• Keine Ergebnisse gefunden

RNAi-mediated knockdown of the endogenous TCR improves safety of immunotherapy with TCR gene-modified T cells

N/A
N/A
Protected

Academic year: 2022

Aktie "RNAi-mediated knockdown of the endogenous TCR improves safety of immunotherapy with TCR gene-modified T cells"

Copied!
131
0
0

Wird geladen.... (Jetzt Volltext ansehen)

Volltext

(1)

RNAi-mediated knockdown of the endogenous TCR improves safety of immunotherapy with

TCR gene-modified T cells

D i s s e r t a t i o n

zur Erlangung des akademischen Grades d o c t o r r e r u m n a t u r a l i u m

(Dr. rer. nat.)

im Fachbereich Biologie

eingereicht an der

Lebenswissenschaftlichen Fakultät der Humboldt-Universität zu Berlin

von

D i p l o m - B i o c h e m i k e r M a r i o B u n s e

Präsident der Humboldt-Universität zu Berlin Prof. Dr. Jan-Hendrik Olbertz

Dekan der Lebenswissenschaftlichen Fakultät Prof. Dr. Richard Lucius

Gutachter/innen: 1. Prof. Dr. Wolfgang Uckert 2. Prof. Dr. Thomas Blankenstein

3. Prof. Dr. Christian Schmitz-Linneweber Tag der mündlichen Prüfung: 12.12.2014

(2)

!!

!

!

(3)

! ! ! ! "#$%&!

!

! "!

!"#$%%&'($##"')* +*

#"%%$,-* .*

+ ! /'0,12"30/1'* 4 !

!"!

!

#$%&''$()*+&,-.*)/$-,$.0&$.0123/$+&,&)4.&$.0&$#56$)&(&).*-)&$71$/*24.-%$)&%*27-,4.-*,$ 8

!

!"9

!

#0&$#56$4//*%-4.&/$:-.0$5;<$()*.&-,/$=*)$/3)=4%&$&>()&//-*,$ ?

!

!"<

!

#012-%$/&'&%.-*,$-2(*/&/$@A5$)&/.)-%.-*,$4,B$/&'=$.*'&)4,%&$*,$.0&$#$%&''$)&(&).*-)&$ C

!

!"D

!

#$%&''/$/3)E&1$(&(.-B&$/42('&/$*=$()*.&-,/$()*B3%&B$71$0*/.$4,B$=*)&-+,$%&''/$ F

!

!"8

!

GB*(.-E&$#$%&''$.0&)4(1$ !H

!

'()('

!

*+,-.+%/!$%0,1%$!20.3!-43.0!5#-,6%#/!50%!0%7.6#,8%$!9:!;!7%<</! '=

!

'()('('

!

;43.0!5#-,6%#/!50%!60.4+%$!,#-.!75-%6.0,%/!95/%$!.#!->%,0!%&+0%//,.#!,#!!

#.035<!-,//4%! ''!

'()(?

!

;05#/2%0!.2!4#3.$,2,%$!;!7%<</! '?

!

'()(?('

!

@.#.0A$%0,1%$!;!7%<</!75#!3%$,5-%!->%!0%3,//,.#!.2!0%<5+/%$!3:%<.,$!<%4B%3,5!!

,#!9.#%!3500.C!0%7,+,%#-/! '?!

'()(?(?

!

D,04/A/+%7,2,7!;!7%<</!7.#2%0!,334#.<.6,75<!+0.-%7-,.#!-.!,334#./4++0%//%$!+5-,%#-/!'E

!

'()(?(E

!

*&!1,1.!%&+5#$%$!-43.0A,#2,<-05-,#6!;!7%<</!75#!3%$,5-%!-43.0!0%60%//,.#!,#!

+0%7.#$,-,.#%$!+5-,%#-/! 'F

!

'()(E

!

;05#/2%0!.2!;GH!6%#%A3.$,2,%$!;!7%<</! 'I

!

'()(E('

!

;GH!6%#%A3.$,2,%$!;!7%<</!75#!3%$,5-%!-43.0!0%60%//,.#!5#$!54-.,334#,-:!!

,#!+5-,%#-/! 'I!

'()(E(?

!

;GH!6%#%A3.$,2,%$!;!7%<</!%&+0%//!$,22%0%#-!;GH!$,3%0/!.#!->%,0!/40257%! 'J

!

'()(E(E

!

;GH!$,22%0!,#!->%,0!+0.+%#/,-:!2.0!/40257%!%&+0%//,.#!,#!;GH!6%#%A3.$,2,%$!;!7%<</! ?=

!

'()(E(F

!

;>%!K45#-,-:!.2!;GH!+0.-%,#!,#!;GH!6%#%A3.$,2,%$!;!7%<</!522%7-/!->%!7.3+./,-,.#!!

.2!;GH!.#!->%!7%<<!/40257%! ?'

!

(4)

! ! ! ! "#$%&!

!

! ""!

'()(E()

!

"3+0.1%3%#-!.2!;GH!%&+0%//,.#!9:!+0.-%,#!%#6,#%%0,#6!,/!#.-!/422,7,%#-!-.!+0%1%#-!

3,&%$!;GH!$,3%0!2.035-,.#! ??

!

'()(E(I

!

L-05-%6,%/!->5-!$,0%7-<:!-506%-!->%!%&+0%//,.#!.2!->%!%#$.6%#.4/!;GH! ?E

!

5 ! $/%#*1(*06&*06&#/#* 57 !

. ! ,&#"80#* 59 !

<"!

!

IB&,.-=-%4.-*,$*=$.4)+&.$/-.&/$=*)$.0&$6JG-K2&B-4.&B$L,*%LB*:,$*=$2*3/&$#56$ 9M

!

E('('

!

M.-%#-,5<!HNO,!-506%-!/,-%/!>51%!-.!9%!<.75-%$!,#!->%!.+%#!0%5$,#6!2053%!.2!->%!!

;GH!7.#/-5#-!0%6,.#/! ?P!

E('(?

!

M.-%#-,5<!-506%-!/,-%/!C%0%!/%<%7-%$!4/,#6!->%!.1%0<5+!.2!->%!0%/4<-/!20.3!2.40!!

HNO,!-506%-!/,-%!+0%$,7-,.#!+0.6053/! ?J!

E('(E

!

/>HNO!$,0%7-%$!5-!->%!+0%$,7-%$!-506%-!/,-%/!,#$47%$!/-0.#6!HNO,!%22%7-/!,#!5#!!

0%+.0-%0!5//5:!%3+<.:,#6!+<5/3,$!1%7-.0/! E=!

<"9

!

;&E&'*(2&,.$*=$4$NK)&.)*E-)4'$E&%.*)$=*)$6JG-K2&B-4.&B$#56$)&('4%&2&,.$ <!

!

E(?('

!

Q50#%//,#6!->%!RMS'!;GH!1%7-.0!2.0!3,HNO!%&+0%//,.#! E'

!

E(?(?

!

;>%!<%#6->!.2!->%!5#-,/%#/%!/%K4%#7%!522%7-/!->%!B#.7B$.C#!%22,7,%#7:!.2!!

0%$,0%7-%$!3,HNO! EE!

E(?(E

!

"$%#-,2,75-,.#!.2!5#!%22,7,%#-!3,HNO!2.0!->%!B#.7B$.C#!.2!->%!3.4/%!;GHT!7>5,#! E)

!

E(?(F

!

"$%#-,2,75-,.#!.2!5#!%22,7,%#-!3,HNO!2.0!->%!B#.7B$.C#!.2!->%!3.4/%!;GHU!7>5,#! EI

!

E(?()

!

"#-0.#,7!3,HNO!0%/4<-/!,#!/4+%0,.0!-05#/6%#%!%&+0%//,.#!7.3+50%$!-.!EV!%&.#,7!3,HNO! EJ

!

<"<

!

G,4'1/-/$*=$6JG-K#56$+&,&K2*B-=-&B$2*3/&$#$%&''/$ DH

!

E(E('

!

L,<%#7,#6!.2!->%!%#$.6%#.4/!;GH!/4++.0-/!->%!%&+0%//,.#!.2!5#!HNO,A0%/,/-5#-!!

/%7.#$!;GH! F'!

E(E(?

!

RQG!34<-,3%0!/-5,#,#6!.2!-05#/$47%$!;GHA-05#/6%#,7!;!7%<</!$%3.#/-05-%/!->%!!

B#.7B$.C#!.2!->%!%#$.6%#.4/!;GH! F?!

E(E(E

!

HNO,A3%$,5-%$!;GH!0%+<57%3%#-!,#!7.#-05/-!-.!;GH!6%#%!.+-,3,85-,.#!0%/4<-/!,#!%K45<!

/40257%!<%1%</!.2!->%!-05#/2%00%$!;GH!7>5,#/! FE!

(5)

! ! ! ! "#$%&!

!

! """!

E(E(F

!

HNO,A;GH!6%#%A3.$,2,%$!;!7%<</!/>.C!5#-,A-43.0!0%57-,1,-:!5#$!,#70%5/%$!!

5#-,6%#A/+%7,2,7!+0.<,2%05-,.#! F)!

E(E()

!

M'F!;GH!6%#%!-05#/2%0!,#$47%/!->%!2.035-,.#!.2!/%<2A0%57-,1%!3,&%$!;GH!$,3%0/! FS

!

E(E(I

!

HNO,A3%$,5-%$!;GH!0%+<57%3%#-!/%1%0%<:!0%$47%/!->%!,#7,$%#7%!.2!;"AWDQ@! FJ

!

<"D

!

O&,&)4.-*,$4,B$4,4'1/-/$*=$0324,$#56$+&,&K2*B-=-&B$#$%&''/$:-.0$$

/-'&,%&B$&,B*+&,*3/$#56$ 8H$

E(F('

!

"$%#-,2,75-,.#!.2!%22,7,%#-!3,HNO!2.0!->%!B#.7B$.C#!.2!>435#!;GH! )=

!

E(F(?

!

G.#/-047-,.#!.2!5!3,HNO!75//%--%!2.0!->%!B#.7B$.C#!.2!9.->!>435#!;GH!7>5,#/! )?

!

E(F(E

!

HNO,A3%$,5-%$!;GH!0%+<57%3%#-!,#!>435#!;!7%<</! )E

!

: ! 2/#3"##/1'* 4; !

D"!

!

G,4'1/-/$4,B$()&E&,.-*,$*=$2->&B$#56$B-2&)$=*)24.-*,$ 8C

!

D"9

!

P,*%LB*:,$*=$.0&$#56$+&,&/$71$6JG-$ ?H

!

D"<

!

#0&$)-/L$*=$6JG-K-,B3%&B$*==K.4)+&.$&==&%./$ ?!

!

D"D

!

Q-23'.4,&*3/$&>()&//-*,$*=$2-6JG$4,B$.)4,/+&,&/$ ?9

!

D"8

!

P,*%L*3.$*=$.0&$&,B*+&,*3/$#56$71$+&,*2&$&B-.-,+$ ?<

!

D"?

!

G'.&),4.-E&$/.)4.&+-&/$*=$#$%&''K74/&B$%4,%&)$-223,*.0&)4(1$ ?8

!

D"C

!

#0&$.0&)4(&3.-%$(*.&,.-4'$*=$B-==&)&,.$#$%&''$/37.1(&/$ ?C

!

4 ! %$0&,/$8*$'2*%&0612#* ;< !

8"!

!

@4.&)-4'$ ?F

!

)('('

!

R,7%! IJ

!

)('(?

!

G%<<!<,#%/! IJ

!

)('(E

!

M%+-,$%/! S=

!

)('(F

!

O#-,9.$,%/!5#$!RQG!34<-,3%0/! S=

!

)('()

!

L:#->%/,8%$!@NO!.<,6.#47<%.-,$%/! S'

!

(6)

! ! ! ! "#$%&!

!

! "D!

8"9

!

@&.0*B/$ CM

!

)(?('

!

HNO,!-506%-!/,-%!+0%$,7-,.#! SP

!

)(?(?

!

G.#/-047-,.#!.2!+<5/3,$!1%7-.0/!2.0!->%!0%+.0-%0!5//5:! SJ

!

)(?(E

!

@45<A<47,2%05/%!0%+.0-%0!5//5:! P'

!

)(?(F

!

"#-0.$47-,.#!.2!3,HNO!,#-.!->%!RMS'AWXM!1%7-.0! P?

!

)(?()

!

W%#%05-,.#!.2!24<<A<%#6->!3,HNO!9:!.1%0<5+!MGH! PE

!

)(?(I

!

W%#%05-,.#!.2!HNO,A;GH!0%+<57%3%#-!1%7-.0/! PF

!

)(?(S

!

M0.$47-,.#!.2!1,05<!/4+%0#5-5#-/! P)

!

)(?(P

!

;,-05-,.#!.2!1,05<!/4+%0#5-5#-/! P)

!

)(?(J

!

"/.<5-,.#Y!-05#/$47-,.#!5#$!74<-40%!.2!3.4/%!/+<%#.7:-%/! PI

!

)(?('=

!

"/.<5-,.#Y!-05#/$47-,.#!5#$!74<-40%!.2!>435#!;!7%<</! PS

!

)(?(''

!

;05#/$47-,.#!.2!;!7%<<!<,#%/! PS

!

)(?('?

!

O#5<:/,/!.2!/40257%!+0.-%,#!9:!2<.C!7:-.3%-0:! PS

!

)(?('E

!

R%<5#.35!<4#6!3%-5/-5/%/!3.$%<! PP

!

)(?('F

!

;"AWDQ@!3.$%<! PP

!

)(?(')

!

Q,/-.<.6,75<!5#5<:/,/! PJ

!

)(?('I

!

G:-.B,#%!/%70%-,.#!5//5:! PJ

!

; ! $==,&>/$0/1'#* <? !

7 ! 8/0&,$0",&* <. !

9 ! $3@'1A8&2)&%&'0#* +5. !

< ! B"=8/3$0/1'#* +5: !

+? ! #&8=#0#0C'2/)@&/0#&,@8C,"')* +54 !

(7)

Z4/533%#25//4#6!

!

! '!

R3/422&,=4//3,+$

R,->,<2%! 1.#! 1,05<%#! D%B-.0%#! B[##%#! ;AZ%<<%#!!"# $%$&! 6%#%-,/7>! 1%0\#$%0-! C%0$%#(! @%0! ;05#/2%0!

1.#! W%#%#! 2]0! $,%! UA! 4#$! TA^%--%#! $%/! ;AZ%<<0%8%+-.0/! _;ZH`! +0.60533,%0-! ;AZ%<<%#! /+%8,2,/7>! %,#!

54/6%C\><-%/! O#-,6%#! 84! %0B%##%#! 4#$! $%0! *,#/5-8! /.<7>%0! 6%#3.$,2,8,%0-%#! ;AZ%<<%#! ,#! B<,#,/7>%#!

L-4$,%#! 2]0! $,%! "334#->%05+,%! 1.#! ^0%9/! >5-! 6%8%,6-Y! $5//! /,%! #57>! $%3! ;05#/2%0! ,#! $%#! M5-,%#-%#!

;43.0%! %0B%##%#! 4#$! 59/-.a%#! B[##%#(! W%#3.$,2,8,%0-%#! ;AZ%<<%#! 4#-%0/7>%,$%#! /,7>! b%$.7>! 1.#!

#.035<%#! ;AZ%<<%#Y! C%,<! /,%! 84/\-8<,7>! 84! $%#! W%#%#! $%/! 8%<<%,6%#%#! ;ZH! 547>! $,%! W%#%! $%/!

]9%0-056%#%#! ;ZH! %&+0,3,%0%#(! @,%/%! L,-45-,.#! %0<549-! $,%! c,<$4#6! 1,%0! 1%0/7>,%$%#%0! UTA;ZH!

Q%-%0.$,3%0%d! $%0! 8%<<%,6%#%#! ;ZHY! $%0! ]9%0-056%#%! ;ZH! 4#$! 8C%,! 6%3,/7>-%! ;ZHY! 9%/-%>%#$! 54/!

%,#%0! ]9%0-056%#%#! 4#$! %,#%0! 8%<<%,6%#%#! ;ZH! ^%--%(! @5054/! %06%9%#! /,7>! 8C%,! M0.9<%3%(! *0/-%#/!

%#-/-%>-! %,#%! ^.#B400%#8/,-45-,.#(! @,%! 1%0/7>,%$%#%#! ;ZH! ^%--%#! B.#B400,%0%#! 3,-%,#5#$%0! 43!

Q%-%0.$,3%0%! 84! 9,<$%#! 4#$! $,%! Q%-%0.$,3%0%! B.#B400,%0%#! 43! %,#%! 9%60%#8-%! R%#6%! 5#! G@E!

M0.-%,#%#(!@,%!X.035-,.#!%,#%/!M0.-%,#B.3+<%&%/!54/!;ZH!4#$!G@E!M0.-%,#%#!,/-!%,#%!D.0054/%-84#6!

2]0! $,%! e9%02<\7>%#%&+0%//,.#! 4#$! $,%! W%/53-3%#6%! $%/! ;ZH! 5#! $%0! Z%<<.9%02<\7>%! ,/-! 9%/7>0\#B-!

$407>! $,%! 1%02]6950%! R%#6%! 5#! G@E! M0.-%,#%#(! ZC%,-%#/! /-%<<-! $,%! c,<$4#6! 1.#! 6%3,/7>-%#! ;ZH! %,#!

L,7>%0>%,-/0,/,B.! $50Y! C%,<! $,%! L+%8,2,-\-! $,%/%0! H%8%+-.0%#! $407>! $%#! Z425<<! 9%/-,33-! ,/-! 4#$! /,%!

$%/>5<9!547>!6%/4#$%/!^[0+%06%C%9%!%0B%##%#!B[##-%#(!

"#!$,%/%0!@.B-.0509%,-!C40$%!%,#!#%450-,6%0!fA0%-0.1,05<%0!D%B-.0!%#-C,7B%<-!43!;ZH!W%#%!,#!;A Z%<<%#! 84! ]9%0-056%#! 4#$! 6<%,7>8%,-,6! $,%! *&+0%//,.#! $%/! 8%<<%,6%#%#! ;ZH! $407>! HNO! "#-%02%0%#8!

_HNO,`!84!4#-%0$0]7B%#(!@52]0!C40$%#!843!%,#%#!$,%!W%#%!$%/!84!]9%0-056%#$%#!;ZH!/.!1%0\#$%0-Y!

$5//!/,%!1.#!$%3!HNO,!*22%B-!#,7>-!9%%,#2<4//-!C%0$%#Y!4#$!843!5#$%0%#!C40$%#!W%#%!2]0!R,B0.AHNO!

_O9B(!%#6<(d!3,HNO`Y!$,%!$%#!HNO,!*22%B-!54/<[/%#Y!,#!$%#!1,05<%#!D%B-.0!RMS'!%,#6%2]6-(!@407>!$,%!

*&+0%//,.#! $%0! 3,HNO! 0%$48,%0-%! /,7>! $,%! R%#6%#! $%/! 8%<<%,6%#%#! ;ZH! 542! $%0! e9%02<\7>%! 1.#!

6%#3.$,2,8,%0-%#!;AZ%<<%#!542!Ig!4#$!'?gY!59>\#6,6!$51.#!.9!$,%!3,HNO!$,%!UA!.$%0!TA^%--%!$%/!;ZH!

4#-%0$0]7B-%(! O#>5#$! 1.#! D%B-.0%#Y! $,%! 5#/-5--! %,#%/! #%4%#! ;ZH! %,#! R50B%06%#! %#->,%<-%#Y! C40$%!

6%8%,6-Y!$5//!/,7>!547>!$,%!*&+0%//,.#!$%/!R50B%06%#/!,#!$%#!6%#3.$,2,8,%0-%#!;AZ%<<%#!59>\#6,6!1.#!

$%0!M./,-,.#!$%0!3,HNO!,#!$%3!D%B-.0!1%0\#$%0-%(!@5/!*&+0%//,.#/#,1%54!9%-046!E?gY!?g!4#$!')gY!

59>\#6,6!$51.#Y!.9!$,%!3,HNO!,#!$5/!"#-0.#!53!)V!*#$%!$%/!D%B-.0/!.$%0!$,0%B-!1.0!.$%0!>,#-%0!$5/!

R50B%06%#!B<.#,%0-!C40$%(!@,%!8C%,!3,HNO!2]0!$,%!h#-%0$0]7B4#6!$%0!9%,$%#!^%--%#!$%/!8%<<%,6%#%#!

;ZH! C40$%#! $%/>5<9! ,#! $5/! "#-0.#! $%/! 0%-0.1,05<%#! D%B-.0/! RMS'! %,#6%2]6-! 4#$! 5#/7><,%a%#$! $5/!

R50B%06%#!6%6%#!$%#!M'F!;ZHY!$%0!$5/!1,05<%!O#-,6%#!WMEE!%0B%##-Y!54/6%-54/7>-(!@,%!h#-%0$0]7B4#6!

$%/!8%<<%,6%#%#!;ZH!,#!6%#3.$,2,8,%0-%#!;AZ%<<%#!>5--%!840!X.<6%Y!$5//!9%,$%!^%--%#!$%/!M'F!;ZH!,#!

%-C5!6<%,7>%0!R%#6%!542!$%0!Z%<<.9%02<\7>%!%&+0,3,%0-!C40$%#(!"3!W%6%#/5-8!$584!]9%0-052!$,%!R%#6%!

$%0! TA^%--%! $,%b%#,6%! $%0! UA^%--%! 43! $5/! ZC%,257>%Y! C%##! %,#! 4#3.$,2,8,%0-%0! D%B-.0! 2]0! $,%!

6%#-%7>#,/7>%!D%0\#$%04#6!$%0!;AZ%<<%#!1%0C%#$%-!C40$%(!@,%/%!c%.957>-4#6!C50!%,#!B<50%0!c%<%6!

$52]0Y! $5//! $,%! h#-%0$0]7B4#6! $%/! 8%<<%,6%#%#! ;ZH! $,%! c,<$4#6! 1.#! 6%3,/7>-%#! ;ZH! 9%/-%>%#$! 54/!

%,#%0!TA^%--%!$%/!M'F!;ZH!4#$!%,#%0!UA^%--%!$%/!8%<<%,6%#%#!;ZH!1%0>,#$%0-%(!"3!*,#B<5#6!3,-!$,%/%0!

(8)

Z4/533%#25//4#6!

!

! ?!

c%.957>-4#6! B.##-%! ,#! %,#%3! R54/3.$%<<! 6%8%,6-! C%0$%#Y! $5//! $,%! h#-%0$0]7B4#6! $%/! 8%<<%,6%#%#!

;ZH! ,#! 6%#3.$,2,8,%0-%#! ;AZ%<<%#! 547>! $,%! *#-/-%>4#6! 1.#! O4-.,334#,-\-! 1%0>,#$%0-%Y! $,%! $407>!

6%3,/7>-%!;ZH!1%040/57>-!C40$%(!@,%!O#C%#$4#6!1.#!6%#-%7>#,/7>!.+-,3,%0-%#!M'F!;ZH!W%#%#Y!43!

$,%! e9%02<\7>%#%&+0%//,.#! 84! 1%09%//%0#Y! 2]>0-%! ,3! W%6%#/5-8! $584! C%$%0! 84! %,#%0! O#6<%,7>4#6!

9%,$%0! M'F! ;ZH! ^%--%#! 542! $%0! Z%<<.9%02<\7>%Y! #.7>! 84! C%#,6%0! O4-.,334#,-\-! ,3! R54/3.$%<<(!

h#59>\#6,6! $51.#Y! .9! $,%! M'F! ;ZH! W%#%! B.$.#.+-,3,%0-! C40$%#! 4#$! %,#%! 8C%,-%! ,#-053.<%B4<50%!

@,/4<2,$90]7B%!%#->,%<-%#!.$%0!#,7>-Y!%#-C,7B%<-%#!5<<%!;,%0%!#57>!$%3!;05#/2%0!1.#!6%#3.$,2,8,%0-%#!

;AZ%<<%#!%,#%!-[$<,7>%!O4-.,334#B05#B>%,-(!@56%6%#!]9%0<%9-%#!P'g!4#$!JFg!$%0!;,%0%Y!C%##!$,%!;A Z%<<%#!3,-!$%3!#%4!%#-C,7B%<-%#!D%B-.0!6%#%-,/7>!1%0\#$%0-!C40$%#Y!59>\#6,6!$51.#Y!.9!$%0!D%B-.0!

$,%! 4#1%0\#$%0-%#! .$%0! $,%! .+-,3,%0-%#! M'F! ;ZH! W%#%! %#->,%<-(! "#! %,#%3! 8C%,-%#! ;,%0%&+%0,3%#-!

B.##-%!84$%3!6%8%,6-!C%0$%#Y!$5//!$,%!*&+0%//,.#!$%0!3,HNO!$,%!X4#B-,.#!$%0!6%#3.$,2,8,%0-%#!;A Z%<<%#!#,7>-!#%65-,1!9%%,#2<4//-%(!@,%!@.B-.0509%,-!C40$%!3,-!$%0!*#-C,7B<4#6!%,#%/!C%,-%0%#!1,05<%#!

D%B-.0/!596%/7><.//%#Y!$%0!$,%!*&+0%//,.#!$%/!8%<<%,6%#%#!;ZH!,#!3%#/7><,7>%#!;AZ%<<%#!4#-%0$0]7B-(!

@52]0! C40$%#! #%4%! 3,HNO! W%#%! B.#/-04,%0-Y! $,%! $%#! 8%<<%,6%#%#! ;ZH! 542! $%0! e9%02<\7>%! 1.#!

6%#3.$,2,8,%0-%#!3%#/7><,7>%#!;AZ%<<%#!542!'=g!4#$!??g!0%$48,%0-%#Y!,#!O9>\#6,6B%,-!$51.#Y!.9!$,%!

3,HNO! $,%! UA! .$%0! TA^%--%#! $%/! ;ZH! 4#-%0$0]7B-%(! "3! %,#%3! $,0%B-%#! D%06<%,7>! B.##-%! 6%8%,6-!

C%0$%#Y!$5//!$%0!#%4!%#-C,7B%<-%!D%B-.0!$,%!R%#6%#!$%0!^%--%#!%,#%/!;ZHY!$%0!$5/!iG5#7%0j;%/-,/A O#-,6%#i!ROW*AO'!%0B%##-Y!542!$%0!e9%02<\7>%!1.#!6%#3.$,2,8,%0-%#!;AZ%<<%#!%22,8,%#-%0!5#6<,7>Y!5</!

$,%!9%0%,-/!%-59<,%0-%#!R%->.$%#!2]0!$,%!e+-,3,%04#6!$%0!;ZH!W%#%(!

!

(9)

L43350:!

!

! E!

Q3224)1$

;!7%<</!75#!9%!!"#$%$&#6%#%-,75<<:!3.$,2,%$!4/,#6!1,05<!1%7-.0/(!;>%!-05#/2%0!.2!6%#%/!%#7.$,#6!->%!U!

5#$!T!7>5,#!.2!->%!;!7%<<!0%7%+-.0!_;GH`!+0.6053/!->%!;!7%<</!-.!/+%7,2,75<<:!0%57-!-.C50$/!5#!5#-,6%#!.2!

7>.,7%(! L47>! ;GH! 6%#%A3.$,2,%$! ;! 7%<</! 50%! 7400%#-<:! %3+<.:%$! ,#! 7<,#,75<! /-4$,%/! .2! 75#7%0!

,334#.->%05+:! C>%0%! ->%:! 50%! -05#/2%00%$! 957B! ,#-.! ->%! +5-,%#-! ,#! .0$%0! -.! <54#7>! 5#! 5#-,A-43.0!

,334#%!0%/+.#/%(!;GH!6%#%A3.$,2,%$!;!7%<</!$,22%0!20.3!0%64<50!;!7%<</(!;>%:!%&+0%//!-05#/2%00%$!;GH!

6%#%/!,#!5$$,-,.#!-.!->%!6%#%/!.2!->%,0!%#$.6%#.4/!;GHY!C>,7>!5<<.C/!->%!5//%39<:!.2!2.40!$,22%0%#-!

;GH! UjT! >%-%0.$,3%0/d! ->%! %#$.6%#.4/! ;GHY! ->%! -05#/2%00%$! ;GHY! 5#$! -C.! 3,&%$! ;GH! $,3%0/Y!

7.3+./%$!.2!%#$.6%#.4/!5#$!-05#/2%00%$!;GH!7>5,#/(!;>,/!>5/!-C.!35,#!7.#/%K4%#7%/d!X,0/-Y!->%!-.-5<!

53.4#-!.2!;GH!.#!->%!7%<<!/40257%!,/!<,3,-%$!9:!->%!515,<59,<,-:!.2!G@E!+0.-%,#/Y!C>,7>!5//.7,5-%!C,->!

->%! ;GH! $,3%0/! -.! 2.03! ;GHjG@E! 7.3+<%&%/(! Q%#7%Y! ->%! ;GH! 7>5,#/! 7.3+%-%! C,->! %57>! .->%0! 2.0!

$,3%0,85-,.#!5#$!G@E!+0.-%,#/(!L%7.#$Y!->%!2.035-,.#!.2!3,&%$!;GH!$,3%0/!0%+0%/%#-/!5!/52%-:!,//4%!

9%754/%!->%,0!/+%7,2,7,-:!,/!4#+0%$,7-59<%!5#$!->%:!35:!9:!7>5#7%!0%7.6#,8%!/%<2A5#-,6%#/(!

"#!->,/!->%/,/Y!5!#.1%<!fA0%-0.1,05<!HNO,A;GH!0%+<57%3%#-!1%7-.0!C5/!$%1%<.+%$!->5-!/,34<-5#%.4/<:!

%&+0%//%/!3,HNO!2.0!->%!/,<%#7,#6!.2!9.->!%#$.6%#.4/!;GH!7>5,#/!5#$!5!#%C!+5,0!.2!;GH!7>5,#/Y!C>,7>!

C%0%! 0%#$%0%$! HNO,A0%/,/-5#-! 9:! ->%! ,#-0.$47-,.#! .2! /,<%#-! 34-5-,.#/(! X,0/-Y! 3,HNO! $,0%7-%$! 5-! ->%!

3.4/%!;GH!7>5,#/!C%0%!7.#/-047-%$!5#$!,#-0.$47%$!,#-.!5!WXMA%#7.$,#6!RMS'!1%7-.0(!"#!-05#/$47%$!

3.4/%!;!7%<</Y!->%!/40257%!<%1%<!.2!->%!%#$.6%#.4/!;GH!C5/!0%$47%$!-.!Ig!5#$!'?g!9:!->%!%&+0%//,.#!

.2!5!;GHU!.0!T!7>5,#A/+%7,2,7!3,HNOY!0%/+%7-,1%<:(!Q.C%1%0Y!->%!WXM!%&+0%//,.#!C5/!5</.!522%7-%$!9:!

->%!3.$,2,75-,.#!.2!->%!1%7-.0(!@%+%#$,#6!.#!C>%->%0!5!3,HNO!C5/!,#-0.$47%$!,#-.!->%!)V!,#-0.#!.2!->%!

1%7-.0!.0!5-!%&.#,7!+./,-,.#/!)V!5#$!EV!.2!->%!-05#/6%#%Y!->%!WXM!%&+0%//,.#!C5/!0%$47%$!-.!E?gY!?g!

5#$! ')gY! 0%/+%7-,1%<:(! ;>%#Y! 5! 3,HNO! 75//%--%! 7.#-5,#,#6! -C.! 3,HNO! 2.0! ->%! /,34<-5#%.4/!

B#.7B$.C#! .2! 9.->! %#$.6%#.4/! ;GH! 7>5,#/! C5/! 7.#/-047-%$! 5#$! ,#-0.$47%$! ,#-.! ->%! )V! ,#-0.#! .2! 5!!

M'F! ;GHA%#7.$,#6! RMS'! 1%7-.0(! ;>%! M'F! ;GH! 0%7.6#,8%/! ->%! 1,05<! 5#-,6%#! WMEE(! L,<%#7,#6! .2! ->%!

%#$.6%#.4/!;GH!,#!;GH!6%#%A3.$,2,%$!;!7%<</!0%/4<-%$!,#!%K45<!/40257%!<%1%</!.2!9.->!M'F!;GH!7>5,#/Y!

C>%0%5/!3.0%!->5#!-C,7%!5/!347>!M'F!;GHT!7>5,#!7.3+50%$!-.!M'F!;GHU!7>5,#!C5/!%&+0%//%$!5-!->%!

/40257%!.2!;!7%<</!-05#/$47%$!C,->!5#!4#3.$,2,%$!M'F!;GHA%#7.$,#6!RMS'!1%7-.0(!;>,/!$5-5!/-0.#6<:!

,#$,75-%$!->5-!->%!2.035-,.#!.2!3,&%$!;GH!$,3%0/!7.3+./%$!.2!M'F!;GHT!7>5,#!5#$!%#$.6%#.4/!;GHU!

7>5,#! ,/! +0%1%#-%$! 9:! ;GH! /,<%#7,#6(! O2-%0C50$/! 5! 3.4/%! 3.$%<! .2! ;GH! 6%#%! ->%05+:! C5/! 4/%$! -.!

$%3.#/-05-%! ->5-! ->%! /,<%#7,#6! .2! ->%! %#$.6%#.4/! ;GH! ,#! ;GH! 6%#%A3.$,2,%$! ;! 7%<</! 0%$47%/! 3,&%$!!

;GH! $,3%0A$%+%#$%#-! 54-.,334#,-:(! *#6,#%%0,#6! .2! ->%! M'F! ;GH! 9:! 7.$.#! .+-,3,85-,.#! ,#!

7.39,#5-,.#!C,->!->%!,#-0.$47-,.#!.2!5#!5$$,-,.#5<!,#-%0A7>5,#!$,/4<2,$%!9.#$!#%,->%0!0%/4<-%$!,#!%K45<!

/40257%!<%1%</!.2!->%!M'F!;GH!7>5,#/!#.0!0%$47%$!->%!54-.,334#,-:!,#!->%!3.4/%!3.$%<(!O<<!3,7%!->5-!

0%7%,1%$! 7%<</! -05#/$47%$! C,->! ->%! #5-,1%! .0! .+-,3,8%$! M'F! ;GH! $%1%<.+%$! <%->5<! 54-.,334#,-:Y!

C>%0%5/!P'g!5#$!JFg!.2!->%!3,7%!/401,1%$!C>%#!->%!-05#/2%00%$!;!7%<</!C%0%!-05#/$47%$!C,->!->%!

HNO,A;GH! 0%+<57%3%#-! 1%7-.0! %#7.$,#6! ->%! #5-,1%! .0! .+-,3,8%$! M'F! ;GHY! 0%/+%7-,1%<:(! O! /%7.#$!

3.4/%!3.$%<!C5/!4/%$!-.!7.#2,03!->5-!->%!%&+0%//,.#!.2!->%!3,HNO!$,$!#.-!#%65-,1%<:!,#2<4%#7%!->%!

(10)

L43350:!

!

! F!

24#7-,.#5<,-:! .2! ->%! ;GH! 6%#%A3.$,2,%$! ;! 7%<</(! ;>%! +0.b%7-! C5/! 7.3+<%-%$! 9:! ->%! $%1%<.+3%#-! .2! 5!

/%7.#$! HNO,A;GH! 0%+<57%3%#-! 1%7-.0! 2.0! >435#! ;! 7%<</(! N%C! 3,HNO! /+%7,2,7! 2.0! ->%! >435#! ;GH!

7>5,#/! C%0%! 7.#/-047-%$Y! C>,7>! 0%$47%$! ->%! /40257%! <%1%<! .2! ->%! %#$.6%#.4/! ;GHU! 5#$! T! 7>5,#! ,#!

-05#/$47%$!;!7%<</!-.!'=g!5#$!??gY!0%/+%7-,1%<:(!X,#5<<:Y!5!7.3+50,/.#!.2!>435#!;GH!6%#%A3.$,2,%$!!

;!7%<</!,#$,75-%$!->5-!->%!/40257%!<%1%</!.2!9.->!7>5,#/!.2!5!;GH!0%7.6#,8,#6!->%!75#7%0j-%/-,/!5#-,6%#!

ROW*AO'! C%0%! 3.0%! %22,7,%#-<:! 5$b4/-%$! -.! %57>! .->%0! 9:! ;GH! /,<%#7,#6! 7.3+50%$! -.! %/-59<,/>%$!

3%->.$/!.2!;GH!%#6,#%%0,#6(!

!

(11)

"#-0.$47-,.#!

!

! )!

! I,.)*B3%.-*,$

!"! #$%&''$()*+&,-.*)/$-,$.0&$.0123/$+&,&)4.&$.0&$#56$)&(&).*-)&$71$/*24.-%$)&%*27-,4.-*,$

;>%!5$5+-,1%!,334#%!/:/-%3!%K4,+/!->%!>./-!C,->!5!>,6><:!$,1%0/%!0%+%0-.,0%!.2!5#-,6%#A0%7.6#,-,.#!

0%7%+-.0/!%&+0%//%$!9:!<:3+>.7:-%/!.2!->%!;A!5#$!cA7%<<!<,#56%(!@40,#6!<:3+>.7:-%!$%1%<.+3%#-Y!->%!

+0.7%//! .2! /.35-,7! 0%7.39,#5-,.#! 6%#%05-%/! 5#! ,#$,1,$45<! 5#$! >,6><:! /+%7,2,7! 0%7%+-.0! 2.0! %57>! 7%<<(!

;>%/%!0%7%+-.0/!50%!7400%#-<:!,#1%/-,65-%$!5#$!5<0%5$:!,#!7<,#,75<!4/%!2.0!->%!,334#.->%05+:!.2!75#7%0Y!

9%754/%!->%:!5<<.C!-.!$,0%7-!->%!+5-,%#-V/!,334#%!/:/-%3!-.!5!-506%-!.2!7>.,7%(!e2!+50-,74<50!,#-%0%/-!,/!

->%! ;! 7%<<! 0%7%+-.0! _;GH`! %&+0%//%$! 9:! ;! 7%<</Y! 9%754/%! ->%:! 50%! 75+59<%! .2! B,<<,#6! 7%<</! .2! ->%! 9.$:!

/>.C,#6!59%005#-!+0.-%,#!%&+0%//,.#(!;>%!;GH!%#59<%/!->%3!-.!$%-%7-!->%,0!-506%-!7%<</!5#$!;!7%<</!75#!

0%b%7-!-43.0/Y!,2!->%:!%&+0%//!5!-43.0A/+%7,2,7!;GH!5#$!,2!251.059<%!7.#$,-,.#/!50%!,#$47%$(!

;>%!$,/7.1%0:!.2!->%!;GH!C5/!%#59<%$!9:!%&+%0,3%#-5<<:!+0.$47%$!5#-,9.$,%/!05,/%$!565,#/-!7%<<!

/40257%!+0.-%,#/!5#$!4/%$!-.!7>5057-%0,8%!<:3+>.7:-%/!k'Y?YEYFY)YIl(!;>,/!%#$%51.0!C5/!257,<,-5-%$!9:!5!

3%->.$!2.0!->%!6%#%05-,.#!.2!7<.#5<!5#-,9.$:A+0.$47,#6!7%<<!<,#%/!kSl(!h/,#6!5#!3.#.7<.#5<!5#-,9.$:!

_3O9`!/+%7,2,7!2.0!5#!5#-,6%#!.#<:!%&+0%//%$!9:!5!+50-,74<50!;!7%<<!<:3+>.35Y!5!/40257%!+0.-%,#!C5/!

,/.<5-%$! ->5-! 7.#/,/-%$! .2! -C.! $,22%0%#-! $,/4<2,$%A<,#B%$! +.<:+%+-,$%! 7>5,#/! kPl(! "3+.0-5#-<:Y! 5! 1%0:!

/,3,<50!>%-%0.$,3%0,7!+0.-%,#!C5/!5</.!2.4#$!,#!#.035<!;!7%<</!5#$!.->%0!;!7%<<!<,#%/Y!5<->.46>!->./%!

C%0%!#.-!0%7.6#,8%$!9:!->%!3O9Y!/466%/-,#6!5!7<.#5<!#5-40%!.2!->%!>%-%0.$,3%0(!e->%0!3O9/!59<%!-.!

9<.7B! .0! 57-,15-%! 5#-,6%#A/+%7,2,7! ;! 7%<<! 24#7-,.#/! 5</.! +0%7,+,-5-%$! ->%! +4-5-,1%! ;GHY! C>./%! 7>5,#/!

C%0%! 35$%! 4+! .2! 5! 7<.#5<! 150,59<%! 5#$! #.#A7<.#5<! 7.#/-5#-! +50-! 5/! ,#$,75-%$! 9:! +%+-,$%!!

$,6%/-,.#!kJY'=Y''Y'?l(!;C.!60.4+/!/477%%$%$!5-!->%!/53%!-,3%!,#!,/.<5-,#6!5!;GH!7>5,#!/%K4%#7%!9:!

/75##,#6! 7@NO! <,9050,%/! 2.0! 6%#%/! ->5-! 50%! $,22%0%#-,5<<:! %&+0%//%$! ,#! ;! 5#$! c! 7%<</! k'EY'FY')l(! ;>%!

$,/7.1%0%$! 3.4/%! 5#$! >435#! ;GHT! 7>5,#! /%K4%#7%/! C%0%! >.3.<.6.4/! -.! ->%! >%51:! 7>5,#! .2!

5#-,9.$,%/!5#$!7.#/,/-%$!.2!150,59<%!_D`Y!b.,#,#6!_m`Y!$,1%0/,-:!_@`!5#$!7.#/-5#-!_G`!/%63%#-/Y!C>%0%5/!

->%!<5-%0!,$%#-,2,%$!;GHU!7>5,#!/%K4%#7%!0%/%39<%$!->%!<,6>-!7>5,#!.2!5#-,9.$,%/!5#$!7.#/,/-%$!b4/-!.2!

DY!m!5#$!G!/%63%#-/!k'IY'SY'Pl(!;>%!7<.#5<!%&+0%//,.#!,#!;!7%<</!5#$!->%!7.3+./,-,.#!.2!->%!;GH!7>5,#/!

/-0.#6<:!/466%/-%$!->5-!;GH!50%!6%#%05-%$!9:!/.35-,7!0%7.39,#5-,.#!.2!$,/-,#7-!6%#%-,7!/%63%#-/Y!5!

+0.7%//!+0%1,.4/<:!$,/7.1%0%$!,#!c!7%<</!-.!9%!0%/+.#/,9<%!2.0!->%!6%#%05-,.#!.2!5#-,9.$,%/!k'Jl(!

;>%!>435#!;GH!0%+%0-.,0%!7.#/,/-/!.2!50.4#$!'AF&'=I!$,22%0%#-!;GHT!7>5,#/!5#$!->%0%!,/!<,3,-%$!

.1%0<5+! 9%-C%%#! ,#$,1,$45</! k?=Y?'l(! ;>%! 95/,/! 2.0! ->,/! $,1%0/,-:! 50%! 34<-,+<%! ;GH! 6%#%! /%63%#-/!

%#7.$%$! ,#! ->%! ;GH! <.7,! k??Y?El(! M0%7,/%<:Y! ->%! >435#! 6%#.3%! 7.#-5,#/! FI! DUY! )=! mU! 5#$! .#%! GU!

/%63%#-Y!5/!C%<<!5/!FP!DTY!'E!mTY!-C.!@T!5#$!-C.!GT!/%63%#-/Y!->5-!50%!,#1.<1%$!,#!->%!6%#%05-,.#!.2!

->%!;GH!0%+%0-.,0%!k?Fl(!"#!->%!->:34/Y!;!7%<<!+0.6%#,-.0/!/-50-!-.!%&+0%//!->%!0%7.39,#5-,.#!57-,15-,#6!

6%#%/A'! 5#$! A?! _HOW'j?`Y! C>,7>! %#7.$%! %#8:3%/! ->5-! 0%7.6#,8%! /,6#5<! /%K4%#7%/! 2<5#B,#6! ->%! ;GH!

/%63%#-/! 5#$! 3%$,5-%! ,#! 7.39,#5-,.#! C,->! .->%0! 257-.0/! ->%! 0%5005#6%3%#-! .2! ->%! @NO!!

/%K4%#7%! k?)Y?IY?Sl(! HOW! B#.7B.4-! 3,7%! />.C%$! 5! 7.3+<%-%! 9<.7B! ,#! <:3+>.7:-%!!

$%1%<.+3%#-! k?PY?Jl(! O! 24#7-,.#5<! ;GHU! 7>5,#! 6%#%! ,/! 6%#%05-%$! 9:! 5! +0.$47-,1%! DU! -.! mU!

(12)

"#-0.$47-,.#!

!

! I!

0%7.39,#5-,.#! %1%#-Y! C>%0%5/! ,#! 75/%! .2! ->%! ;GHT! 7>5,#! 2,0/-! 5! @T! -.! mTY! 5#$! ->%#! 5! DT! -.! @TAmT!

0%7.39,#5-,.#! -5B%/! +<57%(! ;>%! ;GH! 6%#%! <.7,! 50%! 0%5005#6%$! /477%//,1%<:! /-50-,#6! C,->! ->%! ;GHT!

7>5,#(! O<<%<,7! %&7<4/,.#! +0%1%#-/! ->%! 0%7.39,#5-,.#! .2! ->%! /%7.#$! ;GHT! 7>5,#! <.74/Y! ,2! ->%!

0%7.39,#5-,.#!.2!->%!2,0/-!<.74/!C5/!+0.$47-,1%!kE=l(!;>%!0%7.39,#%$!;GHT!7>5,#!->%#!+5,0/!C,->!5!

6%03<,#%A%#7.$%$!U!7>5,#!#53%$!+0%A;GHU!7>5,#!kE'YE?l(!M0%A;GH!/40257%!%&+0%//,.#!/,6#5</!-.!/-.+!

;GH!0%7.39,#5-,.#!5#$!,#$47%/!5!/>.0-!+>5/%!.2!+0.<,2%05-,.#!2.<<.C%$!9:!->%!0%7.39,#5-,.#!.2!->%!

;GHU!7>5,#!<.7,Y!C>,7>Y!,#!7.#/%K4%#7%Y!6%#%05-%/!;!7%<<!7<.#%/!%&+0%//,#6!->%!/53%!;GHT!7>5,#!+5,0%$!

C,->!$,22%0%#-!;GHU!7>5,#/(!c.->!;GHU!<.7,!50%!0%7.39,#%$!/,34<-5#%.4/<:!5#$!/%1%05<!4#+0.$47-,1%!

DU!-.!mU!0%7.39,#5-,.#/!35:!-5B%!+<57%!4#-,<!5!24#7-,.#5<!;GHU!7>5,#!,/!6%#%05-%$(!O/!5!0%/4<-Y!35-40%!

;!7%<</!75#!%&+0%//!-C.!24#7-,.#5<!;GHU!7>5,#/!kEEYEFYE)l(!;>%!20%K4%#7:!.2!/47>!7%<</!C5/!$%-%03,#%$!

-.!9%!5++0.&,35-%<:!E=g!53.#6!;!7%<</!20.3!>435#!+%0,+>%05<!9<..$!<:3+>.7:-%/!_Mcn`!95/%$!.#!

2<.C!7:-.3%-0:!$5-5!kE)l(!R.$%0#!/,#6<%A7%<<!/%K4%#7,#6!5++0.57>%/!>.C%1%0!,#$,75-%$!5!/.3%C>5-!

<.C%0! 20%K4%#7:Y! 5<->.46>! ->,/! >5/! #.-! 9%%#! /-4$,%$! ,#! $%-5,<! kEIl(! O/! 5#! %&7%+-,.#Y! 35-40%! ;! 7%<</!

%&+0%//,#6!-C.!24#7-,.#5<!;GHT!7>5,#/!C%0%!5</.!0%+.0-%$!-.!%&,/-!kESl(!

c%/,$%/!->%!$,1%0/,-:!6%#%05-%$!9:!->%!0%7.39,#5-,.#!.2!6%#%!/%63%#-/!5#$!->%!2.035-,.#!.2!;GHUT!

>%-%0.$,3%0/Y! 5$$,-,.#5<! $,1%0/,-:! ,/! ,#-0.$47%$! 5-! ->%! b.,#,#6! /,-%/(! X,0/-Y! .#%! /-05#$! .2! ->%! @NO!

/%K4%#7%/!,/!74-!,3+0%7,/%<:!5#$Y!/%7.#$Y!#47<%.-,$%/!35:!9%!$%<%-%$!9:!%&.#47<%5/%/!.0!5$$%$!9:!->%!

%#8:3%! -%03,#5<! $%.&:#47<%.-,$:<! -05#/2%05/%! kEPYEJl(! ;>%0%2.0%Y! ->%! >,6>%/-! $%60%%! .2! $,1%0/,-:! ,/!

<.75-%$!5-!->%!DAm!b4#7-,.#!.2!->%!;GHU!7>5,#!5#$!->%!DA@Am!b4#7-,.#/!.2!->%!;GHT!7>5,#(!"#!5#5<.6:!-.!

5#-,9.$,%/Y! ->%! >:+%0150,59<%! /%K4%#7%/! 5-! ->%! b4#7-,.#/! 50%! 75<<%$! 7.3+<%3%#-50,-:! $%-%03,#,#6!

0%6,.#/!E!_G@H!E`(!"#-0,64,#6<:Y!->%!G@HE!%#7.$%!2.0!->./%!53,#.!57,$/!->5-!50%!35,#<:!0%/+.#/,9<%!2.0!

->%!/+%7,2,7,-:!.2!->%!;GH(!;>%!G@H'!5#$!G@H?!<.75-%$!,#!->%!D!/%63%#-/!240->%0!7.#-0,94-%!-.!<,65#$!

9,#$,#6Y!94-!->%,0!150,59,<,-:!,/!<,3,-%$!5/!->%,0!/%K4%#7%/!50%!6%03<,#%!%#7.$%$(!

!"8 #0&$#56$4//*%-4.&/$9-.0$5:;$()*.&-,/$<*)$/3)<4%&$&=()&//-*,$

;>%! ;GH! $,3%0! 5-! ->%! 7%<<! /40257%! ,/! #.#A7.15<%#-<:! 5//.7,5-%$! C,->! $,22%0%#-! G@E! +0.-%,#/! 5#$!

2.03/! 5! <506%! 34<-,3%0,7! +0.-%,#! 7.3+<%&(! *&+%0,3%#-/! C,->! 57-,15-,#6! 3O9! $,0%7-%$! %,->%0! 565,#/-!

G@E!+0.-%,#/!.0!->%!;GH!$%3.#/-05-%$!->5-!->%!/40257%!%&+0%//,.#!.2!9.->!,/!3.$4<5-%$!,#!5!/,3,<50!

25/>,.#!kIYJl(!"#!5$$,-,.#Y!;GH!7>5,#/!C%0%!7.A+0%7,+,-5-%$!C,->!G@E!+0.-%,#/!k'?l(!R4-5#-/!.2!5!>435#!

;!7%<<!<,#%!<57B,#6!%,->%0!/.3%!.2!->%!G@E!+0.-%,#/!.0!.#%!.2!->%!;GH!7>5,#/!$%3.#/-05-%$Y!->5-!->%!

+0%/%#7%!.2!5<<!7.3+.#%#-/!,/!0%K4,0%$!2.0!->%!/40257%!%&+0%//,.#!.2!->%!;GHjG@E!7.3+<%&!kF=l(!;>%!

2,0/-! >,#-! ->5-! ->%! /,6#5<Y! C>,7>! ,/! ,#$47%$! 4+.#! 5#-,6%#! 0%7.6#,-,.#Y! ,/! -05#/$47%$! 570.//! ->%! 7%<<!

3%3905#%!9:!G@E!+0.-%,#/!C5/!+0.1,$%$!9:!->%!,$%#-,2,75-,.#!.2!/,6#5<,#6!3.-,2/!,#!->%!,#-057%<<4<50!

$.35,#/! .2! ->%! G@E! +0.-%,#/! kF'l(! "#! 7.#-05/-Y! ->%! />.0-! ,#-057%<<4<50! -5,</! .2! ->%! ;GH! 7>5,#/! $.! #.-!

7.#-5,#! %,->%0! ->%! ,334#.0%7%+-.0! -:0./,#%A95/%$! 57-,15-,.#! 3.-,2/! _";OR`! %#7.$%$! 9:! ->%! G@E!

+0.-%,#/!.0!5#:!.->%0!/,6#5<,#6!$.35,#/(!O<->.46>!->%!/-047-40%!.2!->%!;GH!$,3%0!C5/!$%-%03,#%$!9:!

&A05:! 70:/-5<<.605+>:! 5#$! ,-! C5/! $%3.#/-05-%$! >.C! ->%! ;GH! 5//.7,5-%/! C,->! G@E! +0.-%,#/! ,#! ->%!

(13)

"#-0.$47-,.#!

!

! S!

%#$.+<5/3,7! 0%-,74<43! _*H`Y! ->%0%! ,/! /-,<<! /.3%! 4#7%0-5,#-:! 59.4-! ->%!.065#,85-,.#! .2! ->%! ;GHjG@E!

7.3+<%&%/!.#!->%!7%<<!/40257%(!

*57>!;GH!7>5,#!,/!7.3+./%$!.2!-C.!%&-057%<<4<50!$.35,#/!->5-!%&>,9,-!5#!,334#.6<.94<,#!_"6`A-:+%!

2.<$! /-047-40%Y! ->%! NA-%03,#5<! 150,59<%! _D`! $.35,#! 5#$! ->%! GA-%03,#5<! 7.#/-5#-! _G`!!

$.35,#! kF?YFEYFFYF)l(! ;>,/! 7.33.#! 2.<$,#6! 3.-,1%! 7.#/,/-/! .2! -C.! 5#-,A+505<<%<! T! />%%-/! 2.03,#6! 5!

/5#$C,7>A<,B%! /-047-40%! C,->! 5! >:$0.+>.9,7! ,#-%0,.0! 5#$! 5#! ,#-05A3.<%74<50! $,/4<2,$%! 9.#$! 9%-C%%#!

->%!/>%%-/(!Q%-%0.$,3%0,85-,.#!,/!/-59,<,8%$!9:!->%!%&7<4/,.#!.2!>:$0.+>.9,7!0%/,$4%/!20.3!->%!/.<1%#-!

5-!->%!DUADT!$.35,#!7.#-57-!/40257%Y!9:!+.<50!0%/,$4%/!5#$!9:!5#!,#-%0A3.<%74<50!3%3905#%A+0.&,35<!

$,/4<2,$%!9.#$(!;>0%%!<..+/!->5-!7.##%7-!->%!T!/>%%-/!%&-%#$!20.3!-.+!.2!%57>!D!$.35,#!5#$!3%$,5-%!

->%!7.#-57-!-.!->%!5#-,6%#(!;>%:!50%!%#7.$%$!9:!->%!G@H!'!5#$!?!<.75-%$!,#!->%!D!/%63%#-/!5#$!9:!->%!

G@H!E!<.75-%$!5-!->%!b.,#,#6!/,-%/!.2!->%!/%63%#-/(!;>%!;GH!>%-%0.$,3%0!,/!/-59,<,8%$!9:!->%!5//.7,5-,.#!

C,->! ->%! G@E! +0.-%,#/Y! %/+%7,5<<:! ->%! GU! $.35,#! />.C/! 5! $,/-.0-%$! "6A2.<$! C,->! /.3%! %&+./%$!

>:$0.+>.9,7! 0%/,$4%/(! "#! 5$$,-,.#Y! 5#! %&-%#$%$! <..+! .2! ->%! GT! $.35,#! C,->! +.<50! 0%/,$4%/! ,/! <,B%<:!

,#1.<1%$!,#!->%!2.035-,.#!.2!->%!;GHjG@E!7.3+<%&(!Q.C%1%0Y!3./-!,3+.0-5#-!2.0!->%!5//.7,5-,.#!.2!

;GH!5#$!G@E!+0.-%,#/!50%!->0%%!95/,7!0%/,$4%/!,#!->%!-05#/3%3905#%!_;3`!$.35,#/!.2!->%!;GH!$,3%0(!

O!/,#6<%!;GH!$,3%0!5//.7,5-%/!,#!->%!*H!C,->!->0%%!$,22%0%#-!G@E!$,3%0/(!X,0/-Y!5!G@Eop!$,3%0!9,#$/!-.!

->%! ;GHU! 7>5,#Y! ->%#! 5! G@Efp! $,3%0! 9,#$/! -.! ->%! ;GHT! 7>5,#! 5#$! %1%#-45<<:! 5! G@Eqq! $,3%0! ,/!

,#-%605-%$! ,#-.! ->%! ;GHjG@E! 7.3+<%&(! L,#7%! %57>! G@E! 7>5,#! %#7.$%/! 5#! 57,$,7! 0%/,$4%! ,#! ->%,0! ;3!

$.35,#Y!/,&!57,$,7!5#$!->0%%!95/,7!0%/,$4%/!50%!+0%/%#-!;GHjG@E!7.3+<%&(!"#!%57>!5//%39<:!/-%+Y!-C.!

+.<50!0%/,$4%/!.2!->%!G@E!$,3%0/!,#-%057-!C,->!5!/+%7,2,7!+.<50!0%/,$4%!.2!->%!;GH!7>5,#/(!;>%!/%K4%#7%!

.2!->%!%1%#-/Y!->%!,#1.<1%3%#-!.2!->%!+.<50!0%/,$4%/!5#$!->%!/-.,7>,.3%-0:!.2!->%!;GHjG@E!7.3+<%&!

C5/! $%-%03,#%$! 9:! 7.A,334#.+0%7,+,-5-,.#! .2!%'# $%()&! -05#/<5-%$! ;GHjG@E! 7.3+.#%#-/! 20.3! *HA

$%0,1%$!3,70./.3%/!kFIl(!

L%1%05<! /-4$,%/! /466%/-! ->5-! 34<-,+<%! 4#,-/! .2! ->%! ;GHjG@E! 7.3+<%&! 5//.7,5-%! -.6%->%0! 5-! ->%!

/40257%!.2!;!7%<</!5#$!->5-!->%!2.035-,.#!.2!34<-,15<%#-!;GH!7.3+<%&%/!,/!$:#53,75<<:!0%64<5-%$(!X,0/-Y!

C>%->%0! 3.#.A! .0! 34<-,15<%#-! ;GHjG@E! 7.3+<%&%/! 7.4<$! 9%! ,/.<5-%$! 20.3! ;! 7%<<! 3%3905#%/! C5/!

/>.C#! -.! $%+%#$! .#! C>%->%0! 5! $%-%06%#-! ->5-! $%/-0.:/! .0! +0%/%01%/! 7>.<%/-%0.<A$%+%#$%#-! +0.-%,#!

7.3+<%&%/!C5/!4/%$!2.0!/.<49,85-,.#!kFSl(!L%7.#$Y!34<-,15<%#-!;GH!#5#.7<4/-%0!C%0%!$%-%7-%$!.#!->%!

3%3905#%/! .2! #.#A57-,15-%$! ;! 7%<</! 4/,#6! %<%7-0.#! 3,70./7.+:! 5#$! +>.-.57-,15-%$! <.75<,85-,.#!

3,70./7.+:!kFSYFPYFJl(!;>,0$Y!;GH!.<,6.3%0,85-,.#!C5/!/>.C#!-.!9%!5!B%:!%1%#-!,#!;!7%<<!57-,15-,.#!5#$!

->%!$,22%0%#-!/,8%!.2!+0%A2.03%$!;GH!7<4/-%0/!.#!#.#A57-,15-%$!#5,1%!5#$!3%3.0:!;!7%<</!C5/!/466%/-%$!

5/!5#!%&+<5#5-,.#!2.0!->%,0!$,22%0%#-!24#7-,.#5<!51,$,-:!k)=Y)'Y)?l(!

!"; #012-%$/&'&%.-*,$-2(*/&/$>?5$)&/.)-%.-*,$4,@$/&'<$.*'&)4,%&$*,$.0&$#$%&''$)&(&).*-)&$

;>%! <,65#$/! .2! ;GH! 50%! +%+-,$%/! ->5-! 50%! 9.4#$! -.! 35b.0! >,/-.7.3+5-,9,<,-:! 7.3+<%&! _RQG`!

3.<%74<%/(!iRQG!0%/-0,7-,.#i!$%/70,9%/!->%!+>%#.3%#.#!->5-!5#-,6%#A/+%7,2,7!;!7%<</!75##.-!0%7.6#,8%!

5#-,6%#A+./,-,1%!7%<</!%&+0%//,#6!5<<.6%#%,7!RQG!3.<%74<%/(!D,04/A/+%7,2,7!3.4/%!;!7%<</!B,<<%$!1,04/A

(14)

"#-0.$47-,.#!

!

! P!

,#2%7-%$!7%<</!,#!%'#$%()&!5//5:/!.#<:!,2!->%!-506%-!7%<</!/>50%$!RQG!5<<%<%/!C,->!->%!;!7%<<!$.#.0!k)El(!

RQG!0%/-0,7-,.#!$.%/!#.-!0%2<%7-!5!6%#%-,7!$%-%03,#5-,.#Y!5/!;!7%<</!.2!9.#%!3500.C!_cR`!7>,3%05/!_X'!

-.! +50%#-`! 57K4,0%$! 5! 0%/-0,7-,.#! -.! ->%! RQG! 5<<%<%/! .2! ->%! 6052-! 0%7,+,%#-! k)Fl(! "-! C5/! 240->%0!

$%3.#/-05-%$!9:!-05#/+<5#-5-,.#!.2!->:3,7!-,//4%/!,#-.!->:3%7-.3,8%$!cR!7>,3%05/Y!->5-!,#!+50-,74<50!

->%!RQG!5<<%<%/!.2!->%!->:3,7!6052-/!$%-%03,#%$!->%!0%/-0,7-,.#!.2!->%!#%C<:!$%1%<.+,#6!;!7%<</!k))l(!

;>%!3./-!/,6#,2,75#-!$5-5!,#$,75-,#6!->5-!;!7%<</!50%!+./,-,1%<:!/%<%7-%$!9:!->:3,7!RQG!3.<%74<%/!C5/!

+0.1,$%$!9:!RQG!B#.7B.4-!3,7%Y!,#!C>,7>!;!7%<<!$%1%<.+3%#-!,/!9<.7B%$!,#!->%!->:34/!k)IY)SY)PY)Jl(!

n,B%C,/%Y!->%!$%1%<.+3%#-!.2!;!7%<</!,#!;GHA-05#/6%#,7!3,7%!C5/!<506%<:!$%+%#$%#-!.#!->%!+0%/%#7%!.2!

->%!+50-,74<50!RQG!3.<%74<%!2.0!C>,7>!->%!-05#/6%#,7!;GH!C5/!0%/-0,7-%$!kI=l(!*'# $%()&!%&+%0,3%#-/!

4/,#6! 2%-5<! ->:34/! .065#! 74<-40%/! 20.3! 3,7%! C,->! $%2,7,%#7,%/! ,#! +%+-,$%ARQG! +0%/%#-5-,.#!

$%3.#/-05-%$! ->5-! ->%! +./,-,1%! /%<%7-,#6! <,65#$/! ,#! ->%! ->:34/! 7.#/,/-! .2! RQG! 3.<%74<%/! ,#!

7.39,#5-,.#!C,->!/%<2A+%+-,$%/!kI'YI?l(!"3+.0-5#-<:Y!->%!/,6#5<!->5-!,/!6%#%05-%$!9:!->%!,#-%057-,.#!.2!

->%!;GH!C,->!->%!+%+-,$%ARQG!7.3+<%&%/!$40,#6!+./,-,1%!/%<%7-,.#!,/!347>!C%5B%0!->5#!->%!/,6#5<!->5-!

57-,15-%/!35-40%!;!7%<</!,#!->%!+%0,+>%0:(!"#!2%-5<!->:34/!.065#!74<-40%/Y!RQGA+0%/%#-%$!5#-56.#,/-!

+%+-,$%/! C%0%! /422,7,%#-! -.! +./,-,1%<:! /%<%7-! ;GHA-05#/6%#,7! ;! 7%<</! kIEl(! "#! ->%! 59/%#7%! .2! RQG!

3.<%74<%/!,#!->%!74<-40%Y!+./,-,1%!/%<%7-,.#!.2!+.<:7<.#5<!;!7%<</!7.4<$!9%!,#$47%$!4/,#6!5!G@EA/+%7,2,7!

3O9!4#$%0!7.#$,-,.#/!->5-!$,$!#.-!57-,15-%!35-40%!;!7%<</!kIFl(!;>4/Y!+./,-,1%!/%<%7-,.#!6%#%05-%/!5!

;GH! 0%+%0-.,0%!C,->!<.CA522,#,-:! 2.0! /%<2A+%+-,$%/! +0%/%#-%$! 9:! RQG! 3.<%74<%/! .2! ->%! >./-(! O#.->%0!

24#7-,.#!.2!+./,-,1%!/%<%7-,.#!,/!->5-!,-!/%60%65-%/!->%!RQG!"A0%/-0,7-%$!G@P!;!7%<<!<,#56%!20.3!->%!RQG!

""A0%/-0,7-%$!G@F!;!7%<<!<,#56%(!

O2-%0! 9%,#6! +./,-,1%<:! /%<%7-%$Y! ->%! ;! 7%<<! +0.6%#,-.0/! 3,605-%! 20.3! ->%! ->:3,7! 7.0-%&! -.! ->%!

3%$4<<5Y! C>%0%! ->./%! ;GH! 50%! $%<%-%$! ->5-! 0%7.6#,8%! RQGA+0%/%#-%$! /%<2A+%+-,$%/! C,->! >,6>!!

522,#,-:! kI)l(! X,0/-! %1,$%#7%! ->5-! >,6><:! 57-,15-%$! ;! 7%<<! +0.6%#,-.0/! 50%! $%<%-%$! ,#! ->%! ->:34/! C5/!

+0.1,$%$!9:!3,7%!%&+0%//,#6!%#$.6%#.4/<:!5!1,05<!/4+%05#-,6%#(!;>%!+0%/%#-/!.2!->%!/4+%05#-,6%#!,#!

7.39,#5-,.#! C,->! 5! 7%0-5,#! RQG! 3.<%74<%! <%5$! -.! ->%! $%<%-,.#! .2! ;! 7%<<! +0.6%#,-.0/! %&+0%//,#6! 5!

+50-,74<50! DT! ;GH! 7>5,#Y! C>,7>! /+%7,2,75<<:! 0%57-%$! C,->! ->%! /4+%05#-,6%#ARQG! 7.3+<%&! kIIYISl(!

O#-,6%#A/+%7,2,7! 7<.#5<! $%<%-,.#! C5/! $%3.#/-05-%$! ,#! 35<%! ;GHA-05#/6%#,7! 3,7%Y! C>,7>! %&+0%//%$! 5!

;GH!0%7.6#,8,#6!5!35<%!/+%7,2,7!5#-,6%#!kI=l(!R%$4<<50:!->:3,7!%+,->%<,5<!7%<</!50%!->%!3./-!+0.3,#%#-!

7%<<! -:+%! ,#1.<1%$! ,#! #%65-,1%! /%<%7-,.#(! ;>%:! 50%! 75+59<%! -.! %&+0%//! .->%0C,/%! -,//4%A0%/-0,7-%$!

5#-,6%#/!->0.46>!->%!57-,.#!.2!->%!54-.,334#%!0%64<5-.0!_O"H*`!+0.-%,#Y!C>,7>!,#$47%/!+0.3,/74.4/!

6%#%!%&+0%//,.#!kIPYIJl(!O#.->%0!7%<<!-:+%!,#1.<1%$!,#!->%!#%65-,1%!/%<%7-,.#!50%!$%#$0,-,7!7%<</Y!C>,7>!

3,6>-!5</.!9%!0%/+.#/,9<%!2.0!/.3%!$%60%%!.2!#%65-,1%!/%<%7-,.#!,#!->%!->:3,7!7.0-%&!5#$!$40,#6!->%!

-05#/,-,.#!-.!->%!3%$4<<5!kS=YS'l(!;>0.46>!->%!+0.7%//!.2!#%65-,1%!/%<%7-,.#Y!;GH!C,->!>,6>!522,#,-:!2.0!

/%<2A$%0,1%$!+%+-,$%/!+0%/%#-%$!,#!->%!->:34/!50%!$%<%-%$!20.3!->%!0%+%0-.,0%(!

(15)

"#-0.$47-,.#!

!

! J!

!"A #$%&''/$/3)B&1$(&(.-@&$/42('&/$*<$()*.&-,/$()*@3%&@$71$0*/.$4,@$<*)&-+,$%&''/$

;>%!+%+-,$%/!+0%/%#-%$!9:!RQG!"!5#$!""!3.<%74<%/!50%!+0.-%,#!$%605$5-,.#!+0.$47-/!$%0,1%$!20.3!

-C.!$,/-,#7-!7%<<4<50!+5->C5:/(!RQG!"!3.<%74<%/!50%!<.5$%$!,#!->%!*H!C,->!+%+-,$%/!6%#%05-%$!9:!->%!

+0.-%5/.35<! $%605$5-,.#! .2! 7:-./.<,7! 5#$! #47<%50! +0.-%,#/(! O<3./-! %1%0:! 7%<<! %&+0%//%/! RQG! "!

3.<%74<%/Y!C>,7>!5<<.C/!7:-.-.&,7!G@P!;!7%<</!-.!/401%:!/53+<%/!.2!->%!+0.-%.3%!20.3!,#$,1,$45<!7%<</!

->0.46>.4-! ->%! 9.$:! 5#$! -.! 0%57-! -.C50$/! ->./%! />.C,#6! 59%005#-! +0.-%,#! %&+0%//,.#(! "#! 7.#-05/-Y!

RQG! ""! %&+0%//,.#! ,/! 35,#<:! 0%/-0,7-%$! -.! +0.2%//,.#5<! 5#-,6%#! +0%/%#-,#6! 7%<</! _OMG`! ->5-! 50%!

/+%7,5<,8%$!,#!->%!4+-5B%!.2!2.0%,6#!7%<</!.0!$%90,/!9:!3%7>5#,/3/!/47>!5/!+>56.7:-./,/(!;>%!%#64<2%$!

35-%0,5<!0%35,#/!7.#-5,#%$!,#!5!1%/,7<%!#53%$!+>56./.3%Y!C>,7>!35-40%/!5#$!24/%/!C,->!<:/./.3%/!-.!

2.03!+>56.<:/./.3%/(!RQG!""!3.<%74<%/!50%!<.5$%$!,#!->,/!<5-%!1%/,7<%/!C,->!+%+-,$%/!6%#%05-%$!9:!->%!

$%605$5-,.#!.2!%&.6%#.4/!35-%0,5<!$40,#6!->%!35-405-,.#!+0.7%//Y!/.!->5-!G@F!;!7%<</!50%!5//,6#%$!5!

35b.0!0.<%!,#!->%!5$5+-,1%!,334#%!0%/+.#/%!-.C50$/!,#-04$,#6!+5->.6%#/!5#$!->%,0!+0.$47-/(!

L-4$,%/!.#!3570.+>56%/!->5-!C%0%!74<-40%$!C,->!957-%0,5!5#$!4/%$!-.!/-,34<5-%!G@F!;!7%<</!+0.1,$%$!

2,0/-!>,#-/!2.0!->%!0%K4,0%3%#-!.2!5#-,6%#!+0.7%//,#6!,#!->%!+0.$47-,.#!.2!;!7%<<!%+,-.+%/(!R570.+>56%/!

7.4<$!/-,34<5-%!;!7%<</!.#<:!/.3%!-,3%!52-%0!->%:!,#6%/-%$!957-%0,5Y!94-!->%!;!7%<</!C%0%!#.-!59<%!-.!

0%7.6#,8%! ->%! 3570.+>56%! ,33%$,5-%<:! .0! ->%! 957-%0,5! $,0%7-<:! kS?l(! X40->%03.0%Y! ,#>,9,-,.#! .2!

<:/./.35<! 57,$,2,75-,.#! ,#! ->%! 3570.+>56%/! 0%$47%$! 5#-,6%#A+0%/%#-5-,.#! ,#! 5! $./%A$%+%#$%#-!!

35##%0! kSEl(! e->%0! %&+%0,3%#-5<! /:/-%3/! $%3.#/-05-%$! +0%/%#-5-,.#! .2! RQG! ""A0%/-0,7-%$! 5#-,6%#/!

52-%0! ,#7495-,.#! .2! OMG! C,->! #5-,1%! .0! $%#5-40%$! 5#-,6%#,7! +0.-%,#Y! -0:+-,7! +0.-%,#! $,6%/-/! .0!

/:#->%/,8%$! +%+-,$%/Y! 240->%0! 5064,#6! 2.0! +0.-%,#! $%605$5-,.#! 5/! 5! 70,-,75<! /-%+! ,#! 5#-,6%#!!

+0.7%//,#6! kSFYS)l(! L>.0-! +%+-,$%/! C%0%! />.C#! -.! $,0%7-<:! 9,#$! -.! +40,2,%$! RQG! ""! 3.<%74<%/!%'##

$%()&#kSIYSSl(!*1%#-45<<:!<:/./.35<!7:/-%,#%!+0.-%5/%/Y!C>,7>!50%!.#<:!57-,1%!5-!<.C!+QY!C%0%!,$%#-,2,%$!

5/! ->%! +0%$.3,#5#-! %#8:3%/! ,#1.<1%$! ,#! ->%! +0.$47-,.#! .2! +%+-,$%/! 20.3! +0.-%,#/! ,#! +>56.<:/.A!

/.3%/! kSPYSJl(! "#7495-,.#! .2! -506%-! 7%<</! C,->! %&57-<:! $%2,#%$! />.0-! +%+-,$%/Y! C>./%! /%K4%#7%! C5/!

$%0,1%$!20.3!5!1,05<!+0.-%,#Y!C5/!5</.!/422,7,%#-!-.!%<,7,-!7%<<!<:/,/!9:!1,04/A/+%7,2,7!RQG!"A0%/-0,7-%$!G@P!

;!7%<</!kP=l(!c%2.0%!->%!7%<<4<50!+5->C5:!+0.$47,#6!RQG!"A+0%/%#-%$!+%+-,$%/!C5/!$%/70,9%$Y!->%!2,0/-!

70:/-5<!/-047-40%!.2!5!>435#!RQG!"!3.<%74<%!_QnOAO?`!,#$,75-%$!>.C!/47>!+%+-,$%/!C%0%!+0%/%#-%$!5-!

->%!7%<<!/40257%!kP'YP?l(!

RQG!"!3.<%74<%/!7.#/,/-!.2!-C.!+.<:+%+-,$%!7>5,#/(!;>%!+.<:3.0+>,7!U!7>5,#!5#7>.0/!->%!$,3%0!,#!

->%!3%3905#%Y!2.<$/!,#-.!->0%%!$,/-,#7-!%&-057%<<4<50!$.35,#/!_U'AE`!5#$!,/!#.#A7.15<%#-<:!5//.7,5-%$!

C,->!->%!/35<<%0!,#150,5#-!T?A3,70.6<.94<,#!+.<:+%+-,$%!7>5,#!_T?R`(!O!7>5057-%0,/-,7!/-047-40%Y!->%!

+%+-,$%!9,#$,#6!7<%2-Y!,/!2.03%$!9:!->%!3%3905#%!$,/-5<!U'!5#$!U?!$.35,#/!.#!-.+!.2!->%!3.<%74<%d!

;C.!U!>%<,7%/!50%!<5:,#6!+505<<%<!.#!5!+<5#%!T!/>%%-!5#$!2.03!->%!C5<</!.2!5!<.#6!60..1%Y!,#!C>,7>!5#!

%&-%#$%$!+%+-,$%!.2!59.4-!#,#%!53,#.!57,$/!_55`!,/!$%%+<:!940,%$!kP'YP?l(!O!/,3,<50!+%+-,$%!9,#$,#6!

7<%2-!C5/!5</.!2.4#$!<5-%0!.#!-.+!.2!5!>435#!RQG!""!3.<%74<%!_QnOA@H'`Y!C,->!->%!$,22%0%#7%/!->5-!->%!

60..1%!C5/!.+%#!5-!,-/!%#$/!5#$!7.3+./%$!.2!.#%!$.35,#!20.3!%57>!.2!->%!-C.!RQG!""!7>5,#/!_U'!5#$!

T'`!kPEl(!r>%0%5/!7.#/%01%$!0%/,$4%/!5-!->%!%#$!.2!->%!+%+-,$%!9,#$,#6!7<%2-!.2!->%!RQG!"!3.<%74<%!

(16)

"#-0.$47-,.#!

!

! '=!

35B%! 7.#-57-/! -.! 9.->! +%+-,$%! -%03,#,Y! ,/! +%+-,$%! 9,#$,#6! ,#! 75/%! .2! ->%! RQG! ""! 3.<%74<%! 35,#<:!

57>,%1%$! ->0.46>! ,#-%057-,.#/! .2! 7.#/%01%$! 0%/,$4%/! 5<.#6! ->%! 7<%2-! C,->! ->%! +%+-,$%! 957B9.#%(!

O$$,-,.#5<! 7.#-57-/! 9%-C%%#! /.3%! /,$%! 7>5,#/! .2! ->%! +%+-,$%! 5#$! +.<:3.0+>,7! 0%/,$4%/! .2! ->%! RQG!

3.<%74<%/!7.#2%0!5$$,-,.#5<!5<<%<%A/+%7,2,7!0%/-0,7-,.#/!-.!->%!+%+-,$%/(!

O#5<:/,/!.2!RQGA9.4#$!+%+-,$%/Y!2,0/-!,/.<5-%$!20.3!7%<<!<:/5-%/!94-!->%#!$,0%7-<:!%<4-%$!20.3!->%!7%<<!

/40257%Y!+0.1,$%$!$,0%7-!%1,$%#7%!->5-!->%!#5-405<!+0.$47%$!$%-%03,#5#-/!.2!B#.C#!1,05<!5#$!3,#.0!

>,/-.7.3+5-,9,<,-:!5#-,6%#/!_3QO6`!$%-%7-%$!9:!;!7%<</!C%0%!,#$%%$!/>.0-!+%+-,$%/!kPFYP)YPIYPSYPPl(!

R.0%.1%0Y!->%!,#70%5/,#6!#439%0!.2!7>5057-%0,8%$!5#-,6%#,7!+%+-,$%/!+0%/%#-%$!9:!RQG!5<<%<%/!5#$!->%!

/%K4%#7,#6!.2!%<4-%$!+%+-,$%!+..</Y!5<<.C%$!->%!$%/70,+-,.#!.2!->%!+%+-,$%A9,#$,#6!/+%7,2,7,-:!.2!RQG!

3.<%74<%/! kPJYJ=YJ'YJ?l(! M%+-,$%/! .2! %,6>-! -.! #,#%! 5#$! -C%<1%! -.! -C%#-:! 2,1%! 53,#.! 57,$/! 50%!

+0%2%0%#-,5<<:! 9.4#$! 9:! RQG! "! 5#$! ""! 3.<%74<%/Y! 0%/+%7-,1%<:(! ;>%! 522,#,-:! .2! 5! +%+-,$%! 2.0! RQG! "! ,/!

4/45<<:!$.3,#5-%$!9:!-C.!0%/,$4%/!_5#7>.0!0%/,$4%/`(!;>%!+0%2%0%#7%!2.0!5!>:$0.+>.9,7!0%/,$4%!5-!->%!

GA-%03,#4/!,/!7.33.#Y!C>%0%5/!->%!/%7.#$!5#7>.0!0%/,$4%!,/!3.0%!5<<%<%A/+%7,2,7(!M%+-,$%!9,#$,#6!-.!

RQG!""!3.<%74<%/!,/!3.0%!7.3+<%&Y!9%754/%!->%!+./,-,.#!.2!->%!+%+-,$%!5#$!->%!<%#6->!,/!#.-!2,&%$Y!94-!

7.33.#!/%K4%#7%!+5--%0#/!.2!-C.!-.!->0%%!$%2,#%$!0%/,$4%/!,#!5!7>5057-%0,/-,7!$,/-5#7%!-.!%57>!.->%0!

7.4<$!9%!,$%#-,2,%$(!

;>%!/%K4%#7%/!.2!->%!RQG!"A+0%/%#-%$!+%+-,$%/!,$%#-,2,%$!->%3!5/!$%0,1%$!20.3!7%<<4<50!+0.-%,#/(!

@40,#6!->%!7.#/-,-4-,1%!+0.-%,#!-40#.1%0Y!->%!<59%<,#6!.2!+0.-%,#/!C,->!49,K4,-,#!$,0%7-/!->%3!-.!5!<506%!

34<-,75-5<:-,7!7.3+<%&!75<<%$!+0.-%5/.3%Y!C>,7>!,/!0%/+.#/,9<%!2.0!7%<<4<50!+0.-%,#!$,/+./5<(!"#$47-,.#!

.2! $%70%5/%$! +0.-%,#! 49,K4,-,#5-,.#! ,#! 5! 34-5#-! 7%<<! <,#%! .0! +>50357.<.6,75<! ,#>,9,-,.#! .2! ->%!

+0.-%5/.3%! ,#! <:3+>.7:-%/! C5/! />.C#! -.! 7.,#7,$%#7%! C,->! $%70%5/%$! 5#-,6%#! +0%/%#-5-,.#! 9:!!

RQG! "! kJEYJFl(! ;>.46>! 3./-! +%+-,$%/! ,/.<5-%$! $,0%7-<:! 20.3! ->%! 7:-.+<5/3! .0! 6%#%05-%$!%'# $%()&#9:!

+40,2,%$!+0.-%5/.3%!7.3+<%&%/!,#$%%$!+.//%//%$!>:$0.+>.9,7!GA-%03,#,Y!->%!35b.0,-:!C5/!<.#6%0!->5#!

->%! +%+-,$%/! %<4-%$! 20.3! RQG! "! 3.<%74<%/! kJ)YJIl(! *H! 53,#.+%+-,$5/%! 5//.7,5-%$! C,->! 5#-,6%#!

+0.7%//,#6!_*HOOM`!C5/!2.4#$!-.!240->%0!-0,3!->%!NA-%03,#,!.2!->%!+0%740/.0!+%+-,$%/!,#!->%!*H!<43%#!

4#-,<!->%:!57K4,0%!->%!.+-,35<!<%#6->(!R.0%!<.#6!+%+-,$%/!C%0%!,/.<5-%$!20.3!->%!*H!5#$!2%C%0!+%+-,$%A RQG!"!7.3+<%&%/!C%0%!%&+0%//%$!5-!->%!7%<<!/40257%!52-%0!B#.7B$.C#!.2!*HOOM!9:!HNO!,#-%02%0%#7%!

_HNO,`Y!C>%0%5/!,#70%5/%$!*HOOM!%&+0%//,.#!0%/4<-%$!,#!->%!.++./,-%!%22%7-/!kJSYJPYJJl(!H%/+.#/,9<%!

2.0!->%!/>4--<,#6!.2!->%!+%+-,$%/!20.3!->%!7:-./.<!,#-.!->%!*H!<43%#!50%!->%!-05#/+.0-%0/!5//.7,5-%$!

C,->! 5#-,6%#! +0.7%//,#6! '! 5#$! ?! _;OM'j?`! +0.-%,#/(! M%03%59,<,85-,.#! .2! 7%<</! C,->! 5! +.0%A2.03,#6!

957-%0,5<!-.&,#!<%51%/!->%!*H!3%3905#%/!,#-57-(!"#!/47>!+0%+505-,.#/Y!->%!-05#/+.0-!.2!5$$%$!3.$%<!

+%+-,$%/!,#-.!->%!*H!$%+%#$%$!.#!;OM'j?!5#$!O;M!k'==Y'='l(!

!"C D@*(.-B&$#$%&''$.0&)4(1$

!"C"! E(-.*(&/$@&)-B&@$<)*2$.32*)$4,.-+&,/$4)&$)&%*+,-F&@$71$#$%&''/$

"#!->%!9%6,##,#6!.2!->%!<5/-!7%#-40:!,-!C5/!/4/+%7-%$!->5-!->%!,334#%!/:/-%3!7.#/-5#-<:!/4++0%//%/!

75#7%0!$%1%<.+3%#-!5#$!->5-!-43.0/!75#!50,/%!.#<:!,2!->,/!/4++0%//,.#!%&7%+-,.#5<<:!25,</!k'=?l(!;>,/!

(17)

"#-0.$47-,.#!

!

! ''!

>:+.->%/,/!C5/!,#/+,0%$!9:!%&+%0,3%#-/!C,->!-05#/+<5#-59<%!-43.0!<,#%/!+%02.03%$!,#!3,7%!5#$!05-/(!

"#!6%#%05<Y!/+.#-5#%.4/!-43.0/!C%0%!3.0%!.2-%#!0%b%7-%$!->5#!577%+-%$!C>%#!-05#/+<5#-%$!20.3!.#%!

5#,35<!-.!5#.->%0(!"#!5$$,-,.#Y!-43.0!6052-!0%b%7-,.#!C5/!5463%#-%$!52-%0!,334#,85-,.#!C,->!-43.0!

7%<</(! "-! C5/! 240->%0! /4/+%7-%$Y! ->5-! <:3+>.7:-%/Y! C>,7>! 20%K4%#-<:! ,#2,<-05-%$! ->%! -43.0! 6052-/Y!

3%$,5-%$!->%!0%b%7-,.#(!Q.C%1%0Y!5<3./-!5<<!3,7%!/-05,#/!5-!->,/!-,3%!C%0%!.4-90%$Y!C,->!->%!%&7%+-,.#!

.2! ->%! m5+5#%/%! C5<-8,#6! 3.4/%(! O<->.46>! ,-! C5/! #.-,7%$Y! ->5-! -43.0! 6052-! /4/7%+-,9,<,-:! 150,%$!

9%-C%%#!->%!3.4/%!/-05,#/Y!R%#$%<s/!<5C!7.4<$!#.-!%5/,<:!%&+<5,#!->%!0%/4<-/!.2!70.//A90%%$,#6/(!;>,/!

7>5#6%$!C>%#!->%!m5+5#%/%!C5<-8,#6!3.4/%!C5/!70.//%$!-.!5#.->%0! 3.4/%!/-05,#!5#$!->%!.22/+0,#6!

C%0%! 957B70.//%$! -.! ->%! +50%#-5<! 6%#%05-,.#! k'=El(! "#! 560%%3%#-! C,->! R%#$%<s/! <5CY! -43.0! 6052-!

/4/7%+-,9,<,-:!/%%3%$!-.!$%+%#$!.#!5!/35<<!#439%0!.2!,#$%+%#$%#-!-05,-/(!;>%!,#1%/-,65-,.#!.2!->%/%!

6%#%-,7!-05,-/!<%$!-.!->%!$,/7.1%0:!.2!->%!RQG!,#!3,7%Y!C>,7>!,/!#53%$!QA?!52-%0!,-/!2,0/-!7>5057-%0,8%$!

RQGA%#7.$%$! 6%#%! k'=Fl(! O<->.46>! /-0.#6! 5<<.6%#%,7! ,334#%! 0%/+.#/%/! +0.1.B%$! 9:! ->%!

-05#/+<5#-5-,.#!.2!-43.0/!570.//!RQG!9500,%0/!7.4<$!9%!51.,$%$Y!.->%0!,#$,1,$45<!6%#%-,7!$,22%0%#7%/!

9%-C%%#! $.#.0! 5#$! 0%7,+,%#-! ->5-! %#7.$%$! 3QO6! 7.#-,#4%$! -.! 9%! 5! +0.9<%3! ,#! -05#/+<5#-5-,.#!

%&+%0,3%#-/!4#-,<!+40%!,#90%%$!3.4/%!/-05,#/!C%0%!%/-59<,/>%$(!

;>%! 7%#-05<! K4%/-,.#! C>%->%0! -43.0/! %&+0%//! 5#-,6%#/! ->5-! C.4<$! 5<<.C! ->%! 5$5+-,1%! ,334#%!

/:/-%3! -.! 0%7.6#,8%! ->%3Y! C>,7>! ,/! ,2! ->%:! 50%! ,334#.6%#,7Y! C5/! 2,0/-! 5#/C%0%$! 4/,#6! 7>%3,75<<:!

,#$47%$! -43.0/(! R%->:<7>.<5#->0%#%! _RGO`A,#$47%$! -43.0/! ->5-! .->%0C,/%! 7.4<$! 9%! -05#/+<5#-%$!

C%0%! ,#$%%$! 0%b%7-%$! 9:! 3,7%! ->5-! C%0%! ,334#,8%$! 9%2.0%! ->%! -43.0! 7>5<<%#6%! C,->! 7%<</! .2! /53%!

-43.0! <,#%! k'=)l(! O! 7.3+50,/.#! .2! /%1%05<! RGOA,#$47%$! -43.0/! C,->! /+.#-5#%.4/! 353350:!

7507,#.35/! ,#! ->%! /53%! /%--,#6! />.C%$! ->5-! ->%! <5--%0! C%0%! #.-! 0%b%7-%$Y! 5064,#6! 565,#/-! 6%#%-,7!

150,5-,.#/! C,->,#! ->%! 3.4/%! /-05,#! 5/! 5#! %&+<5#5-,.#Y! 5#$! 2.0! 5! 7>5057-%0,/-,7! ,334#.6%#,7,-:! .2!

7>%3,75<<:! ,#$47%$! -43.0/! k'=Il(! ;>%/%! 2,#$,#6/! C%0%! 7.#2,03%$! 9:! 5! /49/%K4%#-! 3.0%! $%-5,<%$!!

/-4$:!k'=Sl(!"334#,85-,.#!+0.-%7-%$!3,7%!565,#/-!5!-43.0!7>5<<%#6%!,#!75/%!.2!-C%<1%!.4-!.2!2.40-%%#!

RGOA,#$47%$!/507.35/Y!94-!C5/!4#/477%//24<!,#!75/%!.2!/%1%#!/+.#-5#%.4/!/507.35/(!"#!5$$,-,.#Y!->%!

-43.0/!5</.!60%C!,#!3,7%!->5-!C%0%!,334#,8%$!C,->!#.035<!-,//4%!,#$,75-,#6!->%!6%#%-,7!>.3.6%#%,-:!

.2!->%!3.4/%!/-05,#(!;>%!+0.-%7-,1%!,334#,-:!C5/!,#!6%#%05<!/+%7,2,7!2.0!->%!,334#,8,#6!-43.0!7%<<!

<,#%Y!5<->.46>!2%C!%&7%+-,.#/!C%0%!.9/%01%$(!*1%#-45<<:Y!,-!C5/!2.035<<:!+0.1%#!->5-!;!7%<</!0%7.6#,8%$!

4#,K4%!-43.0A/+%7,2,7!5#-,6%#/!,#!->,/!3.$%<!k'=Pl(!"334#,85-,.#!.2!->%!54-.7>->.#.4/!>./-/!.2!RGOA ,#$47%$!/507.35/!52-%0!->%!0%3.15<!.2!->%!+0,350:!-43.0!,#$47%$!5!+50-,5<<:!+0.-%7-,1%!,334#,-:!5#$!

;! 7%<</! ,/.<5-%$! 20.3! ->%! ,334#,8%$! 3,7%! 0%7.6#,8%$! ->%! 0%/+%7-,1%! -43.0! 7%<</!%'# $%()&(! N.! 70.//A 0%57-,1,-:!9%-C%%#!->%!,#$%+%#$%#-<:!$%0,1%$!/507.35/!C5/!.9/%01%$(!

!"C"!"! #32*)$4,.-+&,/$4)&$+)*3(&@$-,.*$%4.&+*)-&/$74/&@$*,$.0&-)$&=()&//-*,$-,$,*)24'$.-//3&$

;>%!,334#.6%#,7,-:!.2!7>%3,75<<:!5#$!1,05<A,#$47%$!-43.0/!5#$!->%!$%/70,+-,.#!.2!;!7%<<A3%$,5-%$!

6052-! 0%b%7-,.#/! /-,34<5-%$! ->%! 0%2.034<5-,.#! .2! ->%! ,334#%! /401%,<<5#7%! ->%.0:! k'=JY''=l(! "-! C5/!

+0.+./%$!->5-!;!7%<</!C.4<$!7.#/-5#-<:!+0%1%#-!-43.0!$%1%<.+3%#-!->0.46>!->%!%<,3,#5-,.#!.2! +0%A

(18)

"#-0.$47-,.#!

!

! '?!

35<,6#5#-! -05#/2.03%$! 7%<</! %&+0%//,#6! -43.0! 5#-,6%#/(! e->%0/! >51%! <5-%0! %&-%#$%$! ->,/! ->%.0:! 5#$!

+0.+./%$!->5-!/+.#-5#%.4/!-43.0/!50%!,#!6%#%05<!.2!<.C!,334#.6%#,7,-:! k'''l(!"-!C5/!/-5-%$!->5-!5!

7.#/-5#-!,334#.<.6,75<!+0%//40%!C.4<$!/%<%7-!1%0:!%50<:!2.0!#5/7%#-!-43.0!7%<</!->5-!$.!#.-!+0%/%#-!;!

7%<<!%+,-.+%/(!;>%!+0.+./%$!,#59,<,-:!.2!->%!5$5+-,1%!,334#%!/:/-%3!-.!0%7.6#,8%!/+.#-5#%.4/!-43.0/!

,/Y!>.C%1%0Y!K4%/-,.#%$!9:!->%!<506%!#439%0!.2!-43.0!5#-,6%#/!->5-!C%0%!$%/70,9%$!-.!9%!%&+0%//%$!2.0!

%&53+<%! ,#! >435#! 3%<5#.35/(! "#! 6%#%05<Y! ->%! +0.-%.3%! .2! 75#7%0! 7%<</! $,22%0/! 20.3! #.035<! 7%<</!

9%754/%! .2! 34-5-,.#/! ,#! ->%! 6%#.3%! 5#$! $%0%64<5-%$! %&+0%//,.#! .2! #.#A34-5-%$! 6%#%/(! ;43.0!

5#-,6%#/!50%!60.4+%$!,#-.!75-%6.0,%/!95/%$!.#!->%,0!%&+0%//,.#!,#!#.035<!-,//4%(!ROW*AO'Y!->%!2,0/-!

$%/70,9%$!>435#!3%<5#.35!5#-,6%#!%#7.$,#6!5!;!7%<<!%+,-.+%Y!C5/!$,/7.1%0%$!9:!/70%%#,#6!5!-43.0A

$%0,1%$! @NO! <,9050:! C,->! 54-.<.6.4/! -43.0A0%57-,1%! ;! 7%<<! 7<.#%/! k''?Y''El(! ROW*AO'! ,/! 5! -:+,75<!

-43.0A5//.7,5-%$!5#-,6%#!_;OO`!6%#%05-%$!9:!5!#.#A34-5-%$!7%<<4<50!6%#%(!"-!9%<.#6/!-.!->%!60.4+!.2!

75#7%0j-%/-,/!_G;`!5#-,6%#/Y!C>./%!%&+0%//,.#!,#!#.035<!-,//4%!,/!35,#<:!0%/-0,7-%$!-.!->%!6%03!7%<</!.2!

->%!-%/-,/(!;:0./,#5/%!5#$!R%<5#AOjR50-A'!50%!240->%0!%&53+<%/!.2!;OO!%&+0%//%$!,#!3%<5#.35!5#$!

C%0%! $,/7.1%0%$! 9:! 5! /,3,<50! 5++0.57>! 4/,#6! 54-.<.6.4/! -43.0A0%57-,1%! ;! 7%<</! k''FY'')Y''Il(! c.->!

9%<.#6!-.!->%!60.4+!.2!$,22%0%#-,5-,.#!5#-,6%#/(!O#-,6%#/!.2!->,/!60.4+!50%!7>5057-%0,/-,75<<:!%&+0%//%$!

5-!5!7%0-5,#!$%1%<.+3%#-5<!/-56%!,#!->%!7%<<!<,#56%!20.3!C>,7>!->%!-43.0!.0,6,#5-%/(!"#!7.#-05/-Y!-43.0A /+%7,2,7!5#-,6%#/!_;LO`!50%!6%#%05-%$!9:!/.35-,7!34-5-,.#/!5#$!50%!->%0%2.0%!#.-!%&+0%//%$!,#!#.035<!

-,//4%(! O! ;! 7%<<! %+,-.+%! $%0,1%$! 20.3! 5! 34-5-,.#! ,#! ->%! 7:7<,#A$%+%#$%#-! B,#5/%! F!_G@^F`! 6%#%! .2! 5!

3%<5#.35!C5/!,$%#-,2,%$!-..!4/,#6!54-.<.6.4/!-43.0A0%57-,1%!;!7%<</!k''Sl(!

;>%!59.1%!%&53+<%/!50%!0%+0%/%#-5-,1%!2.0!5!7.#/-5#-<:!60.C,#6!<,/-!.2!,334#.6%#,7!+%+-,$%/!20.3!

-43.0! 5#-,6%#/! .2! C>,7>! .1%0! F==! 50%! <,/-%$! ,#! 5! 7400%#-! $5-595/%! k''Pl(! "-! ,/! ->%0%2.0%! $,22,74<-! -.!

,356,#%! >.C! /47>! ,334#.6%#,7! -43.0/! 75#! $%1%<.+! 4#$%0! ->%! +0.+./%$! 7.#/-5#-! +0%//40%! .2! ->%!

,334#%!/:/-%3(!e#!->%!7.#-050:Y!,-!C5/!$%3.#/-05-%$!,#!5!3.4/%!3.$%<!->5-!,334#.6%#,7,-:!5<.#%!,/!

#.-!/422,7,%#-!-.!%<,7,-!5!$%/-047-,1%!,334#%!0%57-,.#!,#!75/%!.2!/+.#-5#%.4/!-43.0/Y!C>,7>!$%1%<.+!

/<.C<:!,#!->%!>./-!,#!->%!59/%#7%!.2!574-%!,#2<5335-,.#!20.3!/,#6<%!7%<</!k''Jl(!;43.0!60.C->!,#$47%$!

9:!->%!/-.7>5/-,7!57-,15-,.#!.2!5!1,05<!.#7.6%#%!0%/4<-%$!,#!/:/-%3,7!5#-,6%#A/+%7,2,7!-.<%05#7%!,#/-%5$!

.2!-43.0!7%<<!%<,3,#5-,.#(!"334#.->%05+:!.2!75#7%0!->%0%2.0%!>5/!-.!4/%!3%5#/!-.!90%5B!->,/!-.<%05#7%Y!

2.0!%&53+<%!9:!->%!-05#/2%0!.2!!"#$%$&!57-,15-%$!;!7%<</(!;>%!,334#.6%#,7,-:!.2!-43.0/!,/!5!+0%0%K4,/,-%!

2.0!/47>!5!->%05+:(!

!"C"8 #)4,/<&)$*<$3,2*@-<-&@$#$%&''/$

!"C"8"! :*,*)G@&)-B&@$#$%&''/$%4,$2&@-4.&$.0&$)&2-//-*,$*<$)&'4(/&@$21&'*-@$'&3H&2-4$-,$7*,&$

24))*9$)&%-(-&,./$

;>%!-0%5-3%#-!.2!0%<5+/%$!3:%<.,$!<%4B%3,5!52-%0!cR!-05#/+<5#-5-,.#!C,->!$.#.0A$%0,1%$!;!7%<</!,/!

.#%!%&53+<%!20.3!->%!7<,#,7!->5-!/>.C/!9.->!->%!9%#%2,-!5#$!0,/B!.2!5$.+-,1%!;!7%<<!->%05+:(!"#!5#!RQGA 35-7>%$!/%--,#6Y!->%!$.#.0A$%0,1%$!;!7%<</!0%7.6#,8%!3QO6!%#7.$%$!9:!+.<:3.0+>,7!6%#%/!%&+0%//%$!

(19)

"#-0.$47-,.#!

!

! 'E!

9:!-43.0!7%<</!5#$!>%5<->:!-,//4%!k'?=Y'?'l(!"-!C5/!2,0/-!$%3.#/-05-%$!,#!3,7%Y!->5-!-05#/+<5#-5-,.#!.2!

5<<.6%#%,7! 94-! #.-! /:#6%#%,7! cR! 52-%0! ,005$,5-,.#! 3%$,5-%/! ->%! %<,3,#5-,.#! .2! 0%/,$45<! <%4B%3,7!!

7%<</! k'??Y'?El(! Q.C%1%0Y! ,#! <%4B%3,5! +5-,%#-/! -0%5-%$! C,->! 5<<.6%#%,7! cRY! ->%! 7405-,1%! 0%/+.#/%Y!

-%03%$! 6052-A1%0/4/A<%4B%3,5! _WDn`! %22%7-Y! C5/! 5//.7,5-%$! C,->! 5#! 54-.,334#%! +5->.<.6:Y! -%03%$!

6052-A1%0/4/A>./-!$,/%5/%!_WDQ@`!->5-!0%+0%/%#-/!5!<,2%A->0%5-%#,#6!7.3+<,75-,.#!k'?FY'?)l(!;!7%<</!7.A -05#/2%00%$!C,->!->%!cR!C%0%!,$%#-,2,%$!-.!3%$,5-%!9.->Y!->%!WDn!%22%7-!5#$!WDQ@(!;05#/+<5#-5-,.#!.2!

;! 7%<<A$%+<%-%$! cR! $%70%5/%$! ->%! ,#7,$%#7%! .2! WDQ@Y! 94-! 5</.! ,#70%5/%$! ->%! 0,/B! .2! <%4B%3,5!!

0%<5+/%! k'?IY'?SY'?PY'?Jl(! O! 90%5B->0.46>! ,#! ->%! -0%5-3%#-! .2! 0%<5+/%$! 3:%<.,$! <%4B%3,5! C5/! ->%!

5++<,75-,.#! .2! $.#.0! <:3+>.7:-%! ,#24/,.#/! _@n"`! 52-%0! 5<<.6%#%,7! cR! -05#/+<5#-5-,.#!

k'E=Y'E'Y'E?Y'EEY'EFY'E)l(!@n"!,#$47%$!7.3+<%-%!0%3,//,.#/!,#!->%!60%5-!35b.0,-:!.2!->%!+5-,%#-/!5#$!

/,6#,2,75#-<:! $%70%5/%$! ->%! 0,/B! .2! 240->%0! 0%<5+/%(! Q.C%1%0Y! WDQ@! 0%35,#%$! -.! 9%! 5! 35b.0!

7.3+<,75-,.#!5#$!$%1%<.+%$!,#!)Jg!5#$!EPg!.2!->%!+5-,%#-/!-0%5-%$!C,->!@n"!,#!.#%!%50<:!5#$!.#%!

0%7%#-!/-4$:Y!0%/+%7-,1%<:!k'EIY'ESl(!;>%!$,22%0%#7%!,#!->%!,#7,$%#7%!.2!WDQ@!,/!$4%!-.!->%!5++<,75-,.#!

.2!,#70%3%#-5<!$./%/!.2!@n"!5/!7.3+50%$!-.!94<B!0%6,3%/(!e#%!C5:!-.!7.3+<%-%<:!51.,$!WDQ@!C>,<%!

+0%/%01,#6! ->%! WDn! %22%7-! C.4<$! 9%! ->%! -05#/2%0! .2! $%2,#%$! ;! 7%<<! +.+4<5-,.#/! /+%7,2,7! 2.0! 3QO6!

%&7<4/,1%<:!%&+0%//%$!.#!->%!>%35-.+.,%-,7!7%<</!.2!->%!0%7,+,%#-!k'EPY'EJl(!

!"C"8"8 I-)3/G/(&%-<-%$#$%&''/$%*,<&)$-223,*'*+-%4'$()*.&%.-*,$.*$-223,*/3(()&//&@$(4.-&,./$

+!# '&$&! 1,05<! ,#2%7-,.#/! 5#$! 0%57-,15-,.#! .2! <5-%#-! 1,04/! 50%! 7.33.#! 7.3+<,75-,.#/! ,#!

,334#./4++0%//%$!+5-,%#-/(!*/+%7,5<<:!*+/-%,#Ac500!1,04/!_*cD`!5#$!7:-.3%65<.1,04/!_GRD`!0%<5-%$!

7.3+<,75-,.#/!50%!$,22,74<-!-.!51.,$!9%754/%!.2!->%!>,6>!+0%15<%#7%!.2!<5-%#-!,#2%7-,.#/!,#!->%!+.+4<5-,.#!

->5-!50%!4/45<<:!7.#-0.<<%$!,#!,334#.7.3+%-%#-!,#$,1,$45</(!O!3.4/%!3.$%<!->5-!3,3,7B%$!->%!7<,#,75<!

/,-45-,.#! 52-%0! cR! -05#/+<5#-5-,.#! $%3.#/-05-%$! ->%! 70,-,75<! 0.<%! .2! G@P! ;! 7%<</! ,#! 2,6>-,#6! 1,05<!

,#2%7-,.#/! k'F=l(! "#! 5! ->%05+%4-,7! /%--,#6Y! ->%! -05#/2%0! .2! /35<<! #439%0/! .2! <:3+>! #.$%! 7%<</! 20.3!

,334#,8%$!3,7%!0%$47%$!1,05<!0%+<,75-,.#!5#$!-,//4%!$5356%Y!5<->.46>!->%!0%7,+,%#-/!C%0%!0%#$%0%$!

,334#./4++0%//%$!9:!,005$,5-,.#!9%2.0%!9%,#6!,#2%7-%$!C,->!340,#%!GRD(!GRDA/+%7,2,7!G@P!;!7%<</!

C%0%!5</.!$%-%7-%$!,#!>435#/!C,->!<5-%#-!GRD!,#2%7-,.#/!5#$!,-!C5/!/4/+%7-%$!->5-!C%0%!0%/+.#/,9<%!-.!

7.#-0.<! ->%! 1,04/! k'F'l(! X40->%03.0%Y! ->%! 0%7400%#7%! .2! GRDA/+%7,2,7! G@P! ;! 7%<</! ,#! ->%! 9<..$! .2!

,334#./4++0%//%$!+5-,%#-/! 7.00%<5-%$!C,->!+0.-%7-,.#!565,#/-! 0%57-,15-,.#!.2!GRD!k'F?l(!c5/%$! .#!

->%/%! $5-5Y! 5! 2,0/-A.2A,-/AB,#$! /-4$:! C5/! +%02.03%$! ,#! >435#/! k'FEl(! GRDA/+%7,2,7! ;! 7%<<! 7<.#%/! .2!

/%0.+./,-,1%! cR! $.#.0/! C%0%! %&+5#$%$! %'# $%()&! 5#$! ,#24/%$! ,#-.! ->0%%! +5-,%#-/! 52-%0! cR!

-05#/+<5#-5-,.#(!O!7:-.-.&,7!0%/+.#/%!-.C50$/!GRDA,#2%7-%$!54-.<.6.4/!2,90.9<5/-/!C5/!$%-%7-59<%!,#!

9<..$!/53+<%/!20.3!5<<!+5-,%#-/!4+!-.!2.40!C%%B/!52-%0!->%!,#24/,.#!5#$!#.#%!.2!->%!+5-,%#-/!$%1%<.+%$!

GRD!1,0%3,5!.0!+#%43.#,5(!"#!5$$,-,.#Y!#.!-0%5-3%#-A0%<5-%$!-.&,7,-,%/!C%0%!.9/%01%$(!;>,/!,3+.0-5#-!

/-4$:!+0.1,$%$!2,0/-!7<,#,75<!%1,$%#7%Y!->5-!->%!-05#/2%0!.2!<506%!#439%0/!.2!5<<.6%#%,7!5#-,6%#A/+%7,2,7!

;! 7%<</! $,$! #.-! 754/%! WDQ@Y! 94-! 7.#2%00%$! /%<%7-,1%! +0.-%7-,1%! ,334#,-:! -.! ,334#./4++0%//%$!

+5-,%#-/(!G.#/%K4%#-<:Y!$.#.0A$%0,1%$!*cDA/+%7,2,7!;!7%<</!C%0%!4/%$!C,->!/,3,<50!/477%//!-.!-0%5-!*cD!

(20)

"#-0.$47-,.#!

!

! 'F!

,#2%7-,.#/! .0! *cD! ,#$47%$! +./-A+0.<,2%05-,1%! $,/%5/%! ,#! cR! 0%7,+,%#-/! 5#$! ->,0$! +50-:A$%0,1%$! *cDA /+%7,2,7!;!7%<</!C%0%!4/%$!-.!-0%5-!+5-,%#-/!52-%0!/.<,$!.065#!-05#/+<5#-5-,.#!k'FFY'F)Y'FIl(!

!"C"8"; E=$B-B*$&=(4,@&@$.32*)G-,<-'.)4.-,+$#$%&''/$%4,$2&@-4.&$.32*)$)&+)&//-*,$-,$

()&%*,@-.-*,&@$(4.-&,./$

n5-%!/-56%!_"D`!3%<5#.35!+5-,%#-/!C,->!$,//%3,#5-%$!3%-5/-5/,/!>51%!5!+..0!+0.6#./,/!C,->!5!<.C!

.#%A:%50! /401,15<! 05-%! .2! 59.4-! )=g! k'FSl(! L47>! +5-,%#-/! >51%! 5<0%5$:! 4#$%06.#%! 7.#1%#-,.#5<!

-0%5-3%#-/! .0! ->%/%! .+-,.#/! 50%! #.-! <.#6%0! ,#$,75-%$! 9%754/%! .2! ->%! 5$15#7%$! /-5-4/! .2! $,/%5/%(! O-!

+0%/%#-Y! >.C%1%0Y! ->%! 3./-! %22%7-,1%! -0%5-3%#-/! 2.0! ->%/%! +5-,%#-/! 50%! +0.1,$%$! 9:! %&+%0,3%#-5<!

/-4$,%/!.2!75#7%0!,334#.->%05+:Y!C>,7>!0%+.0-!0%+0.$47,9<%!.9b%7-,1%!0%/+.#/%/!_t)=g!0%$47-,.#!,#!

-43.0! 1.<43%`! ,#! 5! /49/-5#-,5<! 2057-,.#! .2! +5-,%#-/! 5#$! $4059<%! 5#$! 7.3+<%-%! 0%3,//,.#/! ,#! /.3%!

+5-,%#-/(!^%:!2.0!->%!/477%//!.2!75#7%0!,334#.->%05+:!,/!->%!,#$47-,.#!.2!5#!%22%7-,1%!5#$!<.#6A<5/-,#6!

;!7%<<!0%/+.#/%!565,#/-!->%!-43.0!5#$!,3+.0-5#-!+0.60%//!>5/!9%%#!35$%!-.!57>,%1%!->,/!6.5<(!X,0/-!

7<,#,75<! 0%/+.#/%/! C%0%! ,#$47%$! 9:! 0%+%5-%$! 7:7<%/! .2! >,6>A$./%! ,#-%0<%4B,#A?! _"nA?`Y! C>,7>!

#.#/+%7,2,75<<:! 57-,15-%/! ;! 7%<<! ,334#,-:(! O$.+-,1%! ;! 7%<<! ->%05+:! _O;;`! C,->!!"# $%$&! %&+5#$%$!

54-.<.6.4/! -43.0A,#2,<-05-,#6! <:3+>.7:-%/! _;"n`! ,#! 7.39,#5-,.#! C,->! "nA?! C5/! $%1%<.+%$! -.! 240->%0!

,3+0.1%! ->%! -0%5-3%#-! 5#$! 0%7%#-! $5-5! 20.3! /35<<! +,<.-! /-4$,%/! ,#$,75-%! ->5-! ->,/! ,/! +.//,9<%! ,2! 5!

7.#$,-,.#,#6!0%6,3%!,/!5++<,%$!-.!->%!+5-,%#-!+0,.0!-.!->%!7%<<!-05#/2%0!_X,6(!'`(!

!

!

!X,0/-!$,/7.1%0%$!5/!5!60.C->!257-.0!/%70%-%$!9:!/-,34<5-%$!<:3+>.7:-%/!+%03,--,#6!.#!,-/!.C#!->%!

7.#-,#4.4/!74<-40%!.2!;!7%<</!!"#$%$&k'FPlY!"nA?!C5/!/>.C#!-.!%#>5#7%$!;!7%<<A3%$,5-%$!,334#,-:!,#!

75#7%0!3.4/%!3.$%</!C>%#!6,1%#!/:/-%3,75<<:!k'FJY')=Y')'l(!O2-%0!->%!7<.#,#6!.2!->%!"nA?!6%#%!k')?lY!

0%7.39,#5#-! "nA?! C5/! +0.$47%$! ,#!,-# .&/%! 5#$! %1%#-45<<:! 9%753%! 515,<59<%! 2.0! 7<,#,75<! /-4$,%/!

k')EY')Fl(!n.C!$./%/!.2!"nA?!5$3,#,/-%0%$!,#!->%!2,0/-!-0,5</!C%0%!#.-!/422,7,%#-!-.!,#$47%!5#!5#-,-43.0!

%22%7-Y! 94-! ,#$47%$! 5! +50-,74<50! 75+,<<50:! <%5B! /:#$0.3%! 5/! 5! 35,#! /,$%! %22%7-! #%&-! -.! 3,#.0!

$

$

S-+3)&$ !T$ 0!12&'1!# )3(!1# &4# 35$3'.!5# 6!/3'&63# 23(%!'(1#

()!3(!5#7%(8#%669'&(8!)32:#%'$&/$%';#*<=>-# #

M<.-! />.C/! ->%! .9b%7-,1%! 0%/+.#/%! 05-%/! 0%+.0-%$! ,#! 7<,#,75<!

/-4$,%/!2.0!+5-,%#-/!C,->!5$15#7%$!3%<5#.35!->5-!4#$%0C%#-!

,334#.->%05+%4-,7! -0%5-3%#-/! ,#1.<1,#6! "nA?(! ;>%!

7>5057-%0,/-,7! 7.3+.#%#-/! .2! ->%! -0%5-3%#-/! 50%! ,#$,75-%$!

9%<.C! ->%! 7.<43#/d! "#-%0<%4B,#A?! _"nA?`u! ;43.0A,#2,<-05-,#6!

<:3+>.7:-%/! _;"n`u! #.#3:%<.59<5-,1%! 7>%3.->%05+:! _NRO`u!

'?! W:! -.-5<! 9.$:! ,005$,5-,.#! _;c"`(! ;>%! :%50/! ,#! C>,7>! ->%!

0%+.0-/! C%0%! +49<,/>%$! 50%! />.C#! ,#! +50%#->%/,/! 5-! ->%!

9.--.3!.2!->%!+,7-40%(!;>%!#439%0!.2!+5-,%#-/!2.0!C>.3!->%!

0%/4<-/!C%0%!0%+.0-%$!20.3!->%!<%2-!-.!->%!0,6>-d!?S=u!E'Fu!PIu!

FEu!?)(!O<<!$5-5!20.3!0%2%0%#7%/!'I?Y!'IFY!'IJ!5#$!'S'(!X,640%!

3.$,2,%$!20.3!0%2%0%#7%!')J(!

(21)

"#-0.$47-,.#!

!

! ')!

7.3+<,75-,.#/!<,B%!2%1%0!5#$!7>,<</!k'))Y')IY')Sl(!"#!7.#-05/-Y!->%!5++<,75-,.#!.2!>,6>!%/75<5-,#6!$./%/!

.2! 0%7.39,#5#-! "nA?! ,#! />.0-! ,#-%015</! _P! >`! ,#$47%$! 0%3,//,.#/! .2! 5$15#7%$! 3%-5/-5-,7! 75#7%0! ,#! 5!

7.#/%74-,1%!/-4$:!k')Pl(!X.40!.2!/%1%#!3%<5#.35!+5-,%#-/!5#$!->0%%!.2!->0%%!+5-,%#-/!C,->!0%#5<!7%<<!

7507,#.35!_HGG`!%&>,9,-%$!.9b%7-,1%!0%3,//,.#/Y!+0.1,$,#6!2,0/-!7<,#,75<!%1,$%#7%!2.0!->%!+.-%#7:!.2!"nA

?!->%05+:(!e#%!3%<5#.35!+5-,%#-!.2!->,/!/-4$:!/-,<<!5<,1%!5#$!,#!7.3+<%-%!0%3,//,.#!/,#7%!_t?J:`!k')Jl(!

n506%!7<,#,75<!/-4$,%/!,#!->%!2.<<.C,#6!:%50/!$%<,1%0%$!+0..2!->5-!->%/%!0%/+.#/%/!C%0%!,#$%%$!,#$47%$!

9:!"nA?!5#$!#.-!9:!5#.->%0!-0%5-3%#-!->5-!C5/!5++<,%$!,#!+505<<%<!k'I=Y'I'l(!'Ig!.2!?S=!+5-,%#-/!C,->!

$,//%3,#5-%$! 3%-5/-5-,7! 3%<5#.35! ->5-! C%0%! -0%5-%$! ,#! %,6>-! 7<,#,75<! -0,5</! C,->! >,6>A$./%! "nA?!

/>.C%$!.9b%7-,1%!0%3,//,.#/Y!,#7<4$,#6!Ig!7.3+<%-%!0%3,//,.#/!_GH`!5#$!'=g!+50-,5<!0%3,//,.#/!_MH`!

_X,6(! '`! k'I?l(! L,3,<50! 0%/4<-/! C%0%! 0%+.0-%$! 2.0! ?))! +5-,%#-/! C,->! 3%-5/-5-,7! HGGY! 'Fg! />.C%$!

.9b%7-,1%! 0%3,//,.#/! _)g! GHY! Jg! MH`! k'IEl(! L,#7%! ->%! %/-59<,/>3%#-! .2! ->%! "nA?! ->%05+:Y! ->%!

%22%7-,1%#%//!.2!->%!-0%5-3%#-!,3+0.1%$!C,->!->%!+0.60%//!,#!7<,#,75<!%&+%0,%#7%(!H%7%#-<:Y!.9b%7-,1%!

0%/+.#/%!05-%/!.2!?Pg!5#$!?Fg!C%0%!0%+.0-%$!2.0!E'F!3%<5#.35!+5-,%#-/!_'?g!GHY!'Ig!eH`!5#$!'PI!

HGG!+5-,%#-/!_Sg!GHY!'Sg!MH`Y!0%/+%7-,1%<:!_X,6(!'`!k'IFl(!

;>%/%!0%+0.$47,9<%!0%/+.#/%/!,#$,75-%!->5-!;!7%<</!/+%7,2,7!2.0!-43.0A$%0,1%$!5#-,6%#/!50%!+0%/%#-!,#!

3%<5#.35!5#$!HGG!+5-,%#-/(!Q.C%1%0Y!->%!>50/>!7.#$,-,.#/!0%K4,0%$!-.!+4/>!->./%!7%<</!-%3+.050,<:!,#!

5#! 57-,1%! /-5-%Y! ->%! />.0-! $405-,.#! .2! 3./-! 0%/+.#/%/! 5#$! ->%! 257-! ->5-! ->%:! .7740! .#<:! ,#! 5! 3,#.0!

2057-,.#!.2!+5-,%#-/!5</.!5064%!565,#/-!5!#5-405<!-43.0A/+%7,2,7!;!7%<<!,334#,-:(!e#!->%!7.#-050:Y!->%!

+.-%#-,5<<:!75#7%0A0%57-,1%!;!7%<</!.2!->%!+5-,%#-/!50%!,#57-,1%!+0,.0!-.!,334#.->%05+:Y!+.//,9<:!$4%!-.!

->%!,#$47-,.#!.2!-.<%05#7%!9:!7>0.#,7!,#2<5335-,.#Y!#%65-,1%!/:/-%3,7!%22%7-/!.#!->%!,334#%!/:/-%3!

754/%$!9:!-43.0!60.C->!5#$!4#251.059<%!7.#$,-,.#/!C,->,#!->%!-43.0!3,70.%#1,0.#3%#-(!;>%!05-,.#5<!

.2! O;;! ,/! -.! .1%07.3%! -.<%05#7%Y! ,334#%! /4++0%//,.#! 5#$! >.3%./-5-,7! 0%64<5-,.#! 9:! 0%3.1,#6! ->%!

-43.0A0%57-,1%!;!7%<</!20.3!->%!>./-!%#1,0.#3%#-(!;>,/!+0.1,$%/!->%!.++.0-4#,-:!-.!57-,15-%Y!%&+5#$!

5#$! /%<%7-! ->%! ;! 7%<</!!"# $%$&Y! 9%2.0%! ->%:! 50%! 0%A,#24/%$! ,#-.! ->%! +5-,%#-! ,#! <506%! #439%0/! 5#$! ,#!

7.#b4#7-,.#! C,->! "nA?(! O! /.407%! .2! /47>! -43.0A0%57-,1%! ;! 7%<</! 50%! 54-.<.6.4/! -43.0A,#2,<-05-,#6!

<:3+>.7:-%/! _;"n`Y! C>,7>! 75#! 9%! /%<%7-,1%<:! %&+5#$%$! 20.3! 0%/%7-%$! -43.0! /53+<%/! 4/,#6!!

"nA?!k'I)Y'IIl(!O2-%0!9%,#6!%&+5#$%$!!"#$%$&Y!;"n!C%0%!75+59<%!-.!B,<<!54-.<.6.4/!-43.0/!%'#$%()&!5#$!-.!

3%$,5-%$!-43.0!0%60%//,.#!,#!3,7%!k'ISl(!"#!->%!2,0/-!/477%//24<!7<,#,75<! -0,5<!4/,#6!;"n!+<4/!"nA?Y!?=!

+5-,%#-/!C,->!3%-5/-5-,7!3%<5#.35!C%0%!-0%5-%$!5#$!''!.2!->%3!%&>,9,-%$!.9b%7-,1%!75#7%0!0%60%//,.#!

_))g`! k'IPl(! ;0%5-3%#-! .2! PI! 3%<5#.35! +5-,%#-/! C,->! /,3,<50! +0.-.7.</Y! 0%/4<-%$! ,#! 5#! .9b%7-,1%!

0%/+.#/%! 05-%! .2! EFgY! ,#7<4$,#6! Ig! GH! 5#$! ?Pg! MH! _X,6(! '`! k'IJl(! ;>%# %'# $%$&#24#7-,.#5<,-:! .2! ->%!

-05#/2%00%$! 7%<</! C5/! ,#! +50-! 7.00%<5-%$! C,->!%'# $%()&! +5053%-%0/! .2! ->%! ;"n! 74<-40%/! /47>! 5/! />.0-!

74<-40%!+%0,.$/!5#$!25/-!$.49<,#6!05-%/Y!5/!C%<<!5/!>,6>!7:-.<:-,7!57-,1,-:!565,#/-!54-.<.6.4/!-43.0(!;>%!

,#$47%$! +50-,5<! 0%/+.#/%/Y! >.C%1%0Y! C%0%! .#<:! />.0-A-%03! _3%$,5#! F! 3.#->/`Y! C>%0%5/! 7.3+<%-%!

0%/+.#/%/!<5/-%$!2.0!?=!3.#->!.0!<.#6%0(!L%1%05<!<,#%/!.2!%1,$%#7%!,#$,75-%$!->5-!+..0!%#6052-3%#-!5#$!

+%0/,/-%#7%! .2! -05#/2%00%$! 7%<</! C%0%! 0%/+.#/,9<%! 2.0! ->%! <,3,-%$! ->%05+%4-,7! /477%//! ,#! ->%! ,#,-,5<!

/-4$,%/Y!C>./%!0%/4<-/!50%!,#!->%!/53%!05#6%!C,->!->./%!.2!+0%/%#-!"nA?!->%05+:!C,->.4-!O;;!_X,6(!'`(!

Referenzen

ÄHNLICHE DOKUMENTE

The relative RNA expression levels were calculated by qPCR method by applying the 2 -ΔΔCT method using actin as reference gene.. The y axis denotes the

In the results section, I characterized stimulation methods to induce transient or sustained TCR-mediated signaling, investigated the activation dynamics of key

In part 3.2 of my thesis, I showed that antibody stimulation induced the degradation of proximal signaling molecules (ζ chain, Lck, and ZAP-70), a transient activation of

Ein Unterschied durch verschiedene Zelltypen kann an dieser Stelle ausgeschlossen werden, da sowohl die in dieser Arbeit erzeugten Zell- pools, als auch die beschriebenen Zellen auf

T cell antigen receptor engagement and specificity in the recognition of stress-inducible MHC class I-related chains by human epithelial gamma delta T cells. Gamma delta

70
 trans‐phosphorylation
 propagates
 Y493
 phosphorylation
 among
 all
 ZAP‐70
 molecules
 in
 the
 synapse.
 In
 contrast,
 tyrosine
 phosphorylation


To clarify if the WT version of HSV-1 escapes or is able to trigger innate responses comparable or different to HSV-1 ∆ UL41, we challenged WT and cGAS KO YAC-1 T- cells with the

Ebenso zeigten die reifen T-ALL-Zelllinien beider TCR-Reihen die Expression des pTα Proteins (s. Postselektionell, so von Ramiro et al. postuliert, führt eine