• Aucun résultat trouvé

Rôle des modulateurs épigénétiques dans la physiopathologie des lymphomes B diffus à grandes cellules

N/A
N/A
Protected

Academic year: 2021

Partager "Rôle des modulateurs épigénétiques dans la physiopathologie des lymphomes B diffus à grandes cellules"

Copied!
196
0
0

Texte intégral

(1)

HAL Id: tel-02479354

https://tel.archives-ouvertes.fr/tel-02479354

Submitted on 14 Feb 2020

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.

Rôle des modulateurs épigénétiques dans la

physiopathologie des lymphomes B diffus à grandes

cellules

Vanessa Szablewski

To cite this version:

(2)

THESE POUR OBTENIR LE GRADE DE DOCTEUR

DE L’UNIVERSITE DE MONTPELLIER

En Biologie Santé

École doctorale CBS2- Sciences Chimiques et Biologiques pour la Santé Unité de recherche PCCI- Pathogénèse et Contrôle des infections Chroniques

Présentée par Vanessa Szablewski

Le 29 Novembre 2019

Sous la direction de Mme Valérie Costes

et de Mme Caroline Bret

Devant le jury composé de

M. Luc XERRI, PU-PH, Institut Paoli Calmettes President et rapporteur

Mme Valérie COSTES, PU-PH, CHU Montpellier

Mme Camille LAURENT, PU-PH, Centre de Recherche en Cancérologie de Toulouse M. Jérôme MOREAUX, CHU Montpellier

(3)

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

=D&!#$7956&!:Q(O-(!! :;<!=2%4>&776&5!! 165&34&F5!@&! 4CH'&!!

=D&!

:$D677&!,*<X-KO!!

:&%45&!@&!X&3C&53C&!&%!:$%39527286&!@&!

O2F72F'&!! X$>>254&F5!!

=Y!,F3!Z-XX0!! 0%'464F4!G$276!:$7D&44&'!! X$>>254&F5!! =Y![95ID&!=QX-*<Z!! :;<!=2%4>&776&5!! -P$D6%$4&F5!! =D&!:$5276%&!+X-O!! :;<!=2%4>&776&5!! 0%?649&!!

(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
(17)
(18)
(19)
(20)
(21)
(22)
(23)
(24)
(25)
(26)
(27)
(28)
(29)
(30)
(31)
(32)
(33)
(34)

! NA! 7`$>>$56462%!@&!7`&P>5&''62%!@&!+:,UY!+:,U!&'4!&P>56D9!>$5!7&'!3&%4523\4&'c!7&'! 3&%452_7$'4&'!&4!>$5!7&'!3&77F7&'!O!723$76'9&'!@$%'!7&!3&%45&!8&5D6%$46J!$725'!EF`67!%`&'4! >$'!&P>56D9!>$5!7&'!7\D>C23\4&'!+!%$hJ'!&4!D9D265&'!&4!>$5!7&'!>7$'D23\4&'Y!($! 'F5&P>5&''62%!&'4!!6%@6'>&%'$_7&!>2F5!7$!J25D$462%!@F!3&%45&!8&5D6%$46JY!! ! ?-)#07.-+,0)2%9#)2+#$Q%,&'!6DDF%2_7$'4&'!+!'46DF79'!>$5!7`$%468H%&!'&! @6JJ95&%36&%4!&%!3&%452_7$'4&'!@$%'!7&!3&%45&!8&5D6%$46J!&4!'`$33FDF7&%4!@$%'!7$!j2%&! '2D_5&!]T68F5&!"N^Y!,&'!3&%452_7$4&'!&P>56D&%4!>&F!@`08!R!7&F5!'F5J$3&!&4!'&!DF746>76&%4! 42F4&'!7&'!U!R!a!C&F5&'Y! ! H5/$-(*,+,0)2'%')(+,03*$'Q!,&'!3&%452_7$'4&'!'F_6''&%4!@&'!DF4$462%'! >2%34F&77&'!'F5!7&'!59862%'!?$56$_7&'!@&'!8H%&'!@&'!08Y!:&!>C9%2DH%&!&'4!$''F59!>$5! 7`&%j\D&!*01AcNY!,&'!C\>&5DF4$462%'!'2D$46EF&'!$''F5&%4!F%&!7$58&!@6?&5'649!

(35)
(36)
(37)

! Ng! ! T68F5&!"NB!!1952F7&D&%4!@&!7$!59$3462%!6DDF%64$65&!@$%'!7&!3&%45&!8&5D6%$46J!

(38)
(39)
(40)
(41)
(42)

! LM! &4!O!S!7&'!,K;!@&!J$6_7&!D$768%649c!7&'!,K;!@&!D$768%649!6%4&5D9@6$65&c!7&'!,K;!@&! D$768%649!97&?9&!&4!F%&!37$''&!5&852F>$%4!@6?&5'&'!%92>7$'6&'"MY!:&44&!37$''6J63$462%! F%6EF&D&%4!_$'9&!'F5!7$!D25>C27286&!JF4!F%!93C&3Y!! ! :`&'4!&%!"ddLc!$?&3!7$!359$462%!@F!852F>&!@`94F@&!6%4&5%$462%$7!@&'!7\D>C2D&'c! 59F%6''$%4!376%636&%'!&4!>$4C27286'4&'!EF&!7$!37$''6J63$462%!@&!X-*,!]X&?6'&@!-F52>&$%B *D&563$%!37$''6J63$462%!2J!,\D>C26@!%&2>7$'D'^!?264!7&!b2F5Y!:&44&!37$''6J63$462%!6%4H85&! 7&'!%2F?&77&'!32%%$6''$%3&'!_627286EF&'!'F5!7&'!7\D>C2D&'!&4!6%37F4!@&'!3564H5&'! 376%6EF&'""Y!-77&'!@6'46%8F&'!7&'!7\D>C2D&'!%2%!C2@8f6%6&%'!+!],K;+^!&4!7&'!7\D>C2D&'! %2%!C2@8f6%6&%'!O!],K;O^!&4!46&%4!32D>4&!@F!'4$@&!@&!D$4F5$462%!@&!7$!3&77F7&!

%92>7$'6EF&Y!(2%!6D>$34!376%6EF&!JF4!>F_769!&%!"ddl"AY!,$!37$''6J63$462%!@&!X-*,!'&5?64!

(43)
(44)
(45)

! LN! O$_7&!N!:7$''6J63$462%!Q=(!AM"U!@&'!%92>7$'6&'!7\D>C2h@&'!+!D$4F5&'Y!,$!45$6&!52F8&!&%!

>26%46779!'9>$5&!7&'!&%4649'!6%@27&%4&'!]&%!C$F4^!@&'!&%4649'!$85&''6?&'!]&%!_$'^"U!

!

(46)
(47)
(48)
(49)
(50)
(51)
(52)
(53)
(54)
(55)

! gN! >>>LW)7%$62'%)#"-$I"3"H&R+6%)6')&##+("$I/("'.$&R+6%) ///0F0.'H*%89*3*6&"' ! ,&'!!8$%8762%'!2F!$F45&'!46''F'!&%?$C6'!'2%4!7&!'6H8&!@`F%&!@9'258$%6'$462%! $53C64&34F5$7&!>$546&77&!2F!424$7&!>$5!F%!6%J6745$4!32%'464F9!@&!%$>>&'!@6JJF'&'!@&!3&77F7&'! @&!4$677&!D2\&%%&!R!85$%@&!>59'&%4$%4!@&'!$'>&34'!3&%452_7$'46EF&'c!6DDF%2_7$'46EF&'! 2F!6%4&5D9@6$65&'!&4!>$5J26'!$%$>7$'6EF&'Y!1$%'!3&44&!@&5%6H5&!J25D&!D25>C27286EF&!7&'! 3&77F7&'!4FD25$7&'!!D2%45&%4!@&'!3$5$34956'46EF&'!?$56$_7&'!$?&3!@&'!%2\$FP! >79h2D25>C6EF&'!&4!>$5J26'!@&'!J25D&'!DF746%F379&'Y!!,&'!,+1e:!32%'464F9'!R!>7F'!@&! dMo!@`6DDF%2_7$'4&'!5&%45&%4!@$%'!7$!3$498256&!D25>C27286EF&!s!6DDF%2_7$'46EF&!t! $725'!EF&!3&FP!32%4&%$%4!D26%'!@&!dMo!@`6DD2_7$'4&'!$>>$546&%%&%4!R!7$!3$498256&! D25>C27286EF&!s!3&%452_7$'46EF&!tY!:&>&%@$%4!3&44&!@6'46%3462%!D25>C27286EF&!%`$!>$'! @`6D>$34!'F5!7&!>52%2'463!&4!@&D&F5&!2>462%%&77&Y!,$!>5276J95$462%!7\D>C2D$4&F'&!&'4! $332D>$8%9&!@`F%!%2D_5&!?$56$_7&!@&!3&77F7&'!6%J7$DD$4265&'!$''236$%4!@&'!>&464'! 7\D>C23\4&'!D$b2564$65&D&%4!Oc!@&'!>7$'D23\4&'c!@&'!C6'4623\4&'!&4!>7F'!5$5&D&%4!@&'! >27\%F379$65&'Y!! ! ///0F0('I9=#*:78"' ! ,&'!,+1e:!&P>56D&%4!7&!:1Lgc!7&'!D$5EF&F5'!>$%B+!6%37F$%4!:1"dc!:1AMc!:1AAc! :1ld$!&4!G*ZgY!07!&'4!3&>&%@$%4!J59EF&%4!@`2_'&5?&5!F%&!%98$46?649!?6'!R!?6'!@F!:1AM!&%! 3$'!@&!5&3CF4&!&%!>$5463F76&5!3C&j!7&'!>$46&%4'!45$649'!>$5!564FP6D$_Y!! ! ,&'!>$%O!%&!'2%4!>$'!&P>56D9'Y!:&>&%@$%4!@&'!3$'!@&!,+1e:!$?&3!&P>5&''62%! $_&55$%4&!@F!:1N!2%4!949!5$>>2549'"lc"aY!G$5!$677&F5'!@&'!,+1e:!&$%2)S)!:1gv!

@9J6%6''&%4!F%!'2F'B852F>&!>C9%24\>6EF&!@&!,+1e:!3$5$34956'9!>$5!F%&!376%6EF&!>7F'!

$85&''6?&"dcAMY!! ! ! ! ! ! ! ! !

! ,`&P>5&''62%!@&'!>52496%&'!:1"Mc!+:,U!&4!=<="!&'4!?$56$_7&!&4!>&5D&4!@&!@9J6%65! 7&'!A!'2F'B852F>&'!>C9%24\>6EF&'!S!!,+1e:!:e!]3&%45&!8&5D6%$46J^!&4!,+1e:!%2%B:e! ]%2%!3&%45&!8&5D6%$46J^!'&72%!7`$782564CD&!@&!;$%'A"Y!:&44&!@6'46%3462%!$!@9D2%459!F%&!

?$7&F5!376%6EF&!>F6'EF&!7&'!,+1e:!%2%B:e!'2%4!$''2369'!R!F%!>52%2'463!>9b25$46JY!-77&!&'4! @9'25D$6'!5&EF6'&!@$%'!7&'!32D>4&!5&%@F'!$%$42D2B>$4C27286EF&'c!725'!@F!@6$8%2'463! @`F%!,+1e:c!@&>F6'!7$!>$5F462%!@&!7$!%2F?&77&!37$''6J63$462%!Q=(!AM"U"UY!,&!3F4B2JJ!@&!

(56)

! gL! !

! T68F5&!"dB!:7$''6J63$462%!@&'!,+1e:!]:e!?&5'F'!%2%B:8^!'&72%!7`$782564CD&!@&!;$%'A"!

(57)
(58)

! gU!

///0J0.'G#*+23&"4'>7:*6=#=:&;5"4'%=>5%%"#:"4'

! 1&'!45$%'723$462%'!@F!8H%&!6<CI!'2%4!5$>>2549'!@$%'!AMo!@&'!,+1e:!KQ(c!7&'! 59$55$%8&D&%4'!6D>76EF$%4!7&!8H%&!6<CT!'2%4!>59'&%4&'!@$%'!NMo!@&'!,+1e:!KQ(!&4! 3&77&'!6D>76EF$%4!7&!8H%&!>B<!@$%'!"Mo!@&'!3$'"gY!:&'!45$%'723$462%'!'2%4!%2%!

&P37F'6?&'!&4!7&F5!>59'&%3&!&'4!$''2369&!R!F%!>52%2'463!>9b25$46JAL€AlY!!

(59)

! gl! '2%4!$''2369'!R!F%!>52%2'463!>7F'!'2D_5&NNY!:&54$6%&'!$_&55$462%'!3C52D2'2D6EF&'! 'F5?6&%%&%4!&P37F'6?&D&%4!@$%'!7&!'2F'B852F>&!e:+!32DD&!7&'!45$%'723$462%!@F!8H%&! 6<CI%&4!7&'!$D>76J63$462%'!@&!!LC%!$725'!EF&!7&'!456'2D6&'!N!2F!7&'!8$6%'n$D>76J63$462%'! @F!_5$'!NEc!7&'!8$6%'!"aE!&4!7&'!>&54&'!UE!'2%4!7`$>$%$8&!@&'!,+1e:!B*+:NLY!,&'!,+1e:!B *+:!'2%4!3$5$34956'9'!&%!2F45&!>$5!F%&!$346?$462%!32%'464F46?&!@&!7$!?26&!KTy+Ng!$725'! EF&!@&'!$%2D$76&'!@&'!8H%&'!6D>76EF9'!@$%'!7&!5&D2@&7$8&!@&!7$!3C52D$46%&!'2%4! >59'&%4'!@$%'!7&'!,+1e:!Be:+NUY! ! *Fb2F5@`CF6!7`$782564CD&!@&!;$%'!&'4!7`$782564CD&!6DDF%2C6'423C6D6EF&!7&!>7F'! 7$58&D&%4!F4676'9!>2F5!6@&%46J6&5!7&'!A!852F>&'!D2793F7$65&'!@&!,+1e:!$?&3!F%&! 32%325@$%3&!@&!aMo!&%!'&!_$'$%4!'F5!7`&P>5&''62%!@&!N!>52496%&'!S!:1"Mc!+:,U!&4!=<="! ]T68F5&!"d^A"Y!Q%!>$57&!$725'!@&!'2F'!852F>&!>C9%24\>6EF&!,+1e:!B:ec!!3255&'>2%@$%4!

(60)
(61)
(62)
(63)
(64)
(65)
(66)
(67)

! Ug! *''236$4&@!@2D$6%^LUcg"Y!,$!J$D677&!@&'!=+1'!&'4!'F_@6?6'9&!&%!N!'2F'B852F>&'!S!7&'!

D94C\745$%'J95$'&'!@&'!C6'42%&'!];=OB=+1c!C6'42%&!D&4C\745$%'J&5$'&!D&4C\7B_6%@6%8! @2D$6%^c!7&'!>52496%&'!=&:GA!&4!7&'!$394C\745$%'J95$'&'!@&'!C6'42%&'!];*OB=+1c! C6'42%&!$394C\745$%'J95$'&!D&4C\7B_6%@6%8!@2D$6%^Y! /K0(0('12'+=:9732:&*#'$"'#*!*'N'CMHAF' ! :C&j!7&'!D$DD6JH5&'!7&!@&859!@&!D94C\7$462%!@&!7`*1K!&'4!598F79!@&!J$u2%! @\%$D6EF&!$F!32F5'!@F!!@9?&72>>&D&%4!&D_5\2%%$65&Y!*>5H'!J932%@$462%c!7&!j\824&! 'F_64!F%&!5&>5285$DD$462%!9>689%946EF&c!32%'6'4$%4!&%!F%&!@9D94C\7$462%!EF$'6! 32D>7H4&!@F!89%2D&c!$''F5$%4!7$!4246>24&%3&gAcgNY!:&>&%@$%4c!3&54$6%&'!59862%'!@F!

89%2D&!$>>&79&'!59862%'!@&!D94C\7$462%!@6JJ95&%46&77&c!'>936J6EF&'!@&'!3&77F7&'! 8&5D6%$7&'!DV7&'!&4!J&D&77&'!&4!32%45I7$%4!7&'!8H%&'!'2FD6'!R!7`&D>5&6%4&!89%2D6EF&! >$5&%4$7&c!32%'&5?&%4!7&F5'!D94C\7$462%'!42F4!$F!72%8!@F!@9?&72>>&D&%4gNY! ! *F!32F5'!@F!@9?&72>>&D&%4!&D_5\2%%$65&c!7&'!%2F?&$FP!>52J67'!@&!D94C\7$462%! '2%4!94$_76'!>$5!7&'!&%j\D&'!1K=ON'!&4!'2%4!D$6%4&%F'!>&%@$%4!42F4&!7$!@F59&!@&!7$!?6&! '2D$46EF&!@&!7`258$%6'D&Y!,&!>52J67!@&!D94C\7$462%!6%646$7!&'4!@2%3!89%959!>&%@$%4!7&'! >5&D6&5'!'4$@&'!@&!@9?&72>>&D&%4!&D_5\2%%$65&!>$5!7&'!@&!%2?2!D94C\745$%'J95$'&'! 1K=ON*c!1K=ON+!&4!1K=ON,Y!!,&'!1K=ON'!F4676'&%4!@&!DF746>7&'!6%4&5$3462%'!>2F5! 36_7&5!@&'!59862%'!>$5463F76H5&'!@F!89%2D&!!6%37F$%4!7$!5&32%%$6''$%3&!@&!'9EF&%3&'! '>936J6EF&'!@&!7`*1Kc!7`6%4&5$3462%!$?&3!7&'!EF&F&'!@&'!C6'42%&'c!7`$''236$462%!$?&3!@&'! J$34&F5'!@&!5&D2@&7$8&!@&!7$!3C52D$46%&!]:*G'^!2F!&%325&!7`$''236$462%!R!7`*XKgNY!,&'! 1K=ON'!6%4&5$86''&%4!>$5!&P&D>7&!'97&346?&D&%4!$?&3!7`C6'42%&!;N!%2%!D94C\79&!'F5!7$! 7\'6%&!L!];N/LD&M^c!@937&%3C$%4!F%&!D94C\7$462%!@&!%2?2gLcggY!1`$F45&'!D2@6J63$462%'! @&'!C6'42%&'c!&%!>$5463F76&5!;N/dD&N!2F!;N/AlD&N!'2%4!6D>76EF9&'!@$%'!7&!8F6@$8&!@&! 7$!D94C\7$462%!@&!7`*1K!$F!%6?&$F!@&!59862%'!3C52D$46%6&%%&'!'>936J6EF&'gUcglY!:&54$6%&'!

(68)
(69)

! Ul! 3C$%8&D&%4'!>5285&''6J'!@&'!>52J67'!@&!D94C\7$462%!>&5D&44$%4!@&!59@F65&!$F!'67&%3&!7&'! 8H%&'!@&'!>5289%64&F5'!$F!>52J64!@&!7`&P>5&''62%!@&'!8H%&'!46''F'B'>936J6EF&'Y!!,$! D94C\7$462%!@&!7`*1K!32%'464F&!F%!D93$%6'D&!6D>254$%4!@&!598F7$462%!46''FB'>936J6EF&! 3$5!&77&!5&>59'&%4&!F%!D93$%6'D&!'4$_7&c!C$F4&D&%4!45$%'D6''6_7&c!$''2369!R!7$! 59>5&''62%!45$%'356>462%%&77&c!&4!EF6!32%456_F&!R!7`94$_76''&D&%4!@&!768%9&'!@6JJ95&%369&'! '4$_7&'Y!! ! =$7859!7$!5&>5285$DD$462%!9>689%946EF&!2_'&5?9&!725'!@&'!>5&D6&5'!'4$@&'!@F! @9?&72>>&D&%4!&D_5\2%%$65&c!3&54$6%&'!59862%'!@F!89%2D&c!'2FD6'&'!R!7`&D>5&6%4&! 89%2D6EF&!>$5&%4$7&c!93C$>>&%4!R!3&44&!?$8F&!@&!@9D94C\7$462%Y!1$%'!7&'!3&77F7&'! @6>72h@&'!@&'!D$DD6JH5&'c!7&'!8H%&'!$F42'2D6EF&'!'2%4!&P>56D9'!9EF64$_7&D&%4!R! >$5465!@&'!$77H7&'!>$4&5%&7'!&4!D$4&5%&7'c!&%45$w%$%4!F%&!&P>5&''62%!_6$77976EF&!@&!3&'! 8H%&'Y!!:&>&%@$%4!F%&!J$6_7&!>52>25462%!@&!8H%&'!&'4!'2FD6'&!R!7`&D>5&6%4&!89%2D6EF&! >$5&%4$7&c!F%!>523&''F'!>$5!7&EF&7!F%!$77H7&!>$5&%4$7!&'4!59@F64!$F!'67&%3&!@$%'!7&!j\824&c! 32%@F6'$%4!R!F%&!&P>5&''62%!D2%2$77976EF&UNY!*6%'6!'&F7!7`F%!@&'!A!$77H7&'!@&'!8H%&'! '2FD6'!R!&D>5&6%4&c!7`$77H7&!D$4&5%&7!2F!>$4&5%&7c!>&F4!p45&!$346J!&4!&P>56D9Y!! ! ,$!D94C\7$462%!@&!7`*1K!6%4&5?6&%4!98$7&D&%4!@$%'!7`6%$346?$462%!@F!3C52D2'2D&! ZY!:&!>523&''F'!'&!>52@F64!3C&j!7&'!D$DD6JH5&'!J&D&77&'!]ZZ^!&4!$''F5&!7`6%$346?$462%! 45$%'356>462%%&77&!@`F%!@&'!A!3C52D2'2D&'!Z!$J6%!@`98$7&5!7&!%6?&$F!@`&P>5&''62%!@&'! 8H%&'!@&!7`F%6EF&!3C52D2'2D&!Z!>59'&%4!3C&j!7&'!DV7&'!]Zk^Y!*6%'6!42F4&'!7&'!D$5EF&'! 9>689%946EF&'!4&77&'!EF&!7$!D94C\7$462%!@&!7`*1Kc!7&'!D2@6J63$462%'!@&'!C6'42%&'!&4!7&'! ?$56$%4'!@`C6'42%&c!'2%4!&%563C6&'!'F5!7`F%!@&'!A!3C52D2'2D&'!Zc!7&!3C52D2'2D&!Z! 6%$346?9!]Z6^c!$J6%!@&!59@F65&!'&'!8H%&'!$F!'67&%3&ULY! ! ,&'!J$34&F5'!&%?652%%&D&%4$FP!>&F?&%4!D2@F7&5!7`94$_76''&D&%4!&4!7$! D$6%4&%$%3&!@&'!D2@6J63$462%'!9>689%946EF&'!'$%'!DF4$462%!89%946EF&!'2F'Bb$3&%4&Y! *6%'6c!7&'!>277F$%4'!3C6D6EF&'c!7&!5986D&!$76D&%4$65&c!7&'!3C$%8&D&%4'!@&!4&D>95$4F5&!&4! @`$F45&'!'45&''!&P4&5%&'!>&F?&%4!$?265!F%!&JJ&4!@F5$_7&!'F5!7&!@9?&72>>&D&%4!2F!7$! '$%49c!>$5J26'!DpD&!'F5!>7F'6&F5'!89%95$462%'UgY!1F5$%4!7$!8&'4$462%c!7&!5986D&! $76D&%4$65&!@&!7$!DH5&!2F!'2%!&P>2'6462%!R!@&'!32D>2'9'!42P6EF&'!'2%4!$''2369'!R!@&'! 3C$%8&D&%4'!9>689%946EF&'!$F!%6?&$F!@&!59862%'!'>936J6EF&'!@F!89%2D&UgcUUY!!1&'!

(70)
(71)

! Ud! &77&'!>&F?&%4!98$7&D&%4!6%J7F&%3&5!@`$F45&'!>523&''F'!4&77&'!EF&!7$!59>763$462%!2F!7$! 59>$5$462%!@&!7`*1K!]O$_7&!g^! ! ! O$_7&!gB!16JJ95&%4&'!37$''&'!@&!D2@6J63$462%!@&'!C6'42%&'! 1"*&K&29'&"() 2I-"#9'&(&6((6) 0/%&*+%)2&83/%) O"(2'&"()-/H+3/6)

72/'.39'&"()4)92) ,\'6%&!]/^!S!/B$3! O5$%'356>462%c!59>$5$462%c! 59>763$462%c!32%@&%'$462%! 1/'I.39'&"()T3.%&(6U)4)#6) ,\'6%&!]/^!S!/BD&"!/BD&A! /BD&N! O5$%'356>462%c!59>$5$462%! 1/'I.39'&"()T9-H&(&(6U)4) #6) *586%6%&!]X^!S!XBD&"!XBD&A! XBD&N! O5$%'356>462%! FI"%$I"-.39'&"()4)$I) (956%&!](^!&4!OC592%6%&! ]O^!S!(B>C!OB>C! O5$%'356>462%c!59>$5$462%c! 32%@&%'$462%!

G8&R+&'.39'&"()4)+8) ,\'6%&!]/^!S!/BF_! O5$%'356>462%!

@+#".39'&"() ,\'6%&!]/^!S!/B'F! O5$%'356>462%!

7BF)-&8"%.39'&"()4)9-) *36@&!87F4$D6EF&!-!S!-B$5! O5$%'356>462%!

B/&#&(9'&"() *586%6%&!]X^! O5$%'356>462%!

(72)
(73)
(74)
(75)

! lN! 3$5$34956'9&'!>$5!F%&!C\>&5D94C\7$462%!$_&55$%4&!@&'!>52D24&F5'!@&'!8H%&'! 'F>>5&''&F5'!@&!4FD&F5!89%95$7&D&%4!$''2369&!R!7&F5!59>5&''62%LlY!(&72%!7&!4\>&!@&! 4FD&F5!2%!2_'&5?&!7`6%$346?$462%!@&!8H%&'!6D>76EF9'!@$%'!7$!598F7$462%!@F!3\37&! 3&77F7$65&!]!YG%?;T%RDZN=G%?;J%RDZN6^c!7&!D$6%46&%!@&!7`6%4985649!@F!89%2D&!]?JAG%6!<=;G% 4>CH;^c!7`$>2>2'&!]<+'/+'$%MG%:=?H^c!7$!D685$462%!&4!7`6%?$'62%!]L[9+&4$-02$G%ER>?[A^c!7$! 59>2%'&!$FP!J$34&F5'!@&!3526''$%3&!]?ELD^Y! DLN)1"*&K&29'&"(%)*6%)I&%'"(6%)*9(%)36)29(26-) ! QF45&!7`$7495$462%!@&'!>52J67'!@&!D94C\7$462%!@&!7`*1K!$F!32F5'!@&!7$! 3$%395289%H'&c!2%!2_'&5?&!@&'!3C$%8&D&%4'!@$%'!7&'!D2@6J63$462%'!@&'!C6'42%&'!EF6! $JJ&34&5$6&%4!7&!5&35F4&D&%4!@&!J$34&F5'!@&!45$%'356>462%!&4!@&'!979D&%4'!32%'464F$%4'!7$! D$3C6%&56&!45$%'356>462%%&77&c!32%456_F$%4!$6%'6!R!7`&P>5&''62%!$_&55$%4&!@&!8H%&'ll€ldY! Q%!2_'&5?&!$6%'6!@$%'!7&'!4FD&F5'!F%&!59@F3462%!872_$7&!@`;L/AMD&N!&4!@`;L/U*3!$F! %6?&$F!@&!'9EF&%3&'!59>949&'!C\>2D94C\79&'llcldY!G$5!$677&F5'c!67!'&D_7&5$64!EF&! 7`$7495$462%!@&'!>52J67'!@&!D2@6J63$462%!@&'!C6'42%&'!'264!>56%36>$7&D&%4!@F&!R!F%&! &P>5&''62%!$_&55$%4&!@&'!$34&F5'!@&!7`$394\7$462%!&4!@&!7$!D94C\7$462%!@&'!C6'42%&'ll€ldY! DLW)5I/-9$&6)/$&H/(/'&R+6) ! :2%45$65&D&%4!$FP!3$F'&'!89%946EF&'!@F!3$%3&5!EF6!$JJ&34&%4!7$!'9EF&%3&!@&! 7`*1Kc!7&'!D2@6J63$462%'!9>689%946EF&'!'2%4!59?&5'6_7&'c!3&!EF6!2F?5&!@&'!>&5'>&346?&'! >52D&44&F'&'!&%!4C95$>6&'Y!! ! ,`$j$3\46@6%&!]gB$j$3\46@6%&c!#6@$j$!…^!&4!7$!@9364$_6%&!]gB$j$BA`B@9'2P\3\46@6%&c! 1$328&%…^!'2%4!@&'!6%C6_64&F5'!@&'!1K=O'c!EF`&77&'!>6H8&%4!&%!'`6%4985$%4!@$%'!7`*1K!R! 7$!>7$3&!@&!59'6@F'!3\42'6%&c!>&5D&44$%4!$6%'6!7$!59&P>5&''62%!@&!8H%&'!'F>>5&''&F5'!@&! 4FD&F5'!94&6%4'!>$5!7`C\>&5D94C\7$462%Y!!:&'!A!D2793F7&'!@&!598F7$462%!9>689%946EF&!2%4! 949!$>>52F?9&'!>$5!7$!T1*!]s!T22@!$%@!15F8!*@D6%6'45$462%!t^!@$%'!7&!45$64&D&%4!@&'! 3$%3&5'Y!! ! ,&'!6%C6_64&F5'!@&'!;1*:!];1*:6^!@2%%&%4!@&'!59'F74$4'!>52D&44&F5'!@$%'!7&! 45$64&D&%4!@&'!3$%3&5'aMY!1&'!;1*:6!&P6'4&%4!'F5!7&!D$53C9!&%!4$%4!EF`$8&%4'! 4C95$>&F46EF&'!$%463$%395&FP!32DD&!7&!?256%2'4$4!]$36@&!'F_&52\7$%676@&! C\@52P$D6EF&c!)276%j$…^!&4!7$!52D6@&>'6%!]T/BAAac!0'42@$P^Y!:&'!$8&%4'!'2%4!

(76)
(77)
(78)

! lU! 3$%3&5'!_52%3C6EF&'!&4!@$%'!7&'!7&F39D6&'!$68F&'!D\972h@&'dlcdaY!-77&!&'4!$''2369&!R!F%&!

(79)

! ll! ! :&54$6%'!2%4!D2%459!7`&P6'4&%3&!@&!59862%'!89%2D6EF&'!6D>254$%4&'!&4!32%46%F&'! 6%$346?9&'!]72%8B5$%8&!&>68&%&463!'67&%36%8c!,X-(^!@$%'!7&'!3$%3&5'"MAY:&'!59862%'!

(80)

! la! O$_7&!UB!*7495$462%'!@&'!1K=O'!@$%'!7&'!3$%3&5'!C9D$427286EF&'! 5.$6)*6)'+#6+-) B?15) 73'/-9'&"() 0/K/-6(26) 71A) 1K=ON*! 1K=ON*! 1K=ON+! 1K=O'! =F4$462%"Ml! 1979462%"""! 1979462%""A! (F5&P>5&''62%!""N! k$%!&4!$7Y!AM""! k$%8!&4!$7Y!AM"U! )C&%8!&4!$7Y!AM"U! =6jF%2!&4!$7Y!AMM"!

1B@) 1K=ON*! =F4$462%"Ma! .$74&5!&4!$7Y!AM""!

!11A) 1K=ON*! =F4$462%""L! ZF!&4!$7Y!AM"L!

!1A) 1K=O'! (F5&P>5&''62%""N! =6jF%2!&4!$7Y!AMM"!

7AA) 1K=ON*! =F4$462%"Md! K&FD$%%!&4!$7Y!AM"N!

A.#$I"#6) 1K=O"! 1K=ON*! 1K=ON+! 1979462%""g! 1979462%""U! 1979462%""l! G&4&5'!&7!$7Y!"M"N! ;$%&\!&4!$7Y!AM"U! #$'$%4C$fFD$5!&4!$7Y!AM"N! ! *=,!S!7&F39D6&!D\972h@&!$68F&!z!=1(!S!'\%@52D&!D\972@\'>7$'6EF&!z!:==,!S!7&F39D6&!D\972D2%23\4$65&! 3C52%6EF&!z!:=,!S!7&F39D6&!D\972h@&!3C52%6EF&c!*,,!S!7\D>C2D&!7\D>C2_7$'46EF&! K/0(0J'/#9&,&:"5%4'$"4'CMHA' ! ,&'!1K=O'!'2%4!@&'!36_7&'!4C95$>&F46EF&'!@`6%495p4!@`F%&!>$54!>$53&!EF!†&77&'! '2%4!@9598F79&'!@$%'!@&!%2D_5&FP!3$%3&5'!&4!@`$F45&!>$54!>$53&!EF&!7$!D94C\7$462%!@&! 7`*1K!&'4!F%!>523&''F'!>59323&!@F!@9?&72>>D&%4!4FD25$7!EF6!6%4&5?6&%4!@$%'!7$! >5285&''62%!3$%395&F'&Y!,&'!$34&F5'!9>689%946EF&'!'2%4!@&'!36_7&'!4C95$>&F46EF&'!@&! 3C26P!>F6'EF`R!7`6%?&5'&!@&'!DF4$462%'!89%946EF&'c!7&'!>523&''F'!9>689%946EF&'!'2%4! 59?&5'6_7&'Y!!G$5!$677&F5'!7$!59$346?$462%!@&'!8H%&'!'F>>5&''&F5'!@&!4FD&F5'c!'F64&!R!F%! 45$64&D&%4!$?&3!@&'!6%C6_64&F5'!@&'!1K=O'!>&F4!32%@F65&!R!7$!D254!3&77F7$65&""ac""dY!!

(81)

! ld! &%!6%C6_$%4!7$!@&5%6H5&!94$>&!@&!7$!59$3462%!@&!D94C\7$462%c!3`&'4!R!@65&!7$!76_95$462%!@&! 7`&%j\D&!EF6!&'4!769&!32?$7&DD&%4!>$5!'$!3\'496%&!3$4$7\46EF&!'F5!7&!3$5_2%&!U!@&!7$! _$'&Y!,&'!&%j\D&'!'2%4!$6%'6!>6989&'!&4!F%&!_$6''&!@&!7$!D94C\7$462%!&'4!2_'&5?9&Y! ,`$3462%!@&!@9D94C\7$462%!@&!3&'!6%C6_64&F5'!$!76&F!R!@&!J$6_7&'!@2'&!$725'!EF`!R!>7F'! C$F4&'!@2'&'!3&'!$%$728F&'!>59'&%4&%4!F%&!42P63649!6D>254$%4&c!6%4&5JH5$%4!$?&3!7$! '\%4CH'&!@&!7`*1K!&4!>52?2EF$%4!@&'!@2DD$8&'!R!7`*1K"AMY!,$!>C$'&!(!&'4!5&EF6'&!>2F5!

7`6%325>25$462%!@&!3&'!6%C6_64&F5'c!3&!EF6!76D64&!7`6%@F3462%!@`F%&!C\>2D94C\7$462%!@$%'! 7&'!3&77F7&'!%&!'&!@6?6'$%4!>$'Y!,$!gB*j$B:@X!>&5D&4!%24$DD&%4!@&!@9D94C\7&5!7&!8H%&! 'F>>5&''&F5!@&!4FD&F5!>"g!C\>&5D94C\79!3C&j!7&'!>$46&%4'!$44&6%4'!@&!'\%@52D&! D\972@\'>7$'6EF&"A"Y!:&>&%@$%4!3&'!6%C6_64&F5'!>59'&%4&%4!7`6%32%?9%6&%4!@`p45&!

6%'4$_7&'!&4!'Fb&4'!R!@&'!@9$D6%$462%'Y!G2F5!$F8D&%4&5!7&F5!'4$_67649!@`$F45&'!$%$728F&'! 2%4!949!@9?&72>>9'!32DD&!7$!j9_F7$56%&!2F!7$!gBJ7F252BALB@&2P\3\46@6%&!]gBTB:@X^Y!

,&'!%2%!$%$728F&'!@&!%F3792'6@&'!

! *!7$!@6JJ95&%3&!@&'!$%$728F&'!@&!%F3792'6@&'c!7&'!%2%!$%$728F&'!%&!'`6%325>25&%4! >$'!@$%'!7`*1K!&4!>59'&%4&%4!@2%3!F%&!42P63649!D26%'!6D>254$%4&Y!,`C\@5$7$j6%&!&4!7$! >523$6%$D6@&!6%@F6'&%4!F%&!C\>2D94C\7$462%!@$%'!7&'!4FD&F5'!'276@&'"AAY!,`!

(82)

! aM! F%&!&P46%3462%!45$%'356>462%%&77&Y!:C&j!7&'!?&549_59'c!7$!J$D677&!@&'!=+1!'&!32D>2'&!@&! g!D&D_5&'!S!=&:GAc!=+1"c!=+1Ac!=+1N!&4!=+1LY!! ! ! ! ! =&:GAc!=+1"c!=+1A!&4!=+1N!'2%4!$''2369'!R!@&'!32D>7&P&'!59>5&''&F5'!@&!7$! 45$%'356>462%Y!,$!>52496%&!=&:GA!&'4!7$!>5&D6H5&!@&'!>52496%&'!R!=+1!R!$?265!949! 94F@69&!>2F5!'2%!3$5$34H5&!@&!59>5&''&F5!45$%'356>462%&7Y!<%!@&'!D93$%6'D&'!D&44$%4! &%!9?6@&%3&!7&!5I7&!@&!=&:GA!@$%'!7$!59>5&''62%!45$%'356>462%%&77&!6D>76EF&!7&! 5&35F4&D&%4!>$5!3&44&!>52496%&!@&!32D>7&P&'!32B59>5&''&F5'!32%4&%$%4!@&'!;1*:Y!1&! J$u2%!6%495&''$%4&!!@$%'!7&'!768%9&'!3&77F7$65&'!%`&P>56D$%4!>$'!=&:GA!F%! &%563C6''&D&%4!&%!C6'42%&'!$394\79&'!&'4!2_'&5?9!$F!%6?&$F!@&'!8H%&'!36_7&'!@&! =&:GA"AL!Y!=+1"!&4!=+1A!'2%4!98$7&D&%4!@&'!59>5&''&F5'!45$%'356>462%&7'!;1*:B

@9>&%@$%4Y!=+1"!&'4!%24$DD&%4!3$>$_7&!@`6%4&5$865!$?&3!;1*:N"AgY!,$!59>5&''62%!

45$%'356>462%%&77&!6%6469&!>$5!=+1"!2>H5&!98$7&D&%4!?6$!7&!5&35F4&D&%4!@&'!;=O'Y! =+1"!6%4&5$864!&%!&JJ&4!$?&3!7&'!;N/d!D94C\7$'&'!(F?NdC"!&4!(-O1+""AUc"Al! ! ,`$b2F4!@F!852F>&D&%4!D94C\7!'F5!7&'!3\42'6%&'!$F8D&%4&!7$!>52_$_67649!@&! DF4$462%Y!-%!&JJ&4c!7$!3\42'6%&!D94C\79&!>&F4!'F_65!F%&!@9'$D6%$462%!'>2%4$%9&!EF6!7$! 45$%'J25D&!&%!4C\D6%&c!359$%4!$6%'6!F%!D9'$>>$56&D&%4!One!@$%'!7`*1KY!,$!>52496%&! =+1L!&'4!3$>$_7&!@&!5&32%%$w45&!3&!D9'$>>$56&D&%4!&4!@`&P36'&5!7$!4C\D6%&!>$5!F%&! $346?649!87\32'\7$'&Y!1`$F45&'!'\'4HD&'!2%4!&%'F64&!>2F5!4V3C&!@&!59>$5&5!7&!'64&! $_$'6EF&Y!+6&%!EF&!=+1L!'264!3$>$_7&!@&!5&32%%$w45&!7&'!:>e!D94C\79'c!'2%!$JJ6%649!>2F5! 7&'!D9'$>>$56&D&%4'!One!&'4!>7F'!J254&!&4!&77&!'&D_7&!'F542F4!&P&53&5!F%!5I7&!@&! 'F5?&677$%3&!@$%'!7&'!89%2D&'!J254&D&%4!D94C\79'Y!! ! 07!&P6'4&!>&F!@&!@2%%9&'!'F5!7$!598F7$462%!@&!7`6%C6_6462%!45$%'356>462%%&77&!=+1B @9>&%@$%4&Y!07!'&D_7&5$64!EF&!@&'!D2@6J63$462%'!>2'4B45$@F3462%%&77&'!@&'!>52496%&'! =+1!>2F55$6&%4!D2@6J6&5!7`$JJ6%649!@F!@2D$6%&!=+1!R!7`*1K!D94C\79!&4n2F!$JJ&34&5! 7`$''&D_7$8&!@&'!>52496%&'!R!=+1!R!7&F5!32D>7&P&!@&!59>5&''62%Y!,&'!59'6@F'!$586%6%&! @F!@2D$6%&!KB4&5D6%$7!@&!=+1A!>&F?&%4!p45&!>2'4B45$@F3462%%&77&D&%4!D94C\79'!>$5! 7&'!$586%6%&!D94C\745$%'J95$'&'!GX=O"!&4!GX=Og!]G524&6%!*586%6%&!]X^!

=&4C\7O5$%'J&5$'&^"AaY!:&44&!D94C\7$462%!@&!=+1A!6%C6_&!'2%!6%4&5$3462%!$?&3!;1*:!&4!

7`*1K!D94C\79!&4c!@9'!725'c!'$!J2%3462%!59>5&''6?&Y!G$5!$677&F5'!7$!(<=Q\7$462%!@&!=+1"! 6%C6_&!7$!59>5&''62%!45$%'356>462%%&77&!=+1"B@9>&%@$%4&!&%!&%45$w%$%4!F%&!>&54&!@&'! D$5EF&'!59>5&''6?&'!@&!456D94C\7$462%!;N/d"AdY!

(83)

! a"! 45$@F3462%%&77&'!@&!3&'!>52496%&'!4&77&'!EF&!7$!D94C\7$462%!2F!7$!(<=Q\7$462%!

32%456_F&%4!R!7$!598F7$462%!@&!7&F5!J2%3462%!59>5&''6?&Y!!

! 1$%'!7&'!3$%3&5'c!@&'!?$56$462%'!6D>254$%4&'!@F!%6?&$F!@`&P>5&''62%!@&'! >52496%&'!R!=+1!'2%4!2_'&5?9&'Y!-%!&JJ&4c!@&'!@9598F7$462%'!@&!7`&P>5&''62%!@&'!8H%&'! >6:I!&4!>L<?I%'2%4!5$>>2549&'!@$%'!7&'!4FD&F5'!'276@&'"NMc"N"!&4!@$%'!7$!,,:"NAY!

! 1&!J$u2%!6%495&''$%4&c!7`6%$346?$462%!36_79&!@&'!>52496%&'!R!=+1c!&4!>7F'! '>936J6EF&D&%4!@&!=+1Ac!32%@F64!R!7$!59$346?$462%!@&!3&54$6%'!8H%&'!59>56D9'!'$%'! $?265!@&!32%'9EF&%3&!872_$7&!'F5!7`&P>5&''62%!89%6EF&c!32%45$65&D&%4!R!@`$F45&'! 6%C6_64&F5'!@&!7$!D94C\7$462%!R!7$58&!'>&345&"NNY! D>LW)Q75%)) ! ,`$394\7$462%!@&'!C6'42%&'!'&!J$64!>59J95&%46&77&D&%4!'F5!@&'!59'6@F'!7\'6%&! '>936J6EF&'Y!,`$394\7$462%!@&!7`C6'42%&!;N!'&!J$64!&%!>2'6462%!/dc!/"Lc!/"a!&4!/AL!$725'! EF&!3&77&!@&!7`C6'42%&!;L!'&!J$64!&%!>2'6462%!/gc!/ac!/"A!&4!/"UY!,`$@@6462%!@`F%! 852F>&D&%4!$394\7&!%&F45$76'&!7$!3C$58&!>2'646?&!@F!59'6@F!7\'6%&c!$JJ$6_76''$%4!$6%'6! 7`6%4&5$3462%!97&3452'4$46EF&!*1KnC6'42%&!&4!>&5D&44$%4!F%&!2F?&54F5&!@&!7$! 3C52D$46%&Y!,&'!;*O!2%4!@2%3!F%&!$3462%!@`$346?$462%!45$%'356>462%%&77&!&4! 6%4&5?6&%%&%4!&%!32%@6462%'!>C\'627286EF&'!&4!>$4C27286EF&'!&%!>$5463F76&5!@$%'! 7`C9D$42>2hH'&!%25D$7&!&4!4FD25$7&Y! ' ,&'!;*O'!6%4&5?6&%%&%4!@$%'!7`$F42B5&%2F?&77&D&%4!&4!7$!@6JJ95&%36$462%!@&'! >5289%64&F5'!C9D$42>26946EF&'"NL!&%!>$5463F76&5!@$%'!7&!32%45I7&!@&!7$!_$7$%3&!&%45&!7$!

>5276J95$462%!!&4!7$!@6JJ95&%36$462%!@&'!3&77F7&'!C9D$42>26946EF&'"Ngc"NUY!!,`$394\7$462%!@&!

(84)

! aA! $68F&'"LAY!:&'!8H%&'!@&!JF'62%!&%45$w%&%4!F%&!$394\7$462%!$%25D$7&!@&'!C6'42%&'!

J$?256'$%4!$6%'6!7$!>$4C289%H'&!@&!3&'!C9D2>$4C6&'!D\972h@&'Y!,&!J$34&F5!@&! 45$%'356>462%!GgN!&'4!F%!@&'!'F_'45$4'!@&'!;*O'Y!,`$394\7$462%!@&!GgN!'F5!3&'!59'6@F'! 7\'6%&'!J$?256'&!'2%!$346?$462%!&4!'$!'4$_676'$462%"LN!!,&'!DF4$462%'!@&!GgN!&%!>2'6462%! /"AM!&D>p3C&!F%&!$394\7$462%!3255&34&!'F5!3&44&!>2'6462%!&4!6%C6_&%4!7`$346?649! 45$%'356>462%%&77&!@&!3&!8H%&Y!(6!@&'!45$%'723$462%'!6D>76EF$%4!>NMMc!:+G!&4!=Q)!'2%4! 5$>>2549&'!@$%'!7&'!7&F39D6&'!D\972h@&'c!3&!%`&'4!>$'!7&!3$'!@&'!7\D>C2D&'!+!&4!OY!-%! 5&?$%3C&c!!&%!3&!EF6!32%3&5%&!7&'!,+1e:!c!@&'!DF4$462%'!@&!<6?%@&!/AOO%2F!&%325&!@&! >FX!'2%4!5$>>2549&'Ndc"LLc"LgY!:&'!DF4$462%'!'2%4!5&'>2%'$_7&'!@`F%&!@6D6%F462%!@&! 7`$346?649!$394\745$%'J95$'&Y!1&!J$u2%!6%495&''$%4&c!7`$394\7$462%!@&!+:,U!@6D6%F&!'2%! $3462%!59>5&''6?&!$725'!EF&!3&77&!@&!GgN!&'4!5&EF6'&!>2F5!7`$346?$462%!@&!3&'!8H%&'!36_7&'Y! 1&!3&!J$64!@$%'!7&'!768%9&'!@&!,+1e:!$?&3!F%&!DF4$462%!@&'!8H%&'!;*O!2%!2_'&5?&!F%! J254!%6?&$F!@&!+:,U!$346J!&4!F%!J$6_7&!%6?&$F!@&!GgN!$346?&"LLY! ! 1&'!6%C6_64&F5'!@&'!;*O'!&P6'4&%4!&4!2%4!D2%459!7&F5!&JJ63$3649!@$%'!7&'! C9D2>$4C6&'!D$768%&'Y!:ULU!F%!6%C6_64&F5!'97&346J!@&!>NMMc!6%C6_&!7$!>5276J95$462%!@&'! 3&77F7&'!7&F39D6EF&'!>254&F'&'!@&!7$!45$%'723$462%!4!]azA"^"LUY!!,`&>68$7723$4&3C6%BNB

(85)

! aN! ! ,&'!;1*:'!b2F&%4!F%!5I7&!@$%'!7`C9D$42>2hH'&!%25D$7&!&4!@$%'!7$!7\D>C2>2hH'&! >C\'627286EF&!+!&4!OY!;1*:!"!&4!A!b2F&%4!F%!5I7&!3&%45$7!@$%'!7`C9D$42>2hH'&!>59323&!&4! @$%'!7`C2D92'4$'6&!@&'!3&77F7&'!'2F3C&'!C9D$42>2h946EF&'Y!;1*:N!&'4!%93&''$65&!R!7$! 59>763$462%!@&!7`*1K!@$%'!7&'!3&77F7&'!'2F3C&'!C9D$42>2h946EF&'!&4!@$%'!7&F5!$>464F@&!R! '&!@6JJ95&%36&5!&%!>5289%64&F5'!+!&4!O"gAY!,&'!;1*:'!b2F&%4!F%!5I7&!@$%'!7$!'68%$76'$462%!

(86)

! aL! D>L^)Q15%) ! ,$!D94C\7$462%!@&'!C6'42%&'!>&F4!'&!J$65&!'F5!7&'!59'6@F'!$586%6%&'!]X^c!7\'6%&'!]/^! &4!C6'46@6%&Y!,&'!59'6@F'!7\'6%&'!>&F?&%4!p45&!D2%2c!@6!2F!456BD94C\79'c!7&'!59'6@F'! $586%6%&'!>&F?&%4!p45&!D2%2c!'\D9456EF&D&%4!2F!$'\D9456EF&D&%4!@6D94C\79'!4$%@6'! EF&!7&'!59'6@F'!C6'46@6%&!'2%4!D2%2BD94C\79'Y!,&'!>56%36>$FP!'64&'!@&!D94C\7$462%!@&'! C6'42%&'!@93564'!&4!94F@69'!'2%4!S!;N/Lc!;N/dc!;N/Alc!;N;NUc!;N/ld!&4!;L/AM!>2F5!7&'! 59'6@F'!7\'6%&'!&4!;NXAc!;NXac!;NX"lc!;NXAU!&4!;LXU!>2F5!7&'!59'6@F'!$586%6%&'Y!-%! J2%3462%!@F!'64&!@&!D94C\7$462%!7&'!;=O!>&F?&%4!$?265!F%!5I7&!@`$346?$4&F5!2F!@&! 59>5&''&F5!45$%'356>462%&7Y!,&'!D94C\7$462%'!@&!;N/L!!&4!;N/NU"U"c"UA!'2%4!$''2369&'!

F%&!$346?$462%!@&!7$!45$%'356>462%!@&'!8H%&'!$725'!EF&!3&77&'!@&!!;N/d!&4!;N/Al!'2%4! 3255979&'!R!F%&!59>5&''62%!89%6EF&"UNc"UL!Y!,&'!D94C\7$462%'!@F!59'6@F!$586%6%&!;NXA!

3$4$7\'9'!>$5!7`&%j\D&!:*X="!&4!@F!59'6@F!$586%6%&!;LXN!3$4$7\'9&'!>$5!7&'!&%j\D&'! G=XO"!&4!G=XOg!'2%4!6D>76EF9'!@$%'!7`$346?$462%!45$%'356>462%%&77&"UgY!!

! ,$!D94C\7$462%!@&'!C6'42%&'!b2F&!F%!5I7&!>59>2%@95$%4!@$%'!@6?&5'!>523&''F'! _627286EF&'!32DD&!7$!598F7$462%!@F!3\37&!3&77F7$65&c!7$!59>2%'&!$F!'45&''!&4!$FP! @2DD$8&'!R!7`*1Kc!7&!@9?&72>>&D&%4!&4!7$!@6JJ95&%36$462%lAc"UUY!

! -%!>$4C27286&!4FD25$7&c!@&'!$_&55$462%'!@&!7$!D94C\7$462%!@&'!C6'42%&'!'2%4! 5$>>2549&'"Ulc"UaY!<%&!@6D6%F462%!@F!%6?&$F!@&!D94C\7$462%!@&'!C6'42%&'!&'4!3255979&!R!

F%!>52%2'463!>9b25$46J!@$%'!@&!%2D_5&FP!3$%3&5'!'276@&'!D$6'!$F''6!@$%'!7&'!

7\D>C2D&'Y!;N/AlD&N!D&4C\745$%'J&5$'&!&'4!>$5!&P&D>7&!F>B598F79&!@$%'!7&'!3$%3&5'! @&!7$!>52'4$4&c!@F!'&6%!&4!@$%'!7&'!7\D>C2D&'"Ud€"l"!Y!1&'!DF4$462%'!$346?$4563&'!&4!

(87)

! ag! ! ,&'!D$5EF&'!C6'42%&!'2%4!6D>76EF9&'!@$%'!7$!@6JJ95&%36$462%!7\D>C2h@&!+! >F6'EF&!'&F7'!7&'!7236!#1[!&%!5&32D_6%$6'2%!$346?&!D2%45&%4!@&'!D94C\7$462%'!@&'! C6'42%&'!'F5!7&'!59'6@F'!7\'6%&!"lLY!!Q%!32%%$w4!$Fb2F5@`CF6!7$!%93&''649!@`F%&!3C52D$46%&! 456BD94C\79!'F5!;N/Al!>2F5!7$!>52D2462%!@&!7$!5&32D_6%$6'2%!#1[!$725'!EF&!7$! D94C\7$462%!;N/d!7`6%C6_&"lgY!,$!456D94C\7$462%!;N/Lc!D$5EF&!9>689%946EF&!$346?&c!$!949! 6@&%46J69&!32DD&!%93&''$65&!$F!5&35F4&D&%4!@&!7$!5&32D_6%$'&!X*eA!'F5!7&'!7236!#1[! "lU€"laY!,`&%563C6''&D&%4!@&!;N/LD&N'F5!7&'!8H%&'![];^!>7F4I4!EF&!'F5!7&'!8H%&'!!#];^!2F! 1];!^!@$%'!F%&!768%9&!>52B+!>&F4Bp45&!5&'>2%'$_7&!@F!J$64!EF&!7&!59$55$%8&D&%4!1];^B [];^!>593H@&!7&!59$55$%8&D&%4!1[];^B#];^"lLY!G$5!$677&F5'c!-);A!32%45I7&!7&'! 59$55$%8&D&%4'!@&'!'&8D&%4'!#];^!@6'4$FP!?6$!'2%!32%45I7&!'F5!7$!D94C\7$462%!@&!/Al! 'F5!;NY!*6%'6!7$!D94C\7$462%!@&'!C6'42%&'!6%4&5?6&%4!R!@6JJ95&%4!4&D>'!'>936J6EF&'!@&!7$! 5&32D_6%$6'2%!#1[Y!-77&!&'4!6%@6'>&%'$_7&!R!7`6%646$462%!@&!3&!>523&''F'!!%24$DD&%4!&%! J$?256'$%4!F%!94$4!3C52D$46%6&%!2F?&54!&4!&%!$''F5$%4!7$!D6'&!&%!>7$3&!@&'!D93$%6'D&'! @&!59>$5$462%!@&'!3$''F5&'!@&!7`*1K!&%!>&5D&44$%4!7&!5&35F4&D&%4!@&'!>52496%&'!@&!7$! D$3C6%&56&!@&!59>$5$462%Y! ! ,&'!;=O!'2%4!6D>76EF9&'!@$%'!7$!7&F39D289%H'&Y!,$!'F5&P>5&''62%!@&!(<Nd;"nA! EF6!3$4$7\'&!7$!D94C\7$462%!@&!;N/d!J$?256'&!7&!@9?&72>>&D&%4!!@&!7\D>C2D&'!+!3C&j!7$! '2F56'Y!*F!32F5'!@&'!7&F39D6&'!$68F&'c!7$!59862%!3C52D2'2D6EF&!""EAN!&'4! J59EF&DD&%4!7$!36_7&!@&!59$55$%8&D&%4'!$JJ&34$%4!7&!8H%&!32@$%4!>2F5!7`;=O!>CC;Y!,&'! 45$%'723$462%'!@&!>CC;%'&!>52@F6'&%4!@$%'!aMo!@&'!7&F39D6&'!>9@6$456EF&'!@&! @6JJ95&%4'!'2F'B4\>&'Y!1$%'!3&54$6%&'!7&F39D6&'!7&!>$54&%$65&!@&!JF'62%!@&!>CC[=@;OG!! >&F4!6%4&5$865!$?&3!!1QO",Y!1QO",!&'4!F%&!;=O!5&'>2%'$_7&!@&!7$!D94C\7$462%!@&! ;N/ld!$F!%6?&$F!@&!7$!59862%!>52D24563&!@F!8H%&!HF]=WY!,&!5&35F4&D&%4!@&!1QO",!>$5! 7$!>52496%&!@&!JF'62%!=,,B*T"M!>&F4!6%@F65&!F%&!45$%'J25D$462%!7&F39D6EF&! @9>&%@$%4&!@&!7`$346?649!@&!1QO",Y!-%!&JJ&4!F%!DF4$%4!1QO",!@2%4!7`$346?649! &%j\D$46EF&!&'4!$74959&c!%`&'4!>7F'!3$>$_7&!@&!>52D2F?265!7$!3526''$%3&!@&'!3&77F7&'! 45$%'J25D9&'!>$5!=,,B*T"M"ldY!-);A!&'4!F%&!;=O!EF6!J$64!>$546&!@F!32D>7&P&! 59>5&''&F5!>27\32D_!A!&4!@2%4!7&!'F_'45$4!'>936J6EF&!&'4!;N/AlY!-);A!!&'4!5&EF6'!>2F5! 7$!>5276J95$462%!3&77F7$65&Y!1&'!DF4$462%'!593F55&%4&'!>2%34F&77&'!@&!-);A!'2%4! 5$>>2549&'!@$%'!AAo!@&'!1,+:,!@F!'2F'!4\>&!:e!&4!@$%'!lo!@&'!,TNlY!,$!DF4$462%!7$! >7F'!J59EF&%4&!$JJ&34&!7&!59'6@F!kUL"Y!:&44&!DF4$462%!6%@F64!7`$33FDF7$462%!@&!

(88)

! aU! F%&!$586%6%&!D&4C\745$%'J95$'&!$!F%!5I7&!>6?24!@$%'!7$!45$%'J25D$462%!D$768%&!6%@F64&! >$5!=,,"aAY! ! ,&'!;=O!'2%4!@&'!36_7&'!$445$346?&'!@$%'!7&!45$64&D&%4!@F!3$%3&5Y!,`6D>763$462%!@F! 32J$34&F5!(*=!](B$@9%2'\7!D94C62%6%&^!32%'464F&!F%&!>$5463F7$5649!'F'3&>46_7&!@&! J$36764&5!7&!@9?&72>>&D&%4!@`6%C6_64&F5'!>C$5D$327286EF&'Y!,`F4676'$462%!@`$%$728F&'!@&! (*=!32DD&!6%C6_64&F5'!$!949!7$58&D&%4!'F88959&Y!:&>&%@$%4!3&'!D2793F7&'!%&!36_7&%4! >$'!'&F7&D&%4!7&'!;=O!D$6'!$F''6!@`$F45&'!&%j\D&'!EF6!F4676'&%4!7&!(*=!32DD&!7&'!*1K! D&4C\745$%'J&5$'&'c!3&!EF6!7&'!5&%@!@6JJ6367&D&%4!32D>$46_7&'!$?&3!F%!@9?&72>>&D&%4! 376%6EF&Y!1&'!6%C6_64&F5'!@`;=O!>7F'!'>936J6EF&'!2%4!949!@932F?&54'Y!,$!3C$94236%&! 6%C6_&!(<#Nd;""aNc!1)K&>!](B$@&%2'\7C2D23\'4&6%&!C\@527$'&!6%C6_6425!NB

@&$j$%&>7$%236%!*^!&'4!F%!6%C6_64&F5!@&!7$!456D94C\7$462%!@&!;N/AlY!!:&44&!D2793F7&! 6%@F64!'97&346?&D&%4!7`$>2>42'&!@&'!3&77F7&'!4FD25$7&'!&4!%2%!@&'!3&77F7&'!%25D$7&'"aLY! +0ZBM"AdL!&'4!F%!6%C6_64&F5!@&!7`;=O!ed$!6D>76EF9&!@$%'!7$!@6D94C\7$462%!@&!;N/dY! +0ZBM"AdL!6%C6_&!'>936J6EF&D&%4!7$!@6D94C\7$462%!@&!;N/d!D9@69&!>$5!ed$!'$%'!$7495&5! 7$!D2%2!%6!7$!456D94C\7$462%"agY!*=0B"!&'4!F%!6%C6_64&F5!'97&346J!@&!7`;=O!GX=O"Y!-%J6%! 7&!@9?&72>>&D&%4!@`6%C6_64&F5'!'>936J6EF&'!@`-);A!2JJ5&!F%&!2>>254F%649!4C95$>&F46EF&! D$b&F5&!@$%'!7&!45$64&D&%4!@&'!7\D>C2D&'Y!!:&'!6%C6_64&F5'!32DD&!-lLNa!&4! e(/Aa"U"AUc!6%C6_&%4!'97&346?&D&%4!7$!DF746>763$462%!@&'!3&77F7&'!7\D>C2D$4&F'&'! >254&F'&'!@&!7$!DF4$462%"aMc"aUY! ! D>L_)Q&%'"(6%)*/#/'I.39%6%) ! ,&'!C6'42%&'!@9D94C\7$'&'!'2%4!3$>$_7&'!@&!5&465&5!@&'!852F>&D&%4'!D94C\7&'! %2%!'&F7&D&%4!'F5!7&'!>52496%&'!C6'42%&'!D$6'!$F''6!'F5!7&'!>52496%&'!%2%B

C6'42%&'"alc"aaY!,$!D94C\7$462%!@&'!C6'42%&'!>&F4!'&!J$65&!'F5!7&'!59'6@F'!$586%6%&!&4!

7\'6%&Y!:&>&%@$%4!7$!@9D94C\7$462%!@&'!59'6@F'!$586%6%&!D9@69&!>$5!>&>46@\7!$586%6%&! @&6D6%$'&!L!]G*10L^!%`&'4!>$'!32%'6@959&!32DD&!F%&!?9564$_7&!@9D94C\7$462%!>F6'EF&! 3&44&!59$3462%!45$%'J25D&!F%&!$586%6%&!&%!3645F776%&!'$%'!7$6''&5!$F!J6%$7!@&!59'6@F! $586%6%&!76_5&"adY!:2DD&!9%2%39!>5939@&DD&%4!!7&'!7\'6%&'!>&F?&%4!p45&!D2%2c!@6!2F!

456D94C\79&'!&4!3&'!94$4'!>&F?&%4!p45&!$''2369'!'264!R!F%&!$346?$462%!'264!R!F%&!59>5&''62%! 45$%'356>462%%&77&!&%!J2%3462%!@&!7$!>2'6462%!@F!59'6@F!36_79!&4!@F!%6?&$F!@&!

D94C\7$462%"aaY!:&'!852F>&D&%4'!D94C\7&'!>&F?&%4!p45&!5&4659'!>$5!@&!?5$6'!C6'42%&'!

(89)

! al! @&D&4C\7$'&!"!]/1="^!&4!7&'![FD$2%b6!:!][D[:^!@2D$6%!32%4$6%6%8!C6'42%&! @&D&4C\7$'&"dMY! ! ,$!J$D677&!@&'!/1="!&'4!32D>2'9&!@&!A!D&D_5&'!S!/1="*!$F''6!32%%F!'2F'!7&! %2D!@&!7\'6%&B'>&36J63!@&D&4C\7$'&!"!],(1"^!&4!/1="+Y!/1="*!@9D94C\7&! '>936J6EF&D&%4!;N/LD&"!&4!;N/LD&A!3&!EF6!59'F74&!&%!F%&!59>5&''62%! 45$%'356>462%%&77&"d"Y!,25'EF&!/1="*!359&!F%!32D>7&P&!$?&3!7&!593&>4&F5!$FP! $%@528H%&'c!&77&!@9D94C\7&!;N/dD&"!&4!!;N/dD&A!!3&!EF6!R!7`6%?&5'&!&%45$w%&!F%&! $346?$462%!@&!7$!45$%'356>462%"dAY!!/1="*!&'4!3&>&%@$%4!6%3$>$_7&!@&!@9D94C\7&5!7&'!

7\'6%&'!456BD94C\79&'Y!1&'!>52496%&'!%2%!C6'42%&'!'2%4!98$7&D&%4!7$!36_7&!@&!/1="*Y! GgN!&'4!>$5!&P&D>7&!F%!@&!'&'!'F_'45$4'Y!,$!@9D94C\7$462%!@&!/NlMD&A!>$5!/1="*! &D>p3C&!7`6%4&5$3462%!GgNngN+G"!]>gN!_6%@6%8!>524&6%!"^!3&!EF6!$!>2F5!32%'9EF&%3&! F%&!>&54&!@&!J2%3462%!@&!>gNc!@2%4!7`6%@F3462%!@&!7`$>2>42'&"dNY!/1="*!>&F4!@9D94C\7&5!

1K=O"!J$?256'$%4!$6%'6!'$!'4$_676'$462%!&4!>&5D&44$%4!R!1K=O"!@&!D$6%4&%65!7&'!>$44&5%! @&!7$!D94C\7$462%!@&!7`*1K!@$%'!7&'!3&77F7&'!'2F3C&'!&D_5\2%%$65&'"alY!O2F4!32DD&!

/1="*c!/1="+!36_7&!'>936J6EF&D&%4!;N/LD&"!&4!;N/LD&AY!,&'!J2%3462%'!598F7$4563&'! @&!/1="+!'2%4!F%!>&F!32%%F&'c!3&>&%@$%4!3&44&!&%j\D&!b2F&5$64!F%!5I7&!@$%'! 7`&D>5&6%4&!>$5&%4$7&!D$4&5%&77&!@$%'!7&'!2?23\4&'!&4!!@$%'!7`$346?$462%!@&!7$!?26&! KTy+"dLc"dgY! ! ,$!!J$D677&!@&'![D[:!@2D$6%!32%4$6%6%8!C6'42%&!@&D&4C\7$'&!32D>5&%@!>59'!@&! AM!7\'6%&!@9D94C\7$'&'Y!*!7$!@6JJ95&%3&!@&'!/1="c!!7&'![D[:!@2D$6%!32%4$6%6%8!C6'42%&! @&D&4C\7$'&'!'2%4!3$>$_7&'!@&!5&465&5!7&'!456BD94C\7$462%'"dUY!!16JJ95&%4&'!'2F'BJ$D677&'!

@&![D[:!/1=!2%!949!6@&%46J69&'!6%37F$%4!&%45&!$F45&'!S!/1=Ac!/1=Nc!/1=Lc!/1=g!&4! /1=UY!,$!'2F'!J$D677&!@&'!/1=A!36_7&!'>936J6EF&D&%4!;N/NUD&A!&4!;N/LD&N"dl]>N^Y!!

-77&!598F7&!&%!>$5463F76&5!G"g!?6$!7$!@9D94C\7$462%!@&!;N/NUD&A!5&'>2%'$_7&!@`F%&! 59>5&''62%!'F5!3&!723F'"dlY!,`6%C6_6462%!@&!/1=A+!&%45$6%&!F%&!6%@F3462%!@&!7$!

'&%&'3&%3&!3&77F7$65&!?6$!7&'!?26&'!GgN!&4!X+"dlY!/1=A*!&'4!3$>$_7&!@&!59>56D&5!7$!?26&!

KTy+"dac"ddY!,$!'2F'!J$D677&!@&'!/1=N!&'4!6D>76EF9&!@$%'!7$!'>&5D$4289%H'&AMMY!,$!

@9D94C\7$462%!@&!;N/dD&Ac!;N/dD&Nc!;N/NUD&A!&4!;N/NUD&N!&'4!3$4$7\'9&!>$5!7$! '2F'BJ$D677&!/1=LY!:&44&!'2F'BJ$D677&!b2F&!F%!5I7&!@$%'!7`$346?$462%!@&!7`&P>5&''62%! 89%6EF&Y!/1=L:!J$?256'&!F%!94$4!@`&F3C52D$46%&!J$?25$_7&!R!7$!45$%'356>462%AM"!&4!

(90)

! aa! 59>5&''6?&Y!!/1=U*!&'4!F%!598F7$4&F5!@F!3\37&!3&77F7$65&!?6$!'2%!$3462%!'F5!7$!>52496%&! X+!EF6!59'F74&!&%!F%!$55p4!@F!3\37&!3&77F7$65&Y!/1=U+!$''F5&!7$!'4$_676'$462%!%F379$65&!@&! GgN!&4!J$?256'&!7`&P>5&''62%!@&!G"U!&4!@&!G"LAMNY! ! 1&'!$7495$462%'!&4!@&'!&P>5&''62%'!$_&55$%4&'!@&'!C6'42%&'!@9D94C\7$'&'!'2%4! 5$>>2549&'!@$%'!@&!%2D_5&FP!3$%3&5'Y!!/1="*!&'4!'F5&P>56D9&!@$%'!7&'!

%&F52_7$42D&'!>&F!@6JJ95&%369'AMLY!/1="*!&D>p3C&!7&!>523&''F'!@&!@6JJ95&%36$462%!&4!

J$?256'&!7&!D$6%46&%!@`F%!>C9%24\>&!4FD25$7!@$%'!7&'!%&F52_7$'42D&'Y!/1="*!&'4!$F''6! F%!979D&%4!379!@F!_723$8&!@&!@6JJ95&%36$462%!@&'!7&F39D6&'!=,,B*TdAMg!&4!'2%!6%C6_6462%!

59$346?&!7&!>523&''F'!@&!@6JJ95&%36$462%!@$%'!7&'!7&F39D6&'!$68F&'!D\972h@&'AMUY!/1=A*!

>52D&F4!7&'!3$%3&5'!@F!>2FD2%!&%!598F7$%4!>2'646?&D&%4!7$!?26&!-X/"nAAMlY!/1=A+!&'4!

F>B598F79!@$%'!7&'!>593F5'&F5'!7&F39D6EF&'!&4!&'4!%93&''$65&!>2F5!7$!45$%'J25D$462%! D$768%&AMaY!,$!'F5&P>5&''62%!@&!/1=A1!&'4!$''2369&!R!F%!D$F?$6'!>52%2'463!@$%'!7&'!

3$%3&5'!@F!>$%359$'AMdY!/1=N*!J$?256'&!7$!3526''$%3&!4FD25$7&A"M!&4!7$!'F5?6&!@&'!

3&77F7&'!D\972D$4&F'&'A""Y!G$5!$677&F5'!7$!59862%!3C52D2'2D6EF&!gEN"!EF6!32%46&%4!F%&!

>25462%!@F!8H%&!Z:>A6%&'4!J59EF&DD&%4!@97949&!@$%'!7&'!'\%@52D&'!

D\972@\'>7$'6EF&'!&4!7&'!7&F39D6&'!$68F&'!D\972h@&'A"AY!/1=N+!&'4!98$7&D&%4!

6D>76EF9&!@$%'!7$!45$%'356>462%!$346?&!@&!7`2%328H%&!7&F39D6EF&!,=QAA"NY!/1=L*!

J$?256'&!7$!45$%'J25D$462%!4FD25$7&!&%!_72EF$%4!7$!'9%&'3&%3&!?6$!F%&!59>5&''62%! 45$%'356>462%%&77&!@F!8H%&!'F>>5&''&F5!@&!4FD&F5!:;1gA"LY!!/1=L:!&'4!@9598F79&!@$%'!

@&!%2D_5&FP!3$%3&5'c!@2%4!7&'!7\D>C2D&'!+!&4!7&!7\D>C2D&!@&!;2@8f6%c!2r!@&'! $D>76J63$462%'!@&!7$!59862%!d>ALc!32%4&%$%4!/1=L:!&4![*/Ac!!'2%4!J59EF&DD&%4!

5$>>2549&'A"gY!/1=L*c!+!&4!:!J$?256'&%4!!7$!45$%'J25D$462%!@&'!3&77F7&'!7&F39D6EF&'!&%!

>$5463F76&5!?6$!F%&!$346?$462%!@&!7$!?26&![*/B(O*O!@$%'!7&'!7&F39D6&'!$68F&'!=,,B*TdA"UY!

/1=g+!&'4!'F5&P>56D9&!@$%'!@&!%2D_5&FP!3$%3&5'!6%37F$%4!7&!3$%3&5!@&!7$!>52'4$4&c!7&! 3$%3&5!@F!'&6%!&4!7&!3$%3&5!@&'!4&'463F7&'Y!1&'!DF4$462%'!'2D$46EF&'!@F!8H%&!/1=U*! '2%4!5$>>2549&'!@$%'!@&'!3$%3&5'!>9@6$456EF&'!&4!@&!7`$@F74&A"lY!/1=U+!b2F&!F%!5I7&!

@$%'!7`6%646$462%!@&'!7&F39D6&'!7\D>C2_7$'46EF&'!OY!

! G7F'6&F5'!D2793F7&'!6%C6_64563&'!@&!/1="*!2%4!949!!>52>2'9&'Y!:&'!D2793F7&'! 36_7&%4!'>936J6EF&D&%4!7&'!852F>&'!_&%j2\7&!&4!_&%P\7$D6%2!5&452F?9'!$F!%6?&$F!@F!'64&! $346J!@&!/1="*A"aY!;:0BAgMd!F%!6%C6_64&F5!'>936J6EF&!@&!/1="*!J$?256'&!7`$>2>42'&!

@$%'!7&'!768%9&'!@&!7&F39D6&!$68F&!D\972h@&!&4!@&!3$536%2D&!&%@2D9456$7A"dcAAMY!

(91)

! ad! 7&F39D6&'!D\972h@&'!$68F&'!59J5$34$65&'!2F!&%!5&3CF4&Y!1&'!6%C6_64&F5'!'97&346J'!@&! /1=g!&4!/1=U!]:G0BLgg!&4!e(/B["!Se(/B[L^!2%4!949!6@&%46J69'AA"cAAAY!!

! ! D>L`)F-"'/&(6%)C0B)6')C=5)) ! <%!_52D2@2D$6%&!&'4!F%!@2D$6%&!@`F%&!>52496%&!EF6!5&32%%$w4!7&'!59'6@F'!7\'6%&! $394\79'Y!,$!J$D677&!@&'!>52496%&'!+-O!]_52D2@2D$6%&!&4!&P45$4&5D6%$7!@2D$6%&^! 32D>5&%@!L!>52496%&'!S!+X1Ac!+X1Nc!+X1L!&4!+X1OY!:&'!>52496%&'!&P45pD&D&%4!_6&%! 32%'&5?9&'!$F!32F5'!@&!7`9?27F462%!>2''H@&%4!A!_52D2@2D$6%&'!]+1"!&4!+1A^c!F%! @2D$6%&!&P45$B4&5D6%$7!]-O^!&4!F%&!'9EF&%3&!G-(O!563C&!&%!>5276%&!]G^c!$36@&! 87F4$D6EF&!]-^c!'956%&!](^!&4!4C592%6%&!]O^Y!!-77&'!b2F&%4!F%!5I7&!J2%@$D&%4$7!$F!32F5'! @F!@9?&72>>&D&%4!&D_5\2%%$65&Y!-%!&JJ&4c!3C&j!7&'!'2F56'!7&!/Q!+X1A!&'4!794$7!R!7`94$4! &D_5\2%%$65&Y!:&'!'2F56'!>59'&%4&%4!&%!2F45&!@&'!@9J$F4'!@&!J25D$462%!@F!4F_&!%&F5$7! &4!F%!5&4$5@!@&!3526''$%3&AANY!,&!/Q!+X1L!&'4!98$7&D&%4!794$7!R!7`94$4!&D_5\2%%$65&!&4!

7&'!'2F56'!C94952j\824&'!D&F5&%4!@$%'!7&'!A!'&D$6%&'!$>5H'!7$!%$6''$%3&AALY!,$!@979462%!

@F!>5&D6&5!_52D2@2D$6%&!@&!+X1O!&'4!$''2369&!R!7`6%J&5467649!3C&j!7&'!'2F56'!DV7&'!! $?&3!@&'!$7495$462%'!@$%'!7&'!'4$@&'!4$5@6J'!@&!7$!'>&5D$4289%H'&AAgY!,&'!

_52D2@2D$6%&'!@&!7$!J$D677&!+-O!D2%45&%4!@&'!$JJ6%649'!@6JJ95&%4&'!>2F5!7&'!C6'42%&'! $394\79&'Y!!,&'!_52D2@2D$6%&'!@&!+X1A!'`$''236&%4!R!7`C6'42%&!;L!$394\79&!>7F4I4!EF&! ;N!$394\79&!&4!'&!76&%4!R!;L/g$3!&4!;L/"A$3AAU!Y!+X1L!5&32%%$w4!32DD&!+X1A!;L/g$3!

&4!;L/"A$3!D$6'!$F''6!;N/"L$3Y!G$5!$677&F5'c!!7&'!>52496%&'!@&!7$!J$D677&!+-O!>&F?&%4! 6%4&5$865!$?&3!@&'!>52496%&'!%2%BC6'42%&!$394\79&'Y!-%!&JJ&4c!+X1L!&'4!3$>$_7&!

@`6%4&5$865!$?&3!7$!'2F'BF%649!$394\79&!@F!J$34&F5!KTy+AAlY!,$!>52496%&!+X1L!&'4!F%!

32$346?$4&F5!45$%'356>462%%&7!>F6''$%4Y!-77&!$346?&!7$!45$%'356>462%!&%!'46DF7$%4!R!7$!J26'! 7&!5&35F4&D&%4!@&!7`*XK!>27\D95$'&!00!&4!'2%!$346?$462%!>$5!>C2'>25\7$462%AAacAAdY!!

1`$F45&'!D&D_5&'!@&!7$!J$D677&!+-O!J2%3462%%&%4!$F''6!32DD&!@&'!598F7$4&F5'! 45$%'356>462%%&7'Y!+X1Ac!>59'&%4!$F!%6?&$F!@&!7$!59862%!>52D24563&!@&!7$!:\376%&!*c! J$?256'&!'$!45$%'356>462%!&4!$3397H5&!$6%'6!7&!3\37&!3&77F7$65&ANMY!+X1A!&4!+X1N!'2%4!

>59'&%4&'!$F!%6?&$F!@&!7$!'9EF&%3&!32@$%4&!@F!8H%&!@&!7$!:\376%&!1"Y!*725'!EF&! 7`6%C6_6462%!@&!+X1N!&%45$w%&!7$!D254!3&77F7$65&c!3&77&!@&!+X1A!&%45$w%&!F%&!_$6''&! '>936J6EF&!@&!7`&P>5&''62%!@&!7$!:\376%&!1"AN"Y!

(92)

! dM! 7`&P>5&''62%!$_&55$%4&!@&!7`2%328H%&!<>B<!@$%'!7&'!7&F39D6&'!D\972h@&'c!7&!7\D>C2D&! @&!+F5f644!&4!7&'!7\D>C2D&'!+!@&!C$F4!85$@&ANA€ANL!Y!+X1L!b2F&!F%!5I7&!@$%'!7$!

4FD25289%H'&!@&'!3$%3&5'!D$DD$65&'!&%!$346?$%4!7$!?26&!@&'!&'4528H%&'ANgY!+X1L!J$64!

>$546&!@&!32D>7&P&!@&!598F7$462%!45$%'356>462%%&77&!J$?256'$%4!7$!45$%'356>462%!@&!:=k:! EF6!&'4!$74959!@$%'!@&!%2D_5&FP!3$%3&5'ANUY!,&'!>52496%&'!+-O!'2%4!>$5!$677&F5'!

'F5&P>56D9&'!@$%'!7&'!8762_7$'42D&'!&4!7&'!D97$%2D&'!D94$'4$46EF&'ANlY!,&'!>52496%&'!

+-O!'2%4!98$7&D&%4!6D>76EF9&'!@$%'!@&'!45$%'723$462%'!J$?256'$%4!7$!8&%H'&!@&! >52496%&'!@&!JF'62%!2%3289%6EF&'Y!<%!&P&D>7&!&'4!3&7F6!@F!3$536%2D&!@&!7$!768%&! D9@6$%&!K<Oc!F%!3$536%2D&!$85&''6J!3$5$34956'9!>$5!7$!45$%'723$462%!4]"g!z"d^! 6D>76EF$%4!7&'!8H%&'!D\E!&4!6!:NANaY!!,&'!DF4$462%'!@F!8H%&!D?>;!'2%4!5$>>2549&'!

@$%'!&%?652%!Ngo!@&'!7&F39D6&'!D\972h@&'!$68F&'Y!07!$!949!D2%459!EF&!3C&j!7&'!>$46&%4'! D?>;%i67@B4\>&c!KG="!6%4&5$86''$64!$?&3!+X1L!@$%'!7&!%2\$F!$J6%!@&!59>56D&5!7$! 45$%'356>462%!6%@F64&!>$5!+X1LANdY!*!7`6%?&5'&!@$%'!7&'!7&F39D6&'!D\972h@&'!$68F&'!

D?>;%DF49!3&!D93$%6'D&!@&!59>5&''62%!45$%'356>462%%&7!@&!+X1L!>$5!KG="!&'4!$%%F79! 59'F74$%4!&%!F%&!$F8D&%4$462%!@&!7$!45$%'356>462%!@`2%328H%&'!6%37F$%4!<>B<!&4!

6<CIANdY!!!

! :2D>4&!4&%F!@&!7&F5!5I7&!2%3289%946EF&c!F%!6%495p4!3526''$%4!$!949!>2549!@$%'!7&! @9?&72>>&D&%4!@`6%C6_64&F5'!@&'!>52496%&'!+-O!&%!>$5463F76&5!@$%'!7&'!>$4C27286&'! C9D$427286EF&'Y!0B+-O"g"!&'4!F%!6%C6_64&F5!@&'!>52496%&'!+-O!36_7$%4!+X1Ac!+X1N!&4! +X1L!EF6!&%45$w%&!F%!@6D6%F462%!@&!7$!>5276J95$462%!&4!F%&!$F8D&%4$462%!@&!7`$>2>42'&! $6%'6!EF`F%&!@2i%B5&8F7$462%!@&!+:,A!&4!:=k:!@$%'!7&'!768%9&'!3&77F7$65&'!@&!7&F39D6&'! D\972h@&'!$68F&'%D?>;!DF49ANdY!,&'!7&F39D6&'!$68F&'!D\972h@&'!$?&3!45$%'723$462%!@F!

8H%&!>CC!'2%4!98$7&D&%4!'&%'6_7&'!$FP!6%C6_64&F5'!@&!+-O!0B+-O"g"!&4![m"!$?&3!32DD&! &JJ&4'!F%&!6%C6_6462%!@&!7$!45$%'356>462%!&4!F%&!@2i%5&8F7$462%!@&'!2%328H%&'!:>B<!&4! 6<CIALMY!,&'!6%C6_64&F5'!@&!+-O!'2%4!3$>$_7&'!@&!59@F65&!7$!?6$_67649!@&'!3&77F7&'!!

4FD25$7&'!@&!7\D>C2D&!7\D>C2_7$'46EF&!+!$?&3!F%&!59@F3462%!@&!7$!>C2'>C25\7$462%! @&![*/A!&4!(O*Og!!&4!F%&!@2i%5&8F7$462%!@&!:=k:ANA!&4!@&!7$!f6%$'&!*F525$!+!b2F$%4!F%!

5I7&!@$%'!7&!@952F7&D&%4!@&!7$!D642'&!!&4!'2F?&%4!'F5&P>56D9!@$%'!7&'!7\D>C2D&'! 7\D>C2_7$'46EF&'!+AL"Y!,&'!1,+:,!@F!'2F'!852F>&!D2793F7$65&!*+:!'&!3$5$34956'&%4!>$5!

(93)

! d"! 98$7&D&%4!3$>$_7&!@&!@6D6%F&5!7`&P>5&''62%!@&!:=k:!@$%'!7&'!768%9&'!3&77F7$65&'!@&! 1,+:,!!2F!@&!7\D>C2D&'!@&!C$F4!85$@&!:>B<%45$%'72EF9!$?&3!32DD&!&JJ&4'!F%&! 6%C6_6462%!@&!7$!'F5?6&!&4!@&!7$!>5276J95$462%ALNY!!,&'!6%C6_64&F5'!@&'!>52496%&'!+-O!J2%4!

@2%3!7`2_b&4!@`&''$6'!376%6EF&'!@$%'!7&'!C9D2>$4C6&'!D$768%&'Y!,`6%C6_64&F5!@&!+-O! QOZM"g!!$!949!4&'49!@$%'!@&'!&''$6'!@&!>C$'&!0!6%37F$%4!@&'!7&F39D6&'c!7\D>C2D&'!&4! D\972D&'ALLcALg!&4!@$%'!F%!&''$6!@&!>C$'&!0_!6%37F$%4!@&'!D\972D&'!&4!7\D>C2D&'!

(94)
(95)

! dN! ! ,&'!,+1e:!5&>59'&%4&%4!7&!4\>&!C6'427286EF&!@&!7\D>C2D&'!7&!>7F'!J59EF&%4!3C&j! 7`$@F74&Y!!,&!45$64&D&%4!@&!59J95&%3&!5&>2'&!'F5!7`6DDF%24C95$>6&!$''2369&!R!7$! 3C6D624C95$>6&!>$5!XB:;QGY!!(6!F%&!D$b25649!@&!>$46&%4!&'4!&%!59D6''62%!32D>7H4&!$>5H'! 3&!45$64&D&%4!@&!>5&D6H5&!768%&c!>5p4!@`F%!46&5'!'2%4!59J5$34$65&'!2F!&%!5&3CF4&'! >59323&'!$?&3!F%!>52%2'463!45H'!>9b25$46JY!1&!3&!32%'4$4!7`C\>24CH'&!EF&!7&'!,+1e:! 32%'464F&%4!F%!852F>&!C949528H%&!@&!D$7$@6&c!$?&3!@&'!?$56$_67649'!_627286EF&'!'2F'! b$3&%4&'!R!7&F5!9?27F462%!376%6EF&c!$!J$64!'2%!3C&D6%&D&%4Y!:`&'4!@$%'!3&!32%4&P4&!EF&!7&'! >5&D6H5&'!94F@&'!45$%'356>42D6EF&'!2%4!949!&%45&>56'&'Y!1&!3&'!45$?$FP!&'4!%9!7&! 32%3&>4!@&!7$!3&77F7&!@`25686%&!]:QQ!S!3&77!2J!25686%^!EF6!>&5D&4!@&!'F_@6?6'&5!7&'!,+1e:! &%!A!85$%@'!852F>&'!D2793F7$65&'!S!F%!>5&D6&5!852F>&!&%563C6!&%!8H%&'!6D>76EF9'!@$%'! 7$!59$3462%!6DDF%64$65&!7\D>C23\4$65&!+!$F!'&6%!@F!3&%45&!8&5D6%$46Jc!7&!'2F'!,+1e:!B e:+c!&4!F%!'&32%@!852F>&!&P>56D$%4!7&'!8H%&'!6D>76EF9'!@$%'!7`$346?$462%!7\D>C23\4$65&! +!>2'4!3&%45&!8&5D6%$46Jc!7&!'2F'!852F>&!,+1e:!B*+:NAY!(F5!7&!>7$%!376%6EF&!7&!'2F'B 852F>&!*+:!&'4!$''2369!R!F%&!D$7$@6&!>7F'!$85&''6?&Y!,&'!>$46&%4'!$?&3!F%!,+1e:!B*+:!! 2%4!F%!V8&!'F>956&F5!R!UM!$%'!&4!F%!'325&!@&!>&5J25D$%3&!-:Qe!‚"Y!G$5!$677&F5'!@&'! 94F@&'!2%4!@9D2%459!EF&!7&!4$FP!@&!'F5?6&!R!g!$%'!94$64!@&!Ugo!32%45&!Ngo!@$%'!7&! 852F>&!e:+!?&5'F'!852F>&!*+:!$>5H'!45$64&D&%4!>$5!$%4C5$3\376%&NNY!1&!%2D_5&FP! &''$6'!376%6EF&'!2%4!@&!3&!J$64!4&'49!@&!%2F?&77&'!@528F&'!@$%'!7&'!,+1e:!$F!@6$8%2'463! 2F!&%!5&3CF4&n59J5$34$65&!'&72%!7&!'2F'!852F>&!D2793F7$65&!e:+!?&5'F'!*+:Y!:&'!94F@&'! 2%4!D2%459!F%!6%495p4!@F!7&%$76@2D6@&c!@F!_254&j2D6_!&4!@&!7`6_5F46%6_!@$%'!7&!'2F'! 852F>&!*+:!>$5!5$>>254!$F!'2F'!852F>&!e:+LMcaAcaNY!1`$F45&'!94F@&'!>7F'!593&%4&'!'2%4!

(96)
(97)
(98)
(99)
(100)

Références

Documents relatifs

Nous présentons ici le cas d’un patient âgé de 77 ans atteint d’une LMMC compliquée d’une lymphoprolifération B cutanée induit par le virus Epstein-Barr (EBV)..

Abstention thérapeutique et chimiothérapie standard après l’accouchement Si urgence thérapeutique : monothérapie par rituximab au premier trimestre puis chimiothérapie standard

• pour le traitement des adultes atteints d’un LGCB r/r après au moins deux lignes de traitement systémique, y inclus les adultes atteints d’un lymphome diffus à grandes

Étude NCT03761056 (ZUMA-12) : Efficacy and Safety of Axicabtagene Ciloleucel as First-Line Therapy in Participants With High-Risk Large B-Cell Lymphoma (ZUMA-12) Statut de l’étude

Ce biais de sélection attribuable au délai de production des cellules CAR-T favorise la thérapie avec le tisagenlecleucel, car les patients qui ont une forme plus agressive de

Young patients with non-germinal center B-cell- like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP

LMO2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with anthracycline-based chemotherapy with and without rituximab..

Les données sont présentées sous forme de moyenne ± écart-type (n=7 souris dans les conditions ODN-ctl et n=6 dans les conditions ODN-CpG). Nous pouvons noter que le