• Aucun résultat trouvé

Lipopolysaccharides-mediated increase in glucose-stimulated insulin secretion: Involvement of the glucagon-like peptide 1 (GLP1) pathway.

N/A
N/A
Protected

Academic year: 2021

Partager "Lipopolysaccharides-mediated increase in glucose-stimulated insulin secretion: Involvement of the glucagon-like peptide 1 (GLP1) pathway."

Copied!
38
0
0

Texte intégral

(1)

HAL Id: inserm-00880061

https://www.hal.inserm.fr/inserm-00880061

Submitted on 5 Nov 2013

HAL is a multi-disciplinary open access archive for the deposit and dissemination of sci- entific research documents, whether they are pub- lished or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.

L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

glucagon-like peptide 1 (GLP1) pathway.

Anh Thoai Nguyen, Stéphane Mandard, Cédric Dray, Valérie Deckert, Philippe Valet, Philippe Besnard, Daniel Drucker, Laurent Lagrost, Jacques

Grober

To cite this version:

Anh Thoai Nguyen, Stéphane Mandard, Cédric Dray, Valérie Deckert, Philippe Valet, et al..

Lipopolysaccharides-mediated increase in glucose-stimulated insulin secretion: Involvement of the glucagon-like peptide 1 (GLP1) pathway.. Diabetes, American Diabetes Association, 2014, 63 (2), pp.471-82. �10.2337/db13-0903�. �inserm-00880061�

(2)

12 2

123434567899A8B2CD7EFDC28DC 29BD87D 2 5947DE72F58DC 2752 7D9BD2445DFD4AD5984E52D3D32CD138A86

!A"A482#6D12

$%&3A8D'8C8BC12

$(&CB29)B8613

$*85&B2D)D9DB12

$A25233D

*85D1 3

$ A25233D +D78BC1 2

$ )82D5 , )B9DB1 4

$ 18BD 18B471 256

8C ,89-D7 B4.DB121

1

7899A9B1CACDEF11E9293E1D832B9DAE1ECA4E1

21 E9CE1 4E1 7E3E3E1 7 ! 7"##51 $238DC%1 4E1 %4E3A9E51 !9A&EAC%1 4E1 '8BB9E51 ()*+1,A-913E4E.51$293E

61E9CE1/AC2DAE1!9A&EAC2AE1,A-951/0AC2D1481'32BE51()121,A-913E4E.51$293E1 11 31 7 1 !9AC%1 )2"51 9CAC8C1 4E1 2D24AE1 %C26DA38E1 EC1 24A&238D2AE51 48D8E51

$293E1!9A&EAC%14E148D8E51!9A&EAC%128D1262CAE5148D8E51$293E1 11 1

41 ,E2C5E9C1 61 E4A3A9E51 258ED1 89E96ED41 7EE231 9CAC8CE51 C71 A92A1 /AC2D51

!9A&EAC816149C5149C5199C2A512924271 1

1

E94E93EF1 :2338E1 6E1 1 28E9C1 2BC1 1 7 1 ! 7"##51 *1 641 :E299E1 4;<351()*+1,A-913E4E.51$293E714ED7F1=11111")11+11(1#2>162.F1=11111")11+11212*7152AD1 244EF1-2338E7B6E?868BB9E7611D28E9C7D2BC?868BB9E761

1

@41389CF11"+A1 856E1616AB8EF1"1 1

1 1

(3)

1 1

!.7B89

AD82332A4E1BC161CE13EDD1D2DD161251BC1623CEA21CABBE1A96D2552CA951DA31 A1 23A2CE41 DAC1 52E41 329BE1 A91 BD83E1 5EC26DA571 /8EBD83E5A21 A1 6E38E9CD81 6E&E4148A9B1623CEA2D1A96E3CA912941AC1A12152E1612113DA9A32D18C35E1A913ACA32DD81 ADD12CAE9C714E12A5161CE1EE9C1C8481D21C1A9&ECAB2CE1CE1E66E3C161291238CE1A9-E3CA911 39CA9881 A968A91 61 1 91 E.EA5E9C2DD8A9483E41 8EBD83E5A21 A91 DAD4C8E1 2941 BE9ECA32DD8E9BA9EEE415A3E714E1238CE1A9-E3CA916121A9BDE14E1611483E41291A93E2E1 A91 BD83E1 4A2D1 2941 BD83ECA58D2CE41 A98DA91 E3ECA91 BC71 9CA9881 A968A91 61 1 C8B1 5A9A5CA31 851 D21 2D1 23A2CE41 DAC1 A93E2E41 71 $A92DD851 529A8D2CA916114EC.A6A32CA9168193A9B18C1CE1D2521DAA41C296E1CEA91 B4C1DE41C1A93E2E41BD83E14A2D12941719&E2DD51BD83E1CDE293E129411CEC1 8CE41 CE1 8CEA1 C2C1 5A3E1 CE2CE41 DAC1 1 4E&ED1 BD83EA9483E41 8EA98DA9E5A271 4E1 E66E3C1 61 191 BD83E1 5EC26DA51 DEE1 AB9A6A329CD81 2DCEE412121 E8DC1 61 EACE1 CE1 233858D2CA91 1 29C2B9A51 61 BD832B9DAE1 ECA4E1 1 BC71 5DE5E9C281 C84AE1 A91 DAD4C8E1 2941 71 938C1 5A3E1 68CE1 A5DA32CE41 CE1 74EE94E9C1 2CD281 A91 5E4A2CA9B1 CE1 5E4A2CE41 329BE1 A91 BD83E1 5EC26DA571 /E93E51E9293E411 E3ECA91294123CA91894EDAE1CE14E&ED5E9C161BD83E5E4A2CE41 8EA98DA9E5A2123A2CE41DAC1E94C.E5A271

B4C924

AD82332A4E1 BC1 1 E94C.A91 2E1 359E9C1 61 CE1 3EDD1 D2DD1 61 251 BC1 623CEA271@E911E9CE1CE16D4CE2551AC123CA&2CE14DDDAE1E3EC121B472C1D32CE412C1

(4)

CE1 8623E1 61 A5589E1 3EDD51 DE24A9B1 C1 CE1 EDE2E1 61 A96D2552C81 38CA9E1 2941 C1 A96D2552CA91BC71.3EA&E1A96D2552C81E9E1C1132916E12568D129415281DE241C1 E94C.A313129418DCA52CED814E2C71'E328E1251BC1623CEA212E1EE9C1A91D2BE12589C1 A91CE1B8C1D85E912941CE1E9&A95E9C51623CEA2D1C29D32CA912941CE1E8DCA9B1E94C.E5A21 3291 3381 21 21 E8DC1 61 A96D2552C81 6DED1 4AE2E1 B(C51 21 AB62C1 4AEC1 B1C1 1 3AB2ECCE1 5A9B1 B2C71 @2CE&E1 CE1 E&EAC81 61 CE1 A98DC51 E94C.E5A21 A1 233529AE41 681 52E41 5EC26DA31 2DCE2CA951 A93D84A9B1 329BE1 A91 BD83E1 5EC26DA551 DA31 A1 61 2CA38D21 A5C293E71 2D81 8EBD83E5A21 A1 21 35591 5EC26DA31 6E2C8E1 6DDDA9B1 E.8E1 C1 623CEA2D1E94C.A91BAC71C1A19D91C139CA68CE1C11A5589E16893CA951.A42CA&E1CE51 A93E2E41 83ECA6ADAC81 C1 A96E3CA81 35DA32CA951 A52AE41 E3&E81 61 B291 62AD8E512941 E94CEDA2D1294158324A2D1486893CA91B#>1*C71913ACA32DD81ADD12CAE9C518EBD83E5A21A19C1 9D812152E161ADD9E1E&EAC8168C12D121E4A3C1612113DA9A32D18C35E1B*C71<DC8B1 E66E3CA&E1 BD83E1 39CD1 C8B1 2BBEA&E1 A98DA91 CE281 21 6EE91 ECE41 C1 A5&E1 3DA9A32D18C35E51AC1E52A91893DE21C1D2C1E.CE9C1A98DA91A968A915281A91623C16E16E9E6A3A2D1 B"C71 /8EBD83E5A251 54E2CE1 C1 E&EE1 8BD83E5A21 2941 8EA98DA9E5A21 2&E1 2DD1 6EE91 68941C16E123A2CE41DAC1291A93E2E41A1614E2C1A913ACA32DD81ADD12CAE9C1245ACCE41C1CE1 A9CE9A&E132E189AC1B+>1)C7191CE2CE415A3E51214E3E2E1A916C1A96D2552CA9129415C2DAC81 D21 ECE41 DE91 CE1 D2521 BD83E1 DE&ED1 D21 CA3CD81 52A9C2A9E41 2C1 952D1 &2D8E51 8BBECA9B1 C2C1 2A2CEECABC1 BD83E1 39CD1 A1 21 52-1 4ECE5A929C1 61 8C35E1 BC71

@ECE1 26952DACAE1 A91 BD83E1 39CD1 5281 &281 2334A9B1 C1 CE1 E94C.E5A31 A98DC1 A1 899D9512941CE15DE38D215E329A51A9&D&E412E1D81894EC471

91 CE1 EE9C1 C84851 CE1 BD83E1 2941 A98DA91 E9E1 C1 E.EA5E9C2DD8A9483E41 8EBD83E5A21 DEE1 A9&ECAB2CE41 A91 CE2CE41 58E1 54ED71 94C.A91 DEE1 245A9ACEE41C8B1EACE1CE1238CE1A771A9-E3CA916121A9BDE14E161512139CA9881A771 A968A91 61 21 DD1 4E1 61 1 8A9B1 5A9A5CA31 8551 1 CE1 8E1 61 CE1 DAA41

(5)

C296E1 CEA993E41 8C1 B4F9C1 58E1 54ED51 DA31 A1 9D91 C1 4AD281 291 A52AE413223AC81C1A923CA&2CE129414EC.A6811A91CE16481B(C71912DD161CE154ED18E41A91 CE1 EE9C1 C84851 DE1 68941 C2C1 1 A93E2E41 51 DA31 21 6EE91 D91 C1 6E1 48E51 2C1 DE2C1A912C51C1291A93E2E1A91CE1DE&ED1294123CA&AC8161BD832B9DAE1ECA4E11BC71

(6)

/D7D8B9ACD728CFDA4C7

!2F857

$A&E1 C1 A.59CD41 @41 5A3E1 B2DE1 7A&E51 G<6EDE51 $293EC51 7F91 5A3E1 B1C1 29414F915A3E1B21A941BA6C161,1:A29B1B2CC1651215BE9E81A*'#E:1623B8941 DEE1 8E41 A91 21 39CDDE41 E9&A95E9C71 <DD1 61 CE1 29A52D1E.EA5E9C2D1 3E48E1 6EDD1 DEE1&2DA42CE41681CE1D32D1ECA31355ACCEE161CE1!9A&EAC8161'8B89481BC3D19856E1 ()+C71 A3E12416EE1233E1C1D2CE12941C2942414AEC<)1)72C12941 A3E1'EE4E1,AEC1 B<$51 <!H51 $293EC71 4E1 4AEC1 39C2A9E41 (72I1 CEA951 A7*I1 5A9E2D51 A7I1 62C51 2I1 3EDD8DE129415A.C8E161&AC25A9129415A398CAE9C71

%B2985 3B49DCBD7 8C 20D9247127247 4 1%71 1 DEE1 651234567845891 4AB81 )AAF'A1BAB5251C718A51 9C714E15A3E1DEE1EACE1BA&E91A9C2EAC9E2D1A9-E3CA91611 B)7A51 51 1 (5BEBC1 1 241 21 5A9A5CA31 851 A5D29CE41 8638C29E8D81 B<DJECK1 4ED1 ())2>1<DJ2512D1<DC51<C12941DA9E41C1CE1EAC9E2D132&AC816812132CECE714E1851DEE1 6ADDE41DAC1EACE12D1B)7+IC111C1A968E11))11)))LB7B742816121DEE71<6CE121 DEE51 D2521 25DE1 DEE1 42D91 2941 6JE91 2C1 ()M71 4E1 5A3E1 DEE1 CE91 ADDE41 2941 583DE1 CA8E1 2941 CE1 DA&E1 DEE1 A55E4A2CED81 E.3AE451 A55EE41 A91 DA38A41 (12941 CE41 2C1 N")M16168CE157<1292D8E711

5947D 45DB89D D7 1 <6CE1 62CA9B1 &E9ABC51 CE1 5A3E1 DEE1 6E41 DAC1 BD83E1 681 2D1 B2&2BE1 B7A(BEBC71 'D41 D21 42D91 651 CE1 C2AD1 &EA91 2C1 )51 A51 1)51 #)51 +)1 2941 ()1 5A91 6DDDA9B1CE1BD83E1D24512941BD83E1393E9C2CA91D214ECE5A9E41DAC121BD83E15ECE1 B99E14831!DC2KC7192D1BD83E1CDE293E1CEC1B944C1DEE1E65E41EACE1#18126CE1 CE1 238CE1 A71 A9-E3CA91 61 1 1 2C1 CE1 E941 61 CE1 ("4281 A968A91 EA471 91 5E1 E.EA5E9C51 AC2BDACA91 B:298&A2K51 E31 21 2941 ,5EA6EC51 $293EC1 BA5BEBC1 1 .E94A9+1+1BA1OBE58EC1D21245A9ACEE41&A212D1B2&2BE11A771A9-E3CA951EE3CA&ED8511)1

(7)

5A98CE1 A1 C1 CE1 BD83E1 B2&2BE71 2D1 B)7+IC1 D21 245A9ACEE41 21 21 39CD71 4E1 2E21 894E1CE138&E1B<!C1B)()C1D2132D38D2CE4161E231B81615A3E512941CE1D2521A98DA91 393E9C2CA91 D21 5E28E41 1)1 5A98CE1 6E6E1 2941 A1 5A98CE1 26CE1 CE1 BD83E1 D2471 4E1 A98DA9BE9A31A94E.1BA7E71291A94E.161P3EDD16893CA9C1D2132D38D2CE4121CE14EDC21A98DA91C1CE1 4EDC21BD83E12CA1BQ)RAEQ)RA515DE55DC1

75245DB89DD771<6CE1#16162CA9B515A3E1DEE1BA&E91291A9C2EAC9E2D1A9-E3CA9161 )7A!EB1A98DA91B/852DBKC5129416D41BD83E1D215E28E41215E9CA9E4126&E71

587F8 1 949DB82471 <6CE1 62CA9B1 &E9ABC51 5A3E1 DEE1 BA&E91 291 A9-E3CA91 61 CE1 ,21 A9A6AC1 AC2BDACA91 BA5BEBC71 99E1 81 D2CE51 CE1 5A3E1 DEE1 BA&E91 291 A9C2EAC9E2D1 A9-E3CA91 61 1 B(5BEBC1 1 2D1 B)7+IC1 21 CE1 39CD71 A.1 81 26CE1 CE1 1 1 2D1 A9-E3CA951 CE1 5A3E1 DEE1 BA&E91 (BEB1 61 BD83E1 C8B1 2D1 B2&2BE71 'D41 25DE1 DEE1 3DDE3CE41 A91 ,4<39C2A9A9B1 C86E1 8DE5E9CE41 DAC1 CE1 ,21 A9A6AC1 B ADDAE51

$293EC511)15A98CE16E6E12941A15A98CE126CE1CE1BD83E1D241C12E1CE1D25211 393E9C2CA971

/D85E2FD -8282D (/71 4C2D1 7<1 D21 AD2CE41 651 CA8E1 8A9B1 4AJD1 E2BE9C1 B9&ACBE951 $293EC71 4C2D1 7<1 B)7ALBC1 D21 E&EEC293A6E41 8A9B1 S1 E&EE C293AC2E1 B9&ACBE951 $293EC1 2941 29451 A5E1 2C1 2(M1 61 1 71 T71 DEE1 E65E41 8A9B1 <'1 A51 *+))1 B<DAE41 'A8CE551 $293EC71 A5E1 E38E93E1 61 CE1 C2BECE41 58E1 BE9E1 2E1 2&2AD26DE1 891 E38EC1 B-2338E7B6E?868BB9E76C71 4E1 57<1 E.EA91 DE&ED161C2BEC1 BE9E1 D21952DAJE41 C1 DE&ED161 P23CA9157<1 2941 CE1 E8DC1DEE1E.EE4121ED2CA&E1E.EA91DE&ED714E142C21DEE13829CA6AE41681CE15EC41 61(QQC71

5947D38D2F795D71 83DE1DEE1AD2CE412941EA93862CE4161)15A91A91FE6 /E9EDEAC16866E1B/1*72C139C2A9A9B1(15BE51'<51(155DE14A85188&2CE512941()1

(8)

55DE1/714E1583DE1DEE1CE91A93862CE41612A15A91A91CE126E93E11A91CE1 EE93E161))195DE1A98DA9121E&A8D814E3A6E41BAC71

+249ADF298588567D7711

1393E9C2CA91DEE15E28E41A91CC2D1D25251AB4E9AC81DACEA91B/,C12941CE1 DACEA96EE1 623CA91 B$$C1 C8B1 CE1 3829CAC2CA91 61 1284.858AC2CE1 393E9C2CA91 2334A9B1 C1 CE1 BE9E2D1 3E48E1 E&A8D81 4E3A6E41 B(C71 D2521 A98DA91 29411393E9C2CA91DEE14ECE5A9E41681<1B<9512DE551!<C51 A912334293E1 DAC1 CE1 5298623C8E;1 A9C83CA971 83DE1 BD83BE91 39CE9C1 D21 4ECE5A9E41 DAC1 CE1 D83BE91 89C2E1 2281 AC1 B'A4A&AA951 89C2A91 SAED51 !<C51 A91 2334293E1 DAC1 CE1 5298623C8E;1 A9C83CA971 4E1 393E9C2CA91 61 A9CEDE8A9#1 B#C1 2941 C851 9E3A1 623C31 B4$35C1 DEE1 5E28E41 A91 58E1 D2521 681 ADDADE.K1 21 ADE.1 AC1 B 8E1 8CA9EEE5A9E1 2B9ECA31'E24129EDC1651 ADDAE1B ADDAE51'ADDEA3251 <51!<C1 2334A9B1 C1 CE1 5298623C8EG1 C3D1 2941 8A9B1 21 85A9E.71 222C81 B'ADE.K1())51 'A724C1

%827298588567D7717E8DC12E1EE9CE41215E291U1 71C2CACA32D1AB9A6A3293E161 4A66EE93E1D21292D8JE41681CE1892AE41C1CEC71

2

(9)

/D757

!9D2 320D92441%DA89D75947DE72F58DC27527D9BD24

41E&2D82CE1CE1BD83E12941A98DA91E9E148A9B15E4A2CE41A96D2552CA951DAD4C8E1 5A3E1DEE1BA&E9121A9BDE1238CE1A71A9-E3CA9161(15BEB16171D2521284.858AC2CE1 39CE9C51E6DE3CA9B1D25211DE&ED1D2152E4D81A93E2E418911A9-E3CA91B#)17(1U(7(1 9BE51 A91 A9-E3CE41 5A3E1 B9V"C1 &E81 #"721 U1 #7(1 9BE51 A91 2D1 39CD1 B9V"C>1 W)7))C71 A.1 81 26CE1 CE1 1 A9-E3CA951 8EBD83E5A21 D21 A9483E41 681 B2&2BE1 DAC1 21 BD83E1 D8CA91 B(BEBC71 <1 D91 A91 $AB8E1 <1 2941 '51 CE1 BD83E1 CDE293E1 38&E1 D21 A5&E41 DAC1 CE1 1 A9-E3CA951 2941 BD83ECA58D2CE41 A98DA91 E3ECA91 BC1 A93E2E41 B$AB1 C71 9ACE9C1 E8DC1 DEE1 6C2A9E41 681 8A9B1 CD1 DDE1 4E1 61 71 @EE21 A91 62CA9B1394ACA95191AB9A6A329C14A66EE93E1DEE16E&E41A91A98DA91D2521DE&ED18911 A9-E3CA9161EACE1)7A5BEB115BEB1611B42C219C1D9C512B2A9512941DAC1EACE14E1 61 51 1 26CE1 CE1 BD83E1 D241 D21 AB9A6A329CD81 E9293E41 21 E&E2DE41 681 CE1 A98DA91 D2521 DE&ED12C1 CVA5A91B*##7+1 U1(A7A1 5DE1 A91 A9-E3CE41 5A3E1 B9V)C1 &E81 2121 U1 1*72+15DE1A912D139CD1B9V+C51W)7)A1DAC1CE1)7A15BEB14E>1###7A1U1"+71+15DE1 A91 A9-E3CE41 5A3E1 B9V)C1 &E81 1*17"1 U1 17#1 5DE1 A91 2D1 39CD1 B9V)C51 W)7)1 DAC1CE115BEB14EC714E16893CA9161293E2CA3123EDD1D21E&2D82CE4168132D38D2CA9B1CE1 A98DA9BE9A31 A94E.1 BC1 2C1 CE1 A5A91 CA5E1 A9C1 B8D6D1 A91 CE1 &E81 E2D81 2E1 61 A98DA91 E3ECA9C71<1D91A91$AB8E1,51CE1238CE1A771A9-E3CA91611A93E2E41CE1711

(42472 3 272441%29BD87D75947DE72F58DC27527D9BD24

@E19E.C12EE41CE139E38E93E1618C2A9E411245A9AC2CA91681A5D29CA9B15A3E1DAC1 5A9A5CA31 2DJECK1 851 C2C1 39CA988D81 4EDA&EE41 1 1 2D1 61 ("1 4281 B1))LBEBE428C714A114E1D21ECE41C15A5A31CE15EC26DA31E94C.E5A21A9483E41681 21 AB1 62C1 4AEC1 B1C71 D2521284.858AC2CE1 39CE9C1 D21 54ECD81 68C1 AB9A6A329CD81 A93E2E41 891 1 A968A91 BA968E41 5A3E1 B9V*CF1 A7+1 U1 17+1 9BE51 2D1 39CD1

(10)

B9V2CF11A7"1U17119BE51W)7)AC719139C2C1C1CE1238CE1A771A9-E3CA91611B$AB1<C51CE1 39CA9881A771A968A916114A419C1A5&E1CE1BD83E5A31E9E148A9B1CE19441B$AB1 (<C5121A94A32CE41681A5AD21&2D8E161CE12E21894E1CE138&E1B$AB1('C71/DE&E5112941 1 DEE1 A93E2E41 DAC1 1 CE2C5E9C51 2DC8B1 C1 21 DEE1 E.CE9C1 C291 DAC1 238CE1 1 A9-E3CA91 B$AB1 (5,1 &71 $AB1 5,C71 !A9B1 21 ABE1 4E1 61 1 B5BEBE428C1 48A9B1 39CA9881A968A91DE41C1CE125E1E9293E5E9C1611 26CE121BD83E1D24121D91681 CE1A98DA91D2521DE&ED12C1CVA5A91BA968E415A3E1B9V2CF1"+(7A1U117215DE>12D1 39CD1B9V2CF1217"1U1)715DE51W)7)AC711

1

/DC9DC 1% DB8522824 8C CD43229824 2 1"E45 F29D 27 8774928DC 2A 8F3522982445947D8C2752BD7347D7

4168CE1E&2D82CE1CE1A523C161191BD83E12941A98DA91E9EE1DE1C124&29C2BE161 CE1 4F9158E1 54ED51 DA31 4AD28121 E483E41 3223AC81C1 4EC.A681 1 B(C71<6CE1 238CE1A7711A9-E3CA951D2521284.858AC2CE139CE9C1D21ABE1A914F915A3E121 352E41 C1 @41 5A3E1 B1*7AU1 (2711 9BE51 A91 4F91 5A3E1 B9V#C1 &E81 (+"7*1 U1 (17"1 9BE51A91@4139CD1B9V#C51W)7)AC7191CE126E93E1615141E.EA91F6713614A419C1 54A681 CE1 BD83E1 E9E1 C1 2D1 BD83E1 32DDE9BE1 B$AB1 1<1 2941 1'51 X2DYC71 91 CE2CE41 5A3E51 BD83E1 3DE2293E1 D21 A93E2E41 C1 21 AB9A6A329CD81 BE2CE1 E.CE9C1 A91 4F91 5A3E1C291A91DAD4C8E15A3E1B$AB11<129411'51XYC71@EE211D219C14EE94E9C191 41 E.EA91 A91 CE1 26E93E1 61 CE1 1 32DDE9BE1 B$AB1 151 2DC51 A98DA91 DE&ED1 DEE1 AB9A6A329CD81BE2CE1A914F915A3E126CE1238CE11A9-E3CA91B$AB1151C71A5AD2D851CE1 1D21AB9A6A329CD81A93E2E4126CE1238CE1A771A9-E3CA91611A91@412941A9141F915A3E1 B$AB11,C711

(11)

1@E1 9E.C1 2EE41 CE1 39E38E93E1 61 39A31 1 A968A91 A91 @41 2941 4F91 5A3E71 9CA9881 A968A91 61 21 DD1 4E1 61 1 4A41 9C1 DE241 C1 AB9A6A329C1 4A66EE93E1 A91 1 D2521 DE&ED1 6ECDEE91 @41 2941 4F91 5A3E1 26CE1 ("1 4281 61 1 A968A91 BA(71U1 (7#1 9BE51A914F915A3E1B9V"C51&E81A#7#1U117A19BE51A91@415A3E1B9V*C519C71/DE&E51 29412141A1A9&D&E41A911C296E16ECDEE91CE1D2521DACEA96EE1623CA91B$$C1 2941D2521DACEA951DE19E.C14ECE5A9E41DECE1CA1E.EA5E9C2D1EC81D21E66E3CA&E1 C1548D2CE114ACA68CA916ECDEE91AB14E9AC81DACEA91B/,C12941 $$121ECE41 E2DAE1DAC1238CE1A771A9-E3CA91B(C71912BEE5E9C1DAC1E2DAE16E&2CA9514F915A3E1 C2C1 E3EA&E41 21 39CA9881 A968A91 61 1 C8B1 CE1 A5D29CE41 5A9A5CA31 851 4AD28E4121DDE11284.858ACA3123A4139CE9C161CE1D2521/,1623CA91B$AB12<C5121 ABE1139CE9C161CE1$$1623CA91B$AB12'C1294121DDE1/,1C1$$112CA1B$AB12C71 9168CE18C161CE1BE2CE1A96D2552C81E66E3C1611DE91A968E41A915A3E1DAC121 44E6A3AE9C1C2AC51DA&E13157<1DE&ED1DEE1AB9A6A329CD81ABE1A914F91C291A91

@41 5A3E1 B$AB71 2,C71 52E41 DAC1 42C21 6E6E1 851 A5D29C2CA91 B$AB1 A<51 A'1 XYC51 BD83E13DE2293E1D21A93E2E41A91A968E41@415A3E512941CE1A93E2E1D21E&E91BE2CE1 A91 4F91 5A3E1 B$AB71 A<5'1 X=YC71 98DA91 DE&ED1 2941 1 6C1 A93E2E41 DAC1 1 A968A951A94EE94E9CD816141E.EA91B$AB1A51,C719139C2C51A98DA91E9ACA&AC81D21 ABE1A914F915A3E1B$AB1A51$C711

'E328E1BD83E13DE2293E12941A98DA91E9ACA&AC81A91A968E414F915A3E1DEE1BE2CE1 C291CE1A91A968E41@415A3E51CE126ADAC8161583DE1C18CADAJE1BD83E1D21A9&ECAB2CE471

<1D91A91$AB1#<51A98DA95E4A2CE41BD83E18C2E1D215E1E66A3AE9C1A914F91C291A91

@41 5A3E71 9ACE9CD851 583DE1 BC1 1 2941 B4A61 3C59361 57<1 DE&ED1 DEE1 AB9A6A329CD81 ABE1 A91 4F91 C291 A91 @41 5A3E1 B$AB71 #'1 2941 #51 EE3CA&ED8C71 4E1 BD83BE9139CE9C161583DE1D212D1ABE1A914F915A3E1B$AB1#,C71

1

(12)

1

1

!99F582441F822DCAD1%EFDC28DC29BD87D2%%

<1 1 D21 E&A8D81 A4E9CA6AE41 21 21 4D9CE251 C2BEC1 61 A96D2552C81 38CA9E1 C2C1 2D1 EB8D2CE1 CE1 52B9AC84E1 61 1 B#>1 *C51 DE1 E.25A9E41 CE1 1 2.A1 48A9B1 291 1 32DDE9BE71!94E162CA9B1394ACA951A71A9-E3CA91611AB9A6A329CD81A93E2E41D25211 DE&ED1 A91 @41 5A3E1 B$AB71 *<1 DE6CF1 #71(1 U)7#A1 5DED1 A91 CE2CE413D1 7#1 U)7*1 5DED1 A91 89CE2CE41 @41 5A3E>1 4)7)C71 $8CE5E51 D2521 1 DE&ED1 A93E2E41 68CE1 26CE1 2D1 BD83E1D24A9B1A9139CD1@415A3E512941CE1A93E2E1D21AB9A6A329CD81BE2CE1A91CE2CE41

@41 5A3E1 B$AB1 *<F1 *7"1 U(7+"1 5D1 A91 CE2CE413D1 27)*U1 )7*1 5D1 A91 39CD1 5A3E>1 W)7))C71 $A92DD851 A9483E41 A93E2E1 A91 D2521 A98DA91 DE&ED1 DEE1 6E&E41 6C1 A91 62CA9B1294126CE1CE1BD83E1D241B$AB71*'C51294121AB9A6A329C51ACA&E13ED2CA91D2168941 6ECDEE91D252112941A98DA91DE&ED1B$AB1*C711

E.C51DE12EE41DECE1CE1238CE15E4A2CE412CCE982CA9161BD83E5A31E.38A9138D41 6E1 68CE1 E9293E41 681 A93E2E41 DE&ED1 61 23CA&E1 1 23AE&E41 C8B1 CE2C5E9C1 DAC1 AC2BDACA95121,21A9A6AC1B"C71D83E5A31E.38A91A91E9E1C11D2168CE1E483E41 681CE1356A92CA916112941AC2BDACA91B$AB1*,5C71

1

8B28588427F4AD1BD9D34B.5497AD1%DD94569DF29D39B724

412E1CE1A5C293E16112121C29483E161CE15E4A2CE41BD83E5A31E9E1DE1 2EE41 DECE1 CE1 245A9AC2CA91 61 CE1 71 29C2B9AC1 E.E94A9B+R1+C1 B.+C1 38D41 54A681 CE1 BD83EB8D2C81 23CA91 61 71 <45A9AC2CA91 61 .+1 86C29CA2DD81 2CCE982CE41 CE15E4A2CE41329BE1A91BD83E14A2D1B$AB1*$51C71

(13)

1

11

1%EFDC28DC9A8D7227528C5947DBD7347D78BD.5DC21/E45F29D

4168CE1A9&ECAB2CE1CE1DE161CE1E712CD281A91CE15E4A2CE41329BE1A91 BD83E1 5EC2A51 DE1 2EE41 1 23CA91 A91 71 F91 5A3E1 B+C71 <1 352E41 C1 2DA9-E3CE415A3E1DA314AD28E41DD1DE&ED1611B@415A3E1B9VC51117#1U117A19BE5>1 7F91 5A3E1 B9VC51 217+1 U1 #7(1 9BE51 9C51 D2521 1393E9C2CA91 DEE152E4D81 A93E2E4126CE1238CE1A771A9-E3CA916112941C121A5AD21E.CE9C1A91@4129417F915A3E1 B@415A3E1B9VC511#(7)1U1*7A19BE5>17F915A3E1B9VCF11A(71U1(A7(19BE5519C71 9CEECA9BD851DEE21238CE1A771A9-E3CA91611DE41C1CE125E11D2521DE&ED1A91@412941 7F91 5A3E51 CE1 D2521 DE&ED1 61 #1 2941 4$356A7E71 CD1 52A91 A96D2552C81 38CA9E1C2BEC161C14AD28E41215E19893E41A93E2E1A917F9121352E41C1

@415A3E1B$AB1"<12941"'C714E15E4A2CE41329BE1A91BD83E1E9E1A91@415A3E1D21 35DECED8126E9C1A9171F915A3E1B$AB1""C71$8CE5E51CE15E4A2CE41A93E2E1 A9116E&E41A91@415A3E1D219C16E&E41A917F915A3E1B$AB71"$12941"C51 2941 E9293E4123EDD1 6893CA91 A91 E9E1 C1 1 D21 35DECED81 DC1 A91 7F91 5A3E1 B$AB1"/C711

(14)

)2797724

91CE1EE9C1C84851CE1A98DA91E9E1C1E.EA5E9C2D18EBD83E5A21D21C84AE41A915A3E1 DAC1 5E4A2CE41 A96D2552CA971 981 42C21 8C1 CE1 8CEA1 C2C1 1 A93E2E1 BD83ECA58D2CE41 A98DA91 E3ECA91 BC51 E8DCA9B1 A91 A93E2E41 BD83E1 3DE2293E71 9ACE9C1 6E&2CA91 DEE1 524E1 DAC1 238CE1 &E81 39CA9881 1 A968A912941 C1 21 BE2CE1 E.CE9C1 DE91 CE1 DAA41 C296E1 CEA91 B4C5E4A2CE41 4EC.A6A32CA91 2CD281 61 1 4A41 9C1 E2CE714E1 5E4A2CE41 329BE1 A91 BD83E1 5EC2A1 DEE1 68941C1E38AE1216893CA92D174EE94E9C12CD28711

EA1A19D91C1A52A1DDE16481BD83E14A2D1B()C51E8DCA9B1A918EBD83E5A2516CE91 23A2CE41 DAC1 5EC26DA31 242C2CA91 2941 A93E2E41 A98DA91 E3ECA971 /DE&E51 623CEA2D1 A96E3CA9111245A9AC2CA914E19C12DD281DE241C139ACE9C1329BE1A91BD83E14A2D1 1 A98DA91 E3ECA91 B(("C71 $1 A9C293E51 CE1 E&E9CA91 61 8EBD83E5A21 681 4EDECA9B1 BD83BE91C2BE14A419C126B2CE1CE1A93E2E1A91E851A98DA91DE&ED1A91E94C.E5A3129A52D1 B(+C71 4A1 A94A32CE1 C2C1 CE1 ED2CA9A1 6ECDEE91 E94C.E5A21 2941 BD83E1 5EC2A1 A1 2CE1 35DE.5129419E1 8CEA1 D41 C2C1 CE1 E66E3C161 1 5ABC1 6E1 4EE94E9C1 91 CE1 5EC26DA3139CE.C12941CE1E.EA5E9C2D1394ACA918E41BA93D84A9B1A912CA38D21CE152B9AC84E1 2941 482CA91 61 CE1 E94C.E5A31 32DDE9BEC71 91 CE1 EE9C1 C84851 BD83E1 2941 A98DA91 E9E1DEE16AC1A9&ECAB2CE41A915A3E1BA&E9121A9BDE1A9C2EAC9E2D1A9-E3CA916171A.1 8126CE1CE11A9-E3CA9511AB9A6A329CD81A93E2E451294139ACE9C16E&2CA91DEE1 524E1DAC14ACA93C114E711A93E2E1D2123A2CE41DAC1A93E2E41BD83E14A2D71 9139C2C51A91291E2DAE1C84851214E3E2E1A91BD83E14A2D1D21ECE412"126CE1CE11 A9-E3CA91B1)C714EE139C2CA9B16E&2CA915ABC16E12CD81ED2CE41C1CE52D14A66EE93E71 91 8C1 61 CA1 8CEA51 D2521 1 393E9C2CA91 DEE1 ECE41 C1 E21 9A9E1 81 26CE121A9BDE1A9C2EAC9E2D1A9-E3CA91611A915A3E5168C1EC89E41C162ED814ECE3C26DE1DE&ED1 26CE1 2"181 B(C71 91 EEA9B1 DAC1 CE126&E51 A93E2E41 A98DA91 E9ACA&AC81 D21 6E&E41 (1

(15)

81 26CE1 1 A9-E3CA91 A91 85291 B1>1 1(C51 DEE21 A98DA91 EAC293E1 D21 6E&E41 (21 8126CE1CE1A9ACA2D1132DDE9BE1B11C711

4E18CEA1 61 21 4A66EE9CA2D1 A523C1 61 C29AE9C1 &E81 39CA9881 1 91 BD83E1 5EC26DA51D21244EE41A91CE1EE9C1C8481681352A9B121A9BDE1A9-E3CA91611DAC121 39CA9881 A968A91 23AE&E41 8A9B1 5A9A5CA31 8571 <6CE1 ("1 4281 61 39CA9881 A968A91 61 51 1 D21 68941 C1 6E1 AB9A6A329CD81 A93E2E451 2941 2B2A91 39ACE9C1 6E&2CA91DEE1524E1DAC14ACA93C114E71/DE&E51CEE1DEE191329BE1A91BD83E1 4A2D71 $A92DD851 C1 68CE1 E.DE1 CE1 E66E3C1 61 E.EA5E9C2D1 E94C.E5A21 91 BD83E1 2941 A98DA91 E9E181 8AE1DE1 C84AE41 44E6A3AE9C1 5A3E1 A91 DA31 CE1 6A94A9B1 61 1 C1 D2521AB14E9AC81DACEA91A14ED28E471DACEA9135DE.E12E19D91C16E1DE1 8BE9A31 2941 DE1 23CA&E1 A91 A9483A9B1 CE1 EDE2E1 61 A96D2552C81 38CA9E1 C291 A1 CE1 32E1 61 1 A91 CE1 D2521 DACEA96EE1 623CA91 B121#C51 2941 CE1 44E6A3AE9C1 C2AC1 A1 CEE6E1 23A2CE41 DAC1 A52AE41 9E8C2DAJ2CA91 2941 3DE2293E1 61 1 B(C71 9CEECA9BD851 8A9B1 6C1 238CE1 A9-E3CA91 1 39CA9881 A9C2EAC9E2D1 A968A951 E94C.E5A21 D21 39ACE9CD81 23A2CE41 DAC1 BE2CD81 A93E2E41 1 2941 BD83E1 4A2D1 A91 44E6A3AE9C1 5A3E71 4EE1 6E&2CA91 8C1 CE1 8CEA1 C2C1 1 A1 291 242CA&E1 E9E1 C1 E94C.E5A2711

4E1 894ED8A9B1 5E329A51 61 CE1 5E4A2CE41 329BE1 A91BD83E1 5EC26DA51 21 6EE9121 52CCE161A9CE9E1EE2312941E38D2CA971991CE19E1294511ACED615ABC1E.EC1214AE3C1 A98DA9DAE123CA&AC81B1*1+C71<DCE92CA&ED85115ABC123C1A94AE3CD81C8B1CE1CA58D2CA9161 293E2CA31 A98DA91 E3ECA951 2941 293E21 E.3AE41 651 CE2CE41 29A52D1 4AD281 A93E2E1 A91 6C1 622D1 A98DA91 E3ECA91 B2)>1 2C1 2941 1 B2)2(C71 /DE&E51 9EACE1 E68A9161E.3AE41293E21DAC11B2C51911CE2C5E9C16138DC8E41293E2CA31Z3EDD1 BE.EA9B14721B21CC1DEE126DE1C14AE3CD81A93E2E1A98DA91E3ECA91B22C18BBECA9B1215E1 35DE.1 2CD281 DAC1 A9CE5E4A2CE1 5E4A2C71 51 DA31 21 6EE91 D91 C1 A93E2E1

(16)

A98DA91 E3ECA91 A91 E94C.E5A31 2C1 B2AC51 2941 #51 DA31 21 6EE91 D91 C1 5CE1 8BD83E5A2148A9B1238CE1A9483E41A96D2552CA91B2#C12941C1E9293E1A98DA91E3ECA91 681A93E2A9B1BD832B9DAE1ECA4E1E3ECA9165113EDD129412D213EDD1B*C12E1A6DE1 BD83EB8D2C81C2BEC16171<DC8B1#1E3ECA91A19D91C16E1ABD81A9483A6DE1681 51 21 1 32DDE9BE1 D21 9C1 8E41 A91 CE1 C84AE1 3ACE41 26&E71 4A1 DE41 81 C1 A9&ECAB2CE1 DECE1 A93E2E41 483CA91 61 1 B21 CE9C1 A9483E1 61 A98DA91 E3ECA91 B#CC1 5ABC1 894EDAE1 CE1 5E4A2CE41 A93E2E1 A91 71 981 42C21 3DE2D81 D1 C2C1 1 A9-E3CA91 A93E2E1 D2521 DE&ED1 61 51 894E1 6C1 62CA9B1 2941 BD83ECA58D2CE41 394ACA971 E&E51 A93E2E41 DE&ED1 61 1 3ED2CE41 ACA&ED81 DAC1 A93E2E41 1 2941 DEE1 23A2CE41 DAC1 ABE1 BD83E1 4A2D1 48A9B1 291 2D1 BD83E1 CDE293E1 CEC71 E39451 CE1 BD83E1E9E126CE1CE2C5E9C1DAC11D2161DDE152B9AC84E1DE9114EB242CA91 D21E&E9CE41DAC1AC2BDACA91B"C714A451E.E94A9B+R1+C5129129C2B9AC161CE11E3EC51 E&E9CE41CE15E4A2CE41329BE1A91BD83E15EC2A71$A92DD851CE1A93E2E411 2941BD83E14A2D1D21CC2DD816D89CE41A911E3EC938C15A3E71DDE3CA&ED851CEE1 6A94A9B12B8E161291A5C29C1DE161121214D9CE2515EC26DA31C2BEC1612186EC161 1 23CA971 94EE451 1 21 6EE91 D91 C1 E9293E1 BD83E1 8C2E51 2941 C1 A93E2E1 CE1 39&EA9161BD83E1A9C1BD83BE91B2*C1A91583DE51C8139CA68CA9B1C1291&E2DD1A93E2E1A91 A98DA91E9ACA&AC81B2"C71A5AD216A94A9B1DEE16E&E41A91CE1EE9C1C8481DE914F91 5A3E1 DEE1 39CA988D81 A968E41 DAC1 71 91 852951 1 245A9AC2CA91 21 6EE91 23A2CE41 DAC1 A93E2E4123EDD1 6893CA91 21 E&E2DE41 681 CE1 A93E2E1 A91 CE1 1 B2+C71 91 CE1 EE9C1C84851CE1ABE1126CE11245A9AC2CA91D2135DECED8126B2CE41A917 F91 5A3E1 DA31 21 352E41 C1 @41 5A3E1 4AD28E41 21 5E1 9893E41 A93E2E1 A91 D2521 DE&ED161#129414$3126CE1238CE11A9-E3CA9711

4E1EE9C1C84812441C1CE1E3E9CD81E3B9AJE41E9CEE943A9E12CD281C8B1DA31CE1 A96D2552C81 5E4A2C1 #1 BDEDD9D91 21 291 1 C2BECC1 3291 39CA68CE1 C1 A93E2E41

(17)

A98DA91 E3ECA971 'E328E1 #1 A93E2E1 E9A&E9E1 C1 BD83E1 C8B1 CE1 A93E2E41 483CA91 61 1 681 A9CECA92D1 1 3EDD51 #1 E8DC1 A91 A93E2E41 A98DA91E3ECA91 2941 483CA91681293E2CA316EC213EDDB*C71C1A1A6DE1C2C1CE125E15DE38D215E329A515281 2D81 C16C1 CE1 #1 2941 CE1 5E4A2CE41E66E3C1 B2A1 2941 EE9C1 C84851 EE3CA&ED8C71 C1 D21 8BBECE41 C2C1 #1 A93E2E41 1 483CA91 C8B1 A93E2E41 BD832B91 C293ACA91 2941 E11 E.EA91 B*C71 91 EEA9B1 DAC1 CA1 8CEA51 1 E9ACAJE1 24E98D1383D2E123CA&AC81BA)C12941A93E2E1CE1483CA91613< 1BAC51DA31A19D91C16E1 A9&D&E41A91CE1EB8D2CA9161BD832B91BE9E1E.EA91BA(C7191244ACA951CE1BD832B91 CEA91E381A19D91C1894EB1CC29D2CA92D13EA9B1C8B1CE123CA9161CD1 52A9159E139&EC2E1BC51E112941(1BA1C51A&E91C2C16C1E112941(12E1 A9483E41DE91A5589E13EDD12E1E.E41C11BA2>1AAC5121DE161E9293E41E1123CA&AC81 3299C16E1E.3D84E471<DCE92CA&ED8519E82D12CD28152812D16E1A9&D&E45121E9819E&E1 2&E16EE91D91C16E1A9&D&E41A91CE1BD83E15EC26DA31E9E1C1E94C.A91BA#C512941CE1 E.EA91 61 CE1 9E8ECA4E1 32D3AC9A91 BE9EED2CE41 B7C51 DA31 A1 C8BC1 C1 D281 21 DE1 A91CE1 EB8D2CA91611 E3ECA91 BA*C51 A18EB8D2CE41 681 1 BA"C71 $A92DD851214AE3C1 E66E3C161CE1132DDE9BE191 4721AB92DA9B15ABC152E121AB9A6A329C139CA68CA91C1CE1 A9483E41 483CA91 61 71 94EE451 AC1 21 E3E9CD81 6EE91 D91 C2C1 E9CEE943A9E1 3EDD1E.EE416893CA92D14721BA+C5129418BD83E5A2121DEDD1211DEE1ECE41C16E1 6D89CE41A914724E6A3AE9C15A3E1B1)C71

858D2CA&E1 E&A4E93E1 A91 62&1 61 21 DA91 6ECDEE91 E94C.E5A251 E9CEE943A9E1 3EDD51 2941 BD83E1 5EC26DA51 D21 E3E9CD81 68BC1 A91 2CAE9C1 DAC1 A96D2552C81 6DED1 4AE2E71 91 9;14AE2E1DAC126952DD81EDE&2CE41E94C.E5A21B(C51E9CEE943A9E13EDD123CA&AC81D21 ECE41C16E1E9293E41B#)C71C1D2123A2CE41DAC1ABE1E.EA9129413A38D2CA9B1DE&ED1 61 1 B#)>1 #C71 91 244ACA951 ,21 E.EA91 2941 23CA&AC81 2E1 E483E41 A91 2CAE9C1 DAC1 9;14AE2E51C8152A9B1218C2CA&E139CA68CA91C1A93E2E411E.EA91DE&ED12941

(18)

8EA98DA9E5A2161',1B#(>1#1C7196E&2CA9161CE1EE9C1C848135E1A914AE3C18C161 8C2A9E41 E94C.E5A21 21 21 AB9A6A329C1 39CA68C1 C1 E9293E41 A98DA91 E3ECA951 DA31 39CAC8CE1 9E1 52A91 C2AC1 61 A96D2552C81 6DED1 4AE2E1 2941 21 CE3CA&E1 623C1 91 ED2E1 2CE1B#>1#2C71

1 1

(19)

1

!945DCDFD711

<8C139CA68CA9F1<7471EE23E4142C2717 71EE23E4142C212941E&AEDE4EE4ACE41CE1 52983AC517,1EE23E4142C251S7,71EE23E4142C251E&AEDE4EE4ACE41CE152983AC517S71 E&AEDE4EE4ACE41 52983AC51 7'71 E&AEDE4EE4ACE41 52983AC51 ,7,7:71 39CA68CE41 C1 4A38A91 2941 E&AEDE4EE4ACE41 52983AC51 771 39CA68CE41 C1 4A38A951 DCE1 2941 E&AEDE4EE4ACE4152983AC51:71,EAB9E41EE2351EE23E4142C21DCE1CE152983AC12941 A1CE1B8229C161CA1D12945121835124168DD1233E1C12DD1CE142C21A91CE1C84812941C2E1 E9A6ADAC81 61 CE1 A9CEBAC81 61 CE1 42C21 2941 CE1 23382381 61 CE1 42C21 292D8A71 @E1 C291 ADA1'2C26DE16152983AC1E4ACA9B714A1D1D218CE41681CE19CAC8C12CA92D14E1D21 29C%1 EC1 4E1 D21 7E3E3E1 %4A32DE1 B7 51 E9CE1 4E1 7E3E3E1 !"##C51 CE1 9EAD1 7%BA92D1 4E1 '8BB9E51 4E1 $941 8%E91 4E1 ,%&EDE5E9C1 7%BA92D1 B$,7C51 CE1

!9A&EAC%14E1'8BB9E51294121$E931&E95E9C129C15292BE41681CE1$E9312CA92D1 7EE231 <BE9381 894E1 CE1 B251 X9&ECAE5E9C1 4;<&E9AY1 DAC1 E6EE93E1 <7

<'[))(71 <41 A1 8CE41 5CD81 681 CE1 8D21 355ACCEE1 61 ,9B1 421 &A93E1 BSAEC925C12941681<B81,A-91B$293EC71,:,1A18CE41681CE12924217EE2312A1 B2512941CE1'29CA9B12941'EC1,A26ECE1E9CE1&14A12A1A9193ECA91'ADB871 1CE9CA2D1396DA3C161A9CEEC1EDE&29C1C1CA12CA3DE1DEE1ECE471

1 1

(20)

1 1

(21)

/DDBD9D7

231 456789ABC1 DE1 F51 E1 F31 5B691 A851 AA51 B1 51 61 B51 1 A851 9A519 !51A5 31"9551#$$#%#&'#&()*$$1

#31 6B1 +E1 A91 +E1 4B51 ,E1 -559B1 .4E1 F99B1 /E1 CB1 1 /A591 A59E1 9BB89651 61 5A561 AB0951 91 9 AB1 B51 69551 9BB9161991999531F1/6BAB191D51#$$$%'#$2)#231

*3191-E1 1FE145914E1-B914E15!1E16A591E1.59014E17C1 7E1 ,!B81 54E1 8B1 E1 85A1 E1 5 551 /E1 B!91 6E1 "!951 ,E1 8 BA91 6E1 759551FE1,A91F7E199B19DE1A591 +E157551.4E15914E16!591D1 45AB91 56BAB15 91 99A9A51 B59A1 61 9!91 59A531 95A51

#$$:%2'2:'2)2::#1

331;61FE16B 1DE1BA1FFE179A7561,E1!91816A59156BAB191911 A9C51B B5A1B195AA51 B053185A12&&&%222(#&)(*21

231 +1 ;E1 61 9FE1 .BBA1 E1 "9A751 FF1 /5A1 B1 AB191 61 BAB191 56BAB191659CA9C51B1!B51095A9319!AB18B012&(2%2:*$2)*221

'31 4B51 5E1 48BA1 E1 69A91 6D1 "A5)96!561 855 931 9A91 51991#$$2%2:2$:)2#31

:31,B1F;E1659 19F1;55 9191A8519A59C5151!9A1B1B51<!A11 051B19515C59A31"!9195A9B1#$$2%'#**)#321

(31 ;91 ;E1 =61 "E1 .0 !1 41 6BB61 !B51 BAB1 91 A95A1 9A81 5C551 591 61 5A91 8B031 8B61 <B!1 B1 AB5A5BB1 1 8F91 #$$&%2232*#) 32*'1

&317951"E1+9!16E189AAB01DE1.BAB1DE14!81FE14A8!1E149A8514E17BA51 E1891>E1;565B18DE1DBB1FFE165B B1DE1BB01E14B61/E1B6501-E1

;55A1-E1;5615E1DB9B1691;B5 9161901B165A81919A9191 A95A31.1/1F14561#$2#%*':22$()222(1

2$3151+1DB19E1>?!571/4E1@!9A5B14E1B6B1F;E1656B14E1D5A5B1;E1 DB9B1 9E1 6C961 E1 F9 51 71 ,851 BA5A91 9 A1 B1 6 99B1 9!91

(22)

5C51 B1 A95A1 B!AB 51 91 A851 9A59C51 51 !9A31 F1 ,! 1 !A51 51 "!1

#$2*%:3#:$)#:21

2231 59661 +6E1 "8!51 9E1 +!5601 F-E1 ;B851 ,E1 ,951 D/E1 ,5A91 4E1 40 1 .1 4!91 A9CA9B1 B1 A851 8B8A969B9AB1 *)095ABA591 0951 61 B0AC1A8156!519BB8965)96!5619 A9B191 9531,851FB!1 B18 BB1615159 5A1A855!A91#$$(%*#'*3()*2*1

2#31 9!A951 ,E1 5591 E1 505A1 >E1 5! !11 E1 =951 .E1 "51 +E1 -!1 E1 +51 9!51.E1A891E14BA51,E14B951"E1-9617E1F91DE14B1E1+BA1+1 /5A1 B1 1 8B8B9961 A51 BA591 659951 B1 5A81 56BAB15 91 91 9531F169B185 1#$$(%#(*2(:$#)2(:2$1

2*31 "B891 +E1 6B1 ,FE1 4!01 .E1 6!051 -+E1 !581 6E1 FB51 +E1

!051F19!B519AB551!A1B 1A95A191 9519A811!1 !AA9B191A851

!B)90515A96512155AB15531.A145612&&'%#2#23)2#2(1

2331 F91 DE1 @91 "E1 @9B1 E1 5B1 5E1 +91 4E1 "0B61 E1 D9B1 DE1 ,1 D1 B9BBA591 61 55A9B1 61 A85B5B91 51 655561 91 951 9A81 8B8B996)A51BA5916599531.A14561#$$2%:(3:)(2#1

2231AA51E1C9!61E11E1!!1DE145B5!14E1-5CBA1E1551E1 A)+!514E1>5A1-1591A9 !A51!B51!A051!A1BA19B91918! 1 69B51A9!51511C9CB31F14B1/6B9B1#$22%3'#2)#(1

2'3155 16E1899 19E198A5914E16BB 1"D19!B)90515A965)21:)*'11 89BB9195A9191 31+5A12&(:%#2*$$)2*$31

2:31 /961 ;E1 ;!5 1 4E1 "8!51 6E1 ;91 4E1 69B1 ++E1 45951 ,E1 /51 /E1 6B!7091 5E1 8!55A1 "E1 4!51 EE1 ;51 4E1 D595051 4E1 5B61 E1 9 1 4E1 D59 1 7E1 ;1 -E1 9B 61 FE1 !051 FE1 9951 74E1 /851 FE1BA814E14A55!09)'158519!9155A9B119591!B)9051 5A965)2155A9B1B 1+1516181531.A14561#$22%2:23(2)23(&1

2(31 "!1 "E1 5951 41 "9A9A91 1 5C9531 /15A1 =91 -8 BA851

#$22%2#2'2*)2'##1

(23)

2&31 !91 4FE1 B1 +E1 F!71 "E1 791 F"E1 79A79 B1 ;+E1 F9B1 DE1 661 DFE1 5! 14E16018E1!051FE1;951.19!B)90515A965)2155AB191 9CBC56191591615!BBA5A9B31.A14561#$$*%&22:*)22:&1

#$31 +1 ;E1 B5!1 E1 457B1 51 4!9) 569A561 !B51 !A051 1 969C96!1A9!516!91593145AB9 1991615159 5A12&&$%*&2$&') 22$:1

#231 606189E1 65B1 F;E1 F3E1 "9A751 FF1 ;59!99 1 91 56BAB191 8B01 6B3145AB9 1991615159 5A12&:'%#2':2)'(31

##31+1;E1B5!1E1619FE1"9A751FF1A5561!B51095A9191695A91 A1 6!91 )5A9C51 95A9B31 ,851 591 <B!1 B1 89BB1 2&(:%#2*/2#*)2#&1

#*31 555851 +E1 7B1 6E1 61 9FE1 "9A751 FF1 45AB91 61 8B B1 851 BB91 56BAB191 6 99AA9B1 AB1 695A91 A31 ,851 591 <B!1 B1 89BB12&(#%#3*D::)(21

#33141FE1D9BC991.E1"8951414!915B51AB1BA9!B!1!B51B6191 56BAB1918B0191A8516B31"!195B1=A5A12&::%2322&()#$#1

#231 DB B01 FE1 61 9FE1 6B0 1 /+E1 "9A751 FF1 45561 !51 !B51

!A051 61 AA51 5551 A51 56BAB191 6 99AA9B31 ,851 591 <B!1 B1 89BB12&($%#*&/*22)*2'1

#'31 D9561 /FE1 !B1 D,E1 D59861 E1 5B898591 .41 /5A1 B1 !A51 56BAB15 91 B1 !B5!A9B1 91 B 1 61 695A91 !<5A31 F1 91 /6B9B1 45A12&::%3222*)2#21

#:31655519E1)F9B!91+4E17! 16+E1-AA1FD1/16BAB19)96!561 5AB91 85191A851B9B!E1!5A9561A18B5 916155CA561BB61AA51 B5AA9B19A8B!A1859!95 9319!AB18B012&(2%(23*)22$1

#(31 +1 ;E1 "B91 FE1 =AA01 E1 "9A751 FF1 /5A1 B1 898)6B51 56BAB191 B1

!B51 B6!A9B1 61 !A997A9B31 45AB9 1 991 61 5159 5A1 2&&*%3#2*22)2*2(1

(24)

#&31 ;61 4"E1 75AA 1 4FE1 8651 +9E1 5501 F+E1 4B1 DE1 -8991 D81 45561 !B51 !A051 55651 859!95 91 91 051 56BAB15 91 999319!AB18B012&(*%22#(:)#&21

*$31D5A7817E16BB01.+E165 1F4E14BB515"E1;B901-E155BC1"E1091

"E1 651 F/E1 6691 "E1 40 1 .E1 B 1 ,-1 +9BB89651 9899A9B1 B1

!B51 B6!A9B1A8B!81A851,B)9051 55AB)3E1 5B9616955A9A9B1AB1((E1 61!51AB1011A831;5ABB1#$$&%2$2&#)'$$1

*231!B91=E1D5961E14B01-E1+9AA51DE1B19+14!9159A5161

!AA51!A997A9B1918! 156BAB15 931,851FB!1B199156B9BB161 5AB9 1#$$$%(2*::$)*::(1

*#31 C1 651 51 ".E1 6! 51 D4E1 "A551 4/E1 05 1 4,E1 /65A1 /E1 ,01 48E1 "5951 4FE1 C1 651 -B1 ,E1 "!5591 ;-1 /1 56BAB15 91 9551 59851 61 85A91 9!91 59A9C9A1 91 85A81 8! 31 ,851 FB!1 B1 991 56B9BB161 5AB9 1#$$&%&33'*)3'(1

**31 458A1 ..E1 4999!661 7E1 65B1 -E1 ;9051 E1 "881 DE1 -!9B1 +E1 ,9A)4A9571 FE1 "551 57E1 D9051 4DE1 D591 4-1 /159 5A1 56BAB15 91 96!51 69B51 9 A9B1 61 9!91 59A51 91 8! 31 95A51

#$2$%2&2:#)2(21

*331 C9B1 F4E1 79AA91 E1 ;55)C9B1 .E1 5981 "FE1 851 ;"1 AB0951 5B51 1 BBA51 61 B851 AB1 551 61 9BBA59)B!61 9BB89653145A14 !12&&$%2(#*:2)#*(#1

*231 7551 8E1 8B1 E1 451 .E1 .BA8B1 ;1 4899A9B1 B1 56BAB19)96!561 A9CA9B1 B1 8! 1 BBA51 1 8! 1 9BBA5931 45A1 4 !1 2&(&%2:##*:)

##321

*'31 ;91 ;8E1 9!561 E1 759B61 5DE1 D561 ,/E1 551 F-E1 FB51 +E1 /98! 1 /6E166197E1D1F;18B 9B1A51A851A51B156BAB19E165591A! B1 5B91AB15551615C5A9165A831F1914C5A12&&*%&22$#()2$*31

(25)

*:31 89A50)F!501 +E1 79091 F-1 4!9)9051 A9B1 B1 56BAB191 AB9 1 1 A5B961 61 BA5B961 A9)9 AB1 5A31 9!AB1 8B01 2&(2%(2:*) 2(*1

*(3189A50)F!501+E179091F-1D5A9B1B156BAB191A!A!51AB18B5 9161 9!99051A9B319!AB18B012&(*%22#*)*31

*&31 79091 F-1 /6BAB19)58561 55A9B1 B1 B851 9!9)9051 A9C9A31 F1 D5A9!B56BA851"B12&($%#:2$:)2221

3$31E59814DE179091F-14!918555A9B161BA5A9A9B1B156BAB1918B01 91A851A319!AB18B012&(#%&2(&)'$*1

3231E59814DE179091F-1DB51B19! 191A8519!918555AB1AA51B1A851 56BAB191A15319!AB18B012&(3%233&)'#1

3#31 E5981 4DE1 79091 F-1 4589 1 B1 859!95 91 91 56BAB19B931 ,851 591<B!1B189BB12&($%#*&/22')2'21

3*31>9C5)-91 4E1"B B71.E1 75657)C571FE1>1 7E1B1 -E11E19B 91 DE1+5A14=E1-!<B)6B51D1/C96551B15159B1B156BAB19155AB123E1 AB)905155AB1,+D3161,+D#161B9A561 B5!514)#161B159A9C9A1AB1 56BAB191 B+-"C1 91 95A1 5A1 531 991 61 5159 5A1 9 !BB1

#$$*%2**#$()#2(1

3331 9)4A961 ;4E1 4B!B1 D7E1 4ABC91 4E1 "AB1 4E1 "B1 4E1 9B6511,B)905155AB131B,+D3C15159B1918! 161 !9515A91 5A)515A151C999A1619!918B 5BA9316419 !BB1#$22%2#2(1 3231B51D-1;59!95 91599A56119A55!09)2161B5A8156BAB15 91 91A319!AB18B012&(&%#(2#2)2*$1

3'31,55651E14!915DE14A51F/E18!5817EE1"AB B1,E149!951=-1 45AB915B51AB156BAB19191C9CB191A851B9B!1 B!51B51B19A55!09)'31 45AB9 1991615159 5A1#$22%'$&#)&(1

(26)

3:31 >C5651 4E1 4B51 4E1 5 5A51 7E1 +B57)56B1 44E1 56B1 /E1 -551 E1

>9!5C)-59B1 4+1 9!B)9051 5A9651 21 1 BA5A1 B591 8B B531 7/6"15AA512&&3%*3&*2*)*2'1

3(3146914E1-A91E191"E1B51D1/1569)3195519!9159A9C9A1C911 -4)*)095)65565A1 589 1 BAA91 55A1 B1 9+-)231 69B85 91 8 BB1#$$#%'*&&*)&&'1

3&31 F651 4E1 4661 "E1 4651 F+E1 ;BA1 FF1 /5A1 B1 ')5501 B!51 B1

!B)90515A965121B15 91BABE19!9159A9C9AE1615A)51!A9B1 91A51#1695A5115)B!1A!631+5A1#$$#%*2&(#3)(*$1

2$31=1EE1+551;,E1;98 1E1D!1E1/ 181+9BB8965)96!561 59A97A9B1B165151A9C9A191 !951 B8531 591<B!1B1 89BB15189BB1#$$'%#&$23*)2221

2231 4BB1 /EE1 +551 E"E1 8B91 8"E1 +551 4;1 ,B)9051 55AB1 3) 569A561 4-1 B6!A9B1 !)5!A51 6)51 A9CA91 AB1 5159B1 91 D#'33:1 B8531/159 5A1515581#$22%*2:#33:)#3221

2#31!051FE16!051-+1-B!B15515159B1915!A5611191 4-)65565A1 A81 91 A1 9A5A9531 -B55691 B1 A851 .A9B1 65 1 B1

"9551B1A851G9A561"AA51B1 5912&(&%('*&2*)*&2:1

2*31 DB!951 EE1 4A91 "E1 "A5951 71 955A91 B591 B1 B!B1 1 A851

!A999)9051B8B B51BC5A51-#161-*1AB155A51 59A851!B1B1

!B)90515A96531F169B185 12&&2%#:$#'3(()#'3&'1

2331 >96B1 =E1 451 4E1 9A51 9E1 "9A751 FE1 /9B71 +D1 -B8B B51 BC5A51-#161-*191A15!AB89161 B8531-518519A81 B50589)659C5615A965196!5611+-"191C9CB31.5!B5A96512&&3%#:#*2)

#331

2231+19E1B18E1!B914E16591.E1BB1E17B!9514E1"75A14E11 D1 +9BB89651 569A561 5!A9B1 B1 5!B56B951 B9A561 BBA591 BC5A51 61 5!B5A9651 5!B1 B591 91 A851 A1 5531 FB!1 B1 5!B9 !BB1#$$'%2:22:):21

(27)

2'314B1/E1+1;14CBC5 5A1B199)59A9C515C51915!A91A851 8B B51 61 !B51 5AB91 5B51 AB1 56BAB1931 ,851 591 <B!1 B1 89BB12&&:%#:*/*#()**21

2:31 ;5 )D9051 E1 495B1 9-E1 9B051 61 9AB91 55)5A561 5A9651 BA5A1A9 !A51!B)90515A965)21555191A8519BA5615!561A195! 31 -5A9651#$$$%#23*2)3*:1

2(31 41 8E1 ! BA1 EE1 >5!A551 7E1 @!99B1 D1 +9BB89651 96!51 9AB91 55)5A561 5A9651 91 A851 D8#'33:1 B851 51 9531 4 !BB1

#$2$%2*$*&&)3$&1

2&31 6B!BC91 4E1 C51 ";E1 ,9A1 F"E1 81 ,E1 ;71 .E1 D9B1 ;E1 451 +7E1 -5C1 "/1 /A5B56B951 51 5151 !A9B1 ,B)9051 55AB31 591

<B!1B189BB19AB9A5A91619C5189BB1#$$:%#&#92::$)2:(*1 '$31 4B1 98E1 -5B01 FE1 4+!891 F,1 /A5B56B951 51 91 A5 91 951 B8H1695531F1B81B9A91#$2#%'(:2)(($1

'2316565A1.E1"1/E1B851=E16B81=E18B91E1D BA1EE185914E1;5C91E1 DBBA1 4F1 /8561 !B5)65565A1 !B)9051 5A965)21 61 9!91 55A9B191B81A95A19A81A5 9195! 16955191!5A561AB169551A9C9A1 B195155A9B31"61F19AB5A5B1#$$3%*&'2$)'2'1

'#31 4B1 98E1 =H.591 E1 -69561 -E1 4+!891 F,1 95A961 5A965)31 5159B19156!56191B8H1695531D5!1-5A1#$2#%2::3$)321

'*31 D9B1 @E1 6B!851 D-E1 9B1 4E1 !051 FE1 6!051 -+1 9!A91 5C51 B1

!B)9051 5A965)#1 91 8! 1 !<5A1 9A81 9 AB1 B51 695531 1 F1 -89B1D5!14A51B 1-89B1#$$$%#:(D2$2:)2$'*1

'331 655751 .E1 ;A 1 E1 "A!81 GE1 "8B 5981 FE1 6!1 ,E1 6B859 51 +1 45561 9!91 59A51 61 5A1 51 A9C9A1 91 A95A1 9A81 B8H1 695531 4 16B5191#$$'%2#2*)2'1

1 1

(28)

62BD1DDC7 1

2345671891AB5C713DED13F7BC3F1117FFB711

AD1CDEE2F3227222 !"# !22$%&2FC!2# #&2F!'722()*232 F%&2+2F!'72 !2,E2 #-2-2./%022!2#122&#2!222 2 3 42 ! 2 F---2D2 )&2 !& !2 &1&2 2 32 !2 16 !2 2 !2 &2

&#2&2F32 !2$%&5 !"#2 #2F!'1B2!2()*5 !"#2 #2F32F!'1B-2D1 6!& !! #2 !2-2 , 2 372 $%&5 !"#2 #82 9&#2 372 ()*5 !"#2 #-2 942 72$%&73A-32:2B-7202()*2724B-B2:21-722F!-2;&22!2:2*<=-2>B-B602??>B-B102

???>B-BB10230#2>B-BB1212@ !022>B-B6212$%&2&#2&-2 1

234567191FC3F5513DED13F53F11117FFB71D1

,E2 #2 A2 --2 !2 2 392 42 A 2 $%&2 2 ()*2 F4BBB42 !2 ! #2

&CD-2AD1CDEE2 F32 2 392 42 2 2 $%&2 FC!2 # #&2 F!'52 2 ()*2 F%&2 +F!'82 --2 ! !2 !2 ,E2 #-2D1./%02 2 !2 #12 2 &#2

!2 22 2 3 42 ! 2 F---2D1)&2 !& !2 &1&2 2 32 !2 16 !2 2 !2 &2 &#2 &2 F32 !2 $%&5 !2 #2 F!'52 !2 ()*5 !2 #2 F3&#2 32 F!'8-2D16!& !! #2 !2-2 , 2 372 $%&5 !2 #82 9&#2 372 ()*5 !2 #0294272$%&737-A:2B-4202()*27238-42:2B-622F!-2;&22!2:2*<=-2 30#2>B-BB1212@ !022>B-B6212$%&2&#2&-2?>B-B62

1

2345671 911313FB677!1C11467C761!7467713F1"#$%1&3B71C761B5C713DE13F7BC3F11 1

AD1CDEE2F3227222 -2 !"# !22$%&22()*2F32 !2,E2FC!2

# #&2 F!'62 2 )(E)5EC2 #2 F%&2 +2 F!'6-2D2 ./%02 2 !2 #12 2 &#2

!22223 42! 2F---2D1)&2 !& !2&1&2232!2162 !222&#2&2F32 !2,E2 #2F!'1B2!2)(E)5EC2 #2F!'A-2D16!& !! #2 !2-2, 2372,E2 #829&#2372)(E)5EC2 #-294272,E74B-92:21-5202)(E)5EC72 39-B2:2B-822F!-2;&2 2!2:2 *<=-2?>B-B602??>B-B102???>B-BB102 3072 >B-BB1212 ,E2$%&82#072>B-B6212)(E)2EC2$%&8272>B-B6212,E2()*2

1

2345671'91(FFB7!13F)&&C6*167EF713F1"#$%1&3B713DED13F57!1+3C11

254244 2#!!2 !1F 2G! 42( !2FFG(2FA,021& !22# !2 F(@@2-,1 !2,E2 #2F!'72!2)(E)5EC2 #2F!'7-2D2FG(22(@@2254244 2 -2D1 ( 12 E!32 H$.2 &1&2 !2 ,E2 #2 F!'82 !2 )(E)5EC2 #2 F!'9-2 , 2 372 ,E2 #82 9&#2372)(E)5EC2 #-294272,E7243-12:2B-6202)(E)5EC7241-72:2B-722F!-2;&22

!2:2*<=-272>B-B1212,E202372'B-BA212,E-21 1

1 1 1 1 1 1 1 1 1

(29)

2345671.1)5B7167EF71))+3F413DE13F53F1+3C11313FB677!1C11467C761!7467713F1

"#$%1&3B7D1

AD1CDEE2 F32 2 32 F5()*2 !2 2 2 !2 FI()*2 2 2 -2 ! !2 2 ()*2 F4BBB42 !2,E2 #2FC!2# #&2F!'75112!2)(E)5EC2 #2F%&2+F!'8592 D2./%022!2#122&#2!22223 42! 2F--2D1)&2 !& !2&1&2162 !22!2&2&#2&2F32 !2,E2 #2F!'162!2)(E)5EC2 #2 F!'16517-2D16!& !! #2 !2-2(D1 !& !2 &!#22 2 2 !2 2 2 --2 ! !2 2 ()*2FC!2# #&72,E2 #2F!'1582%&2+72)(E)5EC2 #2F!'15-22D2./%022!2

#12 2 &#2 !2 22 2 3 42 ! 2 F---2 , 2 372 ,E2 #82 9&#2 372)(E)5EC2 #-2;&22!2:*<=-2?>B-B602??>B-B1823072JB-BB1212,E2F5()*82#72

>B-BB1212)(E)2EC2F5()*8272>B-B62212,E2FI()*820"72>B-B6212)(E)2EC2F5()*82K 72>B-B6212 ,E2F5()*2

1

62BD7'795D5947D38D2729BD87DC21"E45F29D2 327DC2A1%1

! 98DA91 5E4A2CE41 BD83E1 8C2E1 A91 @41 5A3E1 B9V*C1 2941 A91 4F91 5A3E1 B9V#C71+ 1 83DE1 D8C21 57<1 DE&ED1 A91 @41 5A3E1 B9V*C1 2941 A91 41 RF91 5A3E1 B9V"C ( 83DE1 D83BE91 89C2E1 1 57<1 DE&ED1 A91 @41 5A3E1 B9V*C1 2941 A91 4F91 5A3E1 B9V"C7 )71 D83BE9139CE9C1A91583DE1A91@415A3E1B9V#C12941A914F915A3E1B9V"C711@ACE162>1@41 5A3E>1'D23162F14F915A3E71S2D8E12E15E291U1 71\W)7)A1

1

2345671/91#81EC+*1313F0)07!13F1#3F!5B7!13FB67713F11

1EE7672 ()*2 !#2 D()512 !2 !& !2 # !2AD1)&2 D()512 &1&2 72 2 2 -2 !"# !2 2 $%&2 F!'92 2 ()*2 F!'1902 32 !2 2 2 &#2 &2 F32D2 )&2 6!& !2 &1&2 32 !2 2!2 &2&#2&2 F32 !2 $%&5 !"#2 #2 F!'92 !2 ()*5 !"#2 #2F!'192F, 2382$%&5 !"#2 #829&#2372()*2 !"#2 #-2D2 )&2 D()512122 6!& !2 &1&2 *!2 #& !-223!!)772 * & !2 !!#2 ()*5 12&#2 &-2D1CDEE2F32 !2()*5 !"#2 #2F32FC!2# #&2F!'52 2 ()*2F3I2* & !F62 !"#2 #2F%&2 +2F!'6-2942 72()*72 34-62 :2 B-52 02 ()*2 I2 & !72 34-62 :2 B-52 2 F!-2(D1./%02 2 !2 #12 2 &#2

!2 22 2 3 42 ! 2 F--2+7691<2! !A2 3&#2 ()*5 12 &#2 &22D1CDEE2 F1-62 !2 ()*2 !"#5 #2 FC!2 # #&2 F!'72 2 ()*2 F32 I2

<2! !A2F6B2F%&2+2F!'7-294272()*721A-72:2B-4202()*2I2<2! !A721A-A2:2 B-322F!-1D1./%022!2#122&#2!22223 42! 2F--2

;&22!2:*<=-2?>B-B602??>B-B102???>B-BB12 1

2345671391#3F!5B7!13FB67713F11F!14)5B71!3E)16714)5FC7!13F1#851$%1&3B71 )&2 &1&2 2 #4 !2 !2 ,E2 #2 F, 2 32 !2 D()15H2 EC2 #2 F9&#2 32 2 2 72 2 2 #2 !"# !2 2 $%&2 2 ()*2 F3-1 AD16!& !2 71F6(7-2D1 E2 !# 2 #2 &2 FE$@3782D1CDEE2 F32 !2 $%&5 !"#2 ,E2 #2 FC!2

# #&F!'112 2 ()*5 !"#2 ,E2 #2 F32 F%&2 +2 F!'11-2 942 72

$%&735-62 :2 B-A2 02 ()*72 35-B2 :2 B-62 2 F!-2D1CDEE2 F32 !2 $%&5 !"#2 D()51H2 EC2 #2 FC!2 # #&2 F!'112 !2 ()*5 !"#2 D()51H2 EC2 #2 F%&2 +2 F!'1B-2 942 72

$%&72 31-82 :2 B-32 02 ()*72 31-B2 :2 B-42 2 F!-2(D1./%02 2 !2 #12 2 &#2 !2 2223 42! -22D1)&2 !& !2&1&216 !22!2&2&#2&2F32 !2$%&5 !"#2 ,E2 #2F!'132 !2()*5 !"#2 ,E2 #2F!'11-2D1)&2 !& !2 &1&2 16 !2 2 !2 &2 &#2&2F32 !2 $%&5 !"#2 D()51H2 EC2 #2 F!'1B2 #2 !2 ()*5 !"#2D()51H2EC2 #22F!'9-226D1 !& !! #2 !2-2, 2372$%&5 !"#2 #02

(30)

9&#2 372 ()*5 !"#2 #2 F3-2 ;&2 2 !2 :2 *<=-2 F?>B-B602 ??>B-B102

???>B-BB12 1

1

(31)

0 5 10 15 20 25

NaCl LPS

15 30 60 90 120

***

**

***

* ** ***

min

Glucose (mmol/L)

0 2 4 6 8

**

Nacl LPS

Glucose AUC (a.u.)

0 50 100 150 200

**

Insulinogenic index (pmol/mmol)

A B

C D

0 200 400 600 800 1000

a a

b

c,d

Insulin (pmol/L)

(32)

0 5 10 15 20 25

NaCl LPS

15 30 60 90 120

min

G lu c o s e ( m m o l/ L )

0 5 10

15

NaCl

LPS

G lu c o s e A U C ( a .u .)

0 10 20 30 40

50

*

in s u li n o g e n ic i n d e x (p m o l/ m m o l)

A B

C D

0 200 400 600 800

Fasting Glucose load

a a

b

c,d

In s u li n (p m o l/ L )

(33)

0 5 10 15 20

*

** *

NaCl LPS

WT PLTP KO

Glucose AUC (a.u.)

0 200 400 600 800

NaCl LPS

e e

f

g

In s u li n o g e n ic i n d e x (p m o l/ m m o l)

C D

0 10 20 30

40

WT

PLTP KO

NaCl

*** * ** * LPS

15 30 60 90 120

* *

*

min

G lu c o s e ( m m o l/ L )

0 1000 2000

3000

*

NaCl LPS NaCl LPS

Insulin (pmol/L)

(34)

0 10 20 30

a W T P L T P K O H D L

-hydroxymyristate (ng/ml)

0 20 40 60 80

b L F F

-hydroxymyristate (ng/ml)

0.0 0.2 0.4 0.6 0.8 1.0

a H D L /L F F

HDL/LFF ratio

a

0.5 1 1.5 2 2.5

Tnf mRNA/actin mRNA (x10

-3)

F IG U R E 4

B

D

Diabetes

(35)

0 5 10 15 20 25

WT PLTP KO

* **

**

*

- LPS + LPS

15 30 60 90 120

min

Glucose (mmol/L)

0 2 4 6 8 10

- LPS + LPS

a a

b

c,d

WT PLTP KO

Glucose AUC (a.u)

0 200 400 600 800

- LPS + LPS

e e

f

g

Insulin (pmol/L)

0 20 40 60

- LPS + LPS

h h

i

i,j

insulionogenic index (pmol/mmol)

0 5 10 15

WT PLTP KO

*

**

*

0 15 30 60 90 120

*

***

**

Glucose (mmol/L)

0 2 4 6 8 10

***

WT

PLTP KO

Glucose AUC (a.u.)

C D

E F

(36)

0 1 2 3

* W T P L T P K O Fold increase

over basal glucose uptake

0.0 0.5 1.0 1.5

*

GLUT4 mRNA/-actin mRNA

0.0 0.2 0.4 0.6

*

Glys-1 mRNA/-actin mRNA

0 5 10 15 20 25

*

Glycogen (µg/mg)

F IG U R E 6

B

D

Diabetes

(37)

0 5 10 15 20

Fasting Glucose Load

**

NaCl

***

LPS

GLP-1 (pmol/L)

0 200 400 600 800

Fasting Glucose Load

*

Insulin (pmol/L)

0 10 20 30

0 200 400 600 800

1000 rhô=0.709; p<0.001

GLP-1 (pmol/L)

Insulin (pmol/L)

0 5 10 15

20 LPS

LPS + Sitagliptin

*

** * *

15 30 60 90 120

*

min

Glucose (mmol/L)

0 5 10 15 20 25

LPS

LPS + Exendin 9

***

* *

0 15 30 60 90 120 -30

Glucose (mmol/L)

0 2 4

6 LPS

LPS + Exendin 9

***

Glucose AUC (a.u)

C

D E

F G

0 2 4 6

8 LPS

LPS + Sitagliptin

*

Glucose AUC (a.u)

(38)

0 10 20 30 40

NaCl

******

LPS

**

* *

15 30 60 90 120

WT

*

min

Glucose (mmol/L)

0 5 10 15 20 25

NaCl LPS

15 30 60 90 120

GLP1-R KO

*** * *

min

Glucose (mmol/l)

0 5 10 15 20

***

WT GLP1-R KO NaCl

LPS

Glucose AUC (a.u)

200 400

600 WT

*

Insulin (pmol/l)

200 400 600

GLP1-R KO

Insulin (pmol/l)

20 40 60 80

100

**

insulinogenic index (pmol/mmol)

A B

C D E

F

100 200

0.1 0.5

NaCl LPS

IL-6 (ng/ml)

0 100 200 300

400 GLP1R-KO

NaCl LPS

TNF (ng/ml)

G H

Références

Documents relatifs

Abbreviations used: DMEM, Dulbecco’s modified Eagle’s medium; ERK, extracellular-signal-regulated kinase; GFP, green fluorescent protein; GST, glutathione S-transferase;

To test whether the vesicular pool of Atat1 promotes the acetyl- ation of -tubulin in MTs, we isolated subcellular fractions from newborn mouse cortices and then assessed

Néanmoins, la dualité des acides (Lewis et Bronsted) est un système dispendieux, dont le recyclage est une opération complexe et par conséquent difficilement applicable à

Cette mutation familiale du gène MME est une substitution d’une base guanine par une base adenine sur le chromosome 3q25.2, ce qui induit un remplacement d’un acide aminé cystéine

En ouvrant cette page avec Netscape composer, vous verrez que le cadre prévu pour accueillir le panoramique a une taille déterminée, choisie par les concepteurs des hyperpaysages

Chaque séance durera deux heures, mais dans la seconde, seule la première heure sera consacrée à l'expérimentation décrite ici ; durant la seconde, les élèves travailleront sur

Figure 8 shows images from the high-speed video as viewed looking down through the crushing platen that are associated with the points indicated on the load