs RC. The Special Topics Section of Alzheimer's & Dementia. Alzheimers Dement 2015;11:1261-4.444.Haapaniemi E, Botla S, Persson J, Schmierer B, Taipale J. CRISPR-Cas9 genome editing induces a p53-mediated DNA damage response. Nat Med 2018;24:927-30.445.Yamamoto N, Fujii Y, Kasahara R, et al. Simvastatin and atorvastatin facilitates amyloid beta-protein degradation in extracellular spaces by increasing neprilysin secretion from astrocytes through activation of MAPK/Erk1/2 pathways. Glia 2016;64:952-62.446.Janson CG. Diverse effects of statins in Alzheimer’s disease. Science Translational Medicine 2016;8:330ec44-ec44.447.Salta E, De Strooper B. microRNA-132: a key noncoding RNA operating in the cellular phase of Alzheimer's disease. FASEB J 2017;31:424-33.448.Chaudhuri AD, Dastgheyb RM, Yoo SW, et al. TNFalpha and IL-1beta modify the miRNA cargo of astrocyte shed extracellular vesicles to regulate neurotrophic signaling in neurons. Cell Death Dis 2018;9:363.449.Martin R, Bajo-Graneras R, Moratalla R, Perea G, Araque A. Circuit-specific signaling in astrocyte-neuron networks in basal ganglia pathways. Science 2015;349:730-4.450.Parikshak NN, Gandal MJ, Geschwind DH. Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders. Nat Rev Genet 2015;16:441-58.451.Colonna M, Wang Y. TREM2 variants: new keys to decipher Alzheimer disease pathogenesis. Nat Rev Neurosci 2016;17:201-7.452.Donath MY, Dalmas E, Sauter NS, Boni-Schnetzler M. Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity. Cell Metab 2013;17:860-72.453.Deeks SG, Lewin SR, Ross AL, et al. International AIDS Society global scientific strategy: towards an HIV cure 2016. Nat Med 2016;22:839-50.454.Hodge JW, Ardiani A, Farsaci B, Kwilas AR, Gameiro SR. The tipping point for combination therapy: cancer vaccines with radiation, chemotherapy, or targeted small molecule inhibitors. Semin Oncol 2012;39:323-39.455.LoRusso PM, Canetta R, Wagner JA, et al. Accelerating cancer therapy development: the importance of combination strategies and collaboration. Summary of an Institute of Medicine workshop. Clin Cancer Res 2012;18:6101-9.456.Tumbarello M, Viale P, Viscoli C, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis 2012;55:943-50.457.Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer's disease prevalence. Lancet Neurol 2011;10:819-28.458.Sink KM, Leng X, Williamson J, et al. Angiotensin-converting enzyme inhibitors and cognitive decline in older adults with hypertension: results from the Cardiovascular Health Study. Arch Intern Med 2009;169:1195-202. ................
................