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84)!+0 )<+C )" + C!<! GL( U 18

)O 12?N.+ 635! 8! :955! 45944! 84< 84488 &> 5! 8! 8! :5=4594 0 ( * & IE.J 5! 8! 8! :5<8498485!!<!!1)" GG+ /J 5! 8! 8! :52622:! * 8J 84<886<65:929?=<8 "! 19

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)C.PP.+ & C;. );. +7 C 24 )&C24 + -(4 & - -$I2 ". L C & ( B )( +7 ;7 C7 & 7 (0! U!0!(% 6 &C24 -(4 & )0.PP.+& 21

7 ).PP2+! )A: T A.PPP+ 6. 3 5: 854<58 <54488 5! 98=8 5:8558 % => & )&C2F+ -( & " 0!!)+ & 3 88 898 88 898 & - D * 7 ( 77 O O = > C <4 )<(+)$ 2??.U O T *.PP.+& )9+ 7 7!0! 22

& 7 6 )9+! (G42 *! (0! 4 ) " + & <( (0! 7 9,0 & (G42 47=> 7 1 23

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R F,; & 4 7 *("( (%! 7 & 25

&. 3 98 48! 4 88 898 <8: & 7 D 3 C D & 7 )@+! D %3 89<54584<=8 26

8 &(.( /( 8( 9( ) +! 6! 689?! 9 ; )4+ )* " $+ &)(S I&+ &)* (S+ &) + $*! 6! 8! 9 * )+ * ( " $* (S I&!* 7 & *(" R*! D G ( )2??N+ * 27

295 < *; C$ % 0 A ).PP.+ =- >X(..92.?492/F *!!1 C <1 $; ).PP2+ =(.H@ : :>X(.2@28/4@29. ACA0 0 0 )2??2+=(:>! $(28.2?489$B AC0 1!<$)2??9+=Q%(% >X(:@82@8.42@9? AC).PP8+=*4>($(99F949@9 AC<!&)2???+=" :>&O 0 1$);+-E 1; "C/P?4/.? C$& 0 O $).PP8+=0 1: Q:>(2./8/49. A S! X; C $)2?@@+ = : : :E>*2?@2N/42NF A*0 :).PP2+=-:>($.N/4?2 A:$O AC).PPP+=-µδ >X(.P2.8?42.9? C<<*"!0 0 0 ")2?N@+=(E 4141:><8P. 2NN42?. CSA1<$O ).PP.+=* : :1:E:>X:9/...?4./? 0!<S1-C)2??.+=A: :* 1 : :E: >*.9@2.@F42.@? 0!< S1-C)2??. + =! 4 4: >X!;E-.F/2/F428F 0!< S1-C)2??/+ =: 1 *-4?2 9P8NNA C4&! : (*!& >!:@?.@P4.N2 0 :XC 1X")2?@8+= : :><$FN@/4?/ 0 "1G)2??8+ =(4: > 9? /?48/ 0 *- )2??/+=(EE)(% +> 9.U2.@42/F 0 12?9N 0 1:A<1()2??8+="": >. *&!* 0 :$!" X()2?N2+=0:: B >*.2/29.@429.? 28

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

* +,- 3 5! 4=72< 4 C( 7 <( (-/ ) /+ (-839 (-FU & * R R )!2?FN+ & D =C- >)C-+ <R )!2??/!2??@*1.PP2+ 7 G% )G1 434+ ( & )L34+ ( )-1! + )- 8+ ; 4 G% ( - 1! & 30

7 (4 & 4 7 *(" *( 6/ @1! 9 2 2 *(. A@1! 9 & /8 C- 9F@ ; N? *( 2P22.@1! 9 " G&(C& 2. 2/ $ 28 *( 29 &"GX(2@@.NN4@.?F)2??@+"B :"" @F2PP242P2.)2??8+/ C:O ;(!**!?F29./?429.88)2???+/$0 0 ; 292@8N42@9@).PP2+$G0 (!**!?.NN9F4NNFP)2??9+)* (2F22/@42289)2??F+%<!X(..2PP@.42PP@@).PP.+B ;E( 2@P 2.242.N).PP2+ 0" (( 2 8.48F)2??N+&( ;(/FN28@429P)2??8+&&<C2..2?F942?@/)2??F+ &;;;E(289?/42P/)2??@+&.0 ((28.2P4.2/ )2??F+&/!10 (2F.N@4.?9)2??F+&$;"@@9P/492.)2??8+ (*( -1 *(" 6 ( ( *(" & ( D 31

( )*B 2?N@+& *(" )0 :2?NF+ ( 4 )"!-+ )!+ ( 4)X 2??P S 2??2+ C( R % *-1!)A 2??/-2??@+( )*1.PP2+& ( * ; B 1 4 7 C(7 * C ( 7-(6 ( 3 &C 2 -(( 32

) 4 4+ ( 3 R ( )C.PP8*.PPP) 598:4; ( 2?8P $ C 0 I1 A & CC 0 A & / 2@ C A $C0 C & C 0 A D * (2?8@0D 6 ; 2NP)*2NP+ & *2NP 0 ; &0 $ & 0 "2?98DD 4 ( (2?9? ( ( ( 7 2?FP *(" ( 33

B 4 % -1 @9 % 7 )".PP/+ X(G[ X4(4 1U 0!G[0 4 1U &/G[: /4 1UC"4γ="4γ 3 98 484 <882 C :4 1 )-1+ : 1 @9 )-(+ % 7-1 @9( :1!)-1!+U<((-8 : 1 < )-1<+U (-/ :1" )- 1" + )N+&@94-1 7-1 " )2??9.PP2+ -1! @9 ( ; 4-1!4@9-1! -1 @9 )?+ " ( D *("! ) *("+! E(7 34

6 R ( & 41 C ( 7-1! * ( C -1! 7 ( @9 ; E ( 7-1! @97! -1! 7-1!)".PPP+6 @9 ( & ( 0,* )".PP/+ &-1 ;$G &/GC"4γ @9X(G (41< 35

( 7 & @9-1! 7 7 C ( 7 4 4 6 3 <<4 98 = 89< &- 1 E = 41>)- 1!48-1!49+ )2P+ * -1 41 ) 2??N+! )C$0 + )O 2??9+ " C$0 &(3 <<498 & -G E = 41> )& 4839+ :4 1 "S*[ :4 C$0[ 4 36

-1! (-/( )0 T 0 12??F+ C -G ; 2P -1 C )1+ $3;1) E+)?+ 4/4% A)&/G+ )C" 4γ+ )" 2???+ C $ $ " 8. )GQT A2???+. 98:%$ & @9 7 8 ;(- -1 (- ; @9-17!$).PP2+"% ( 22.@.4.NP 37

3 488 C(7 7 0 ( 7 ; 3 )0 0 T <2???+C ( 7+ + + * D & ( D & (D ( /P (7 )CB2??/+&7 ( ):2??8+& ( ( -1! -1! ( & ) 94A- + )C2??8+-1!&7( 7 )<2?N.0 1 2?NF <1 2?N@+ 7 ( ( ( "$ 38

)2?N2%2?N8I2??9+ C ( I& )"" G+ (S & 7 ( 4$(!<( -1!$)!2??F 02??@+; 7( ( )I$2+)- 2??N+ I$2 ( 3 8=8! 84 =5 48! 9? C ( 7 C( 7 ( 7 & ( ) 2??. O 2??8+&C42 )*4 2??9+ ) 2??9+-(4 )O 2??@+ ( * 7 ( ) + 7 4-1!4& )002??9+& 39

( ( C ( )0.PP/+ - -1! ( )< 2?N. 0 1 2?NF <1 2?N@+; ( 7 4 6 (!( ) + ) + ) 4 + - )+)$T < : 2???+ 6 ( B 1 4 4 7 )!$%%(&0;(-%8+ * ( 7 7 * O 7 ( *B )A 2?N@+&$)2??9+ ( - 40

)""& +" 9@<C3% B " 9@<C3X => " 9@<C = & ( & ( ( 4 )+ ) + D ; ( ) 2???+ 4( $ )$ T < : 2???U $ 2???*.PP.+ ""& / 5!!! <8 < 54 55< < ; 7 *4 &7 7 ( 0 (! ( U )-(&C42+ 4 ( 7 ; 0 -< - ( 41

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

0 CC -*).PP/+=(B :: B E4142 :14N ( :>";E$*4% U.2)9+F2@4.8 0 1(O 1 ;% )2?NF+=( B >;<*2?N/294/.P 0 X&* 0 1)2??F+ = E -1! :>0 "(@/@24/?P 0 0 *<<CA&E 12P942.N)AC2???+ 0 0 *<<C:XI)2??9+=- B : :1!4& >(0 2@@84@NP 0 X!*(1!)2??@+=(B 4 : -1!4E B >X(2@N8@F4N8?P 0 : O " $1B1 XC -1 & )2?NF+ =( B :: ><$X/N@)2+9/4F. % <X< X)2?N8+=(B E1> ;Q:2PF2??4.P2 ;4: <!A0 )2???+=& B 4:>X"(Q2?U82P)2+@/4N? :< " $!<-)2??8+=-:: ( : Q>!(:/F.884.8F $0*T < :0!)2???+=!:B E : :4>;X(22)/+ N/@4N8F $0* 10 )2??9+=* B Q:B ( Q>*(!.2N?@ $C*"*--C0 )2???+=;( 4( B Q:>@?.F94.@8 *4 < *!! )2??9+ =" 142 4 B : :> < X:2292.F942.@9 ** C G( $ ).PPP+ Y* :4:4 E : B > C * ( 2@UF@).F+/28/49. *B X<)2?N@+=(B 4 ><$% 2/U8./)24.+/P?42@ *1*).PP2+ =( B 1 4 > 0 (!4U.8)24/+2N/4??$B *0! (*).PP.+= E >;X( 29)N+2/.@42/8. -*S-0 S0 SG)2??@+=;E-1!:1 A0"42><*2?P)9+2NP@4.P -0 "0 X0!<)2??N+=- 4>(.29/2498/ $-%"C)2??N+A -1!( -1"(-/ 41-1X<".@/9N.?4 9N8P 43

II0 $0 O 4AZA1-)2??9+=B E : >X(29.PN24.P?F O X0 )2??9+=* 4-1! -1<>;<*/@82.942.? O "X!! *4 < )2??@+ =":1 B :: ><X2.282@4 8.8 O "X*4 <0 6 )2??8+=(B ::::>(F./.@4//2 S A Z S S")2??2+ =; B :><$X.299.)2+29?4F/. 44

. C ( 3-1! & ( 7.3 2&& &. 98: 88 8! :558 1 C22 0(!" 2/ )! + -1!4( ;! )".PP2.PP8.PP9+ C22 )"2?NN+ )4(+7 ( 7 ; ( -1! ( (-/& ( 22 7 )02??N"2???".PPP$.PPP.PP/+ C0(!"2/ )"2???+)4-1!+ -1! ( ; - 1! ( )" 2???.PPP+ C ( 0(!" 2/ 45

E -1! C0(!" 2/ 7-1< -1" 6 R ( @9! 0(!" 2/ -1! 4( 4-1! 4-1!7.38CD<58E!! 22 0(!" 2/ D 4( 3-1! ) + ; 4 ( 3-1! 3" 7D7 7 &4-1!7 4( 5 & D ( &- 1! ( D ( = > ( 7 46

) + - 1! &4B4 7 0(!" 2/7! 0(!" 2/22 @93( & D 22 ( D => ( - 1!! 7. 84! :8 <484 88. &3 548! : 882!! 88) T 2?@@+ & 7 4 I.P µ )9] + )/@] + C7 E - 1 ) + E ) + B 4Q1 ) +& 47

7 18P& *(" 1 C!δ" )$2?N@+ C 4 24. C 7 )A: 2??P+U U 7 )! 2??8+*D )" 2?N@+ )$ 2??2+ )O 4!T " B 2??2+ " 22 )" 2?N?+ 6 )G 2?N?+ )1 T * 2?N@+ ; 7 )" 2??P+ 6 7 4 48

)94.P + 200 Test della Formalina 160 Licking (sec) 120 80 40 0 0-5 MIN 5-10 MIN 10-15 MIN 15-20 MIN 20-25 MIN 25-30 MIN 30-35 MIN 35-40 MIN 22,! 1 )T " 2??/U" 2??P+" D. 3 848485 8 894 =8 998, -4< 84 <8:)<T H2?NN+ & 7 C 4 HS12P 49

C 7 4 C D 7 & <HR 8 D & C < / ).+ 6 ) * 2???+ : )<+ & C 7 ) + C 3 C 2P )2.+ 50

CCI (Costrizione del Nervo Sciatico) Forza (grammi). 14,00 12,00 10,00 8,00 6,00 4,00 2,00 0,00 media ipsi media contr baseline giorno7 giorno14 giorno28 giorno42 giorno64 giorno94 2.,- + ; ; "","!!! &0B.- 51

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

53 $ (XO A: " X! )2?N@+ =! : > )*8+*.99 $(XO * A4 *$)2?N@ +^% 1Q>(C@F2P@4222 O 4!A"B!)2??2+=* B >::2P8/9488

/3 & 1 & /&3894< :! " 2 )" $ C " &:+ /948P * E )..L2K" + )FP] +3 2.! -?PP28PP C =" $;&&!*>)!&(_ 2?N/2F2P?422P+ )C22F3?. " ; NF3FP?3;;" + & 7 * + 4( 22)" 2?NN+ )0 +) + ".PP8U+4-1!0(!" 2/)" 2???+ )0 + ) + ".PP2U +& )& *& 0!+0 - & & 54

& + )+ & 0(!" 2/0 FPµ3.Pµ220 2.9µ3.Pµ 2N U + 30(!"2/0,9µg, 1,875µg, 3,75µg, 7,5µg, 15µg, 30µg, 60µg /20µl 220 2.9µ3.Pµ2.9µ3.Pµ 2N ; + 0(!" 2/ )+ 15µg/ 2N U + 7 0(!" 2/& 2µ3.Pµ2N)" ; +24.9,93129 & % /P E)/PE2.E2/+!! 4A).F4+ )9].Pµ+ 1) + ) + : ) + 0 7-8P 9 55

& )P429+)2948P+C!(% I! 6 4C* /3 5< 2&& &. 2. 9 1 29 & 2 2N C & )..8 P/?N[PF@FPU..8 P9P/[PF22PU22N +! )../ P9.2[PFPP?U../ 28FN[P.92/U + &3 4! 8,(/(! -498! :8! 849<::4988858!! 559 9858=988, 86-&?-8&B?A-:! 4; 845428! <::8 E98! :8584F0! 59<58<::84! 985&B?48=FB5< 8<4=5<::5 9?65889828698G<8<! 5 56

6 0-1!3( 1 C 2/! 2& 0(!"2/0 0(!"2/ (60µg/20µl), alfad11 Mab o alfad11 Fab (12,5µg/20µl). L analisi della varianza metteva in evidenza come non ci fossero differenze significative tra gli animali somministrati con anticorpi Mab e gli animali IgG durante la prima )..N 2.2@[P/228+ e la seconda fase )..N 2/?/ [P.F9P+! 4-1!3( 2 )2/<+ )..F N/8PMPP2+( 7)..F 2FPN[P.2?9+ &. 3 22 4 58!! 5 8 4 28! 5< 98! :8! 8 4 9 98 58!! 5 8594-2&&6(12,5µg/20µl) ed anti-trka MNAC13 Mab (60µg/20µl) 1h prima dell inizio del test, B) 2&& 6 (12,5µg/20µl) ed anti-trka MNAC13 Fab (60µg/20µl) 1h prima dell inizio del test. Un effetto analgesico significatico è osservato esclusivamente nella seconda fase con il trattamento di anticorpi Fab.,-,F&&- α&&,f&(- &.,F&(-4,A-6,F0-α&&6,F&(-&.6,F&(-. HI(($HHI((&=5?5:9=9888<:,5?;5-6 2N 28 & & )..8 2..F[P/22.+ 4(0 4-1! 0 1 57

0(!"2/ 0 (F 2,24 : 5,129 P<0,01) )28!+ C 2N )28<+ 1)../ P8FN[PF/2N+ )../ PP@8[P?.?/+. &/ 22 4 58!! 5 8 4 28! 5< 98! :8! 8 4 9 98 58!! 5 8594-2&&6(12,5µg/20µl) ed anti-trka MNAC13 Mab (60µg/20µl) 18h prima dell inizio del test, B) 2&& 6 (12,5µg/20µl) ed anti-trka MNAC13 Fab (60µg/20µl) 18h prima dell inizio del test. Un effetto analgesico significatico è osservato esclusivamente nella seconda fase con somministrazione dell anti-trka MNAC13 Mab.,-,F&(- α&&,fb-&.,f0-4,a-6,f&(-α&&6,fb-&.6,fb-. HI(($HHI((&=5?5:9=9888<:,5?;5 - L acitivity ed il grooming osservati per 40 min, durante il test della formalina, non venivano modificati dal trattamento farmacologico come mostrato nella Tab.5. Questi risultati dimostravano che il decremento di licking è ascrivibile esclusivamente al potere analgesico degli anticorpi e non ad effetti delle molecole sul comportamento generale dell animale. 58

6$3 4,@ -4! :8,59-:5584;! 4<5428!,(/(! - 98! :8! 49=J88! 984=5! 58!! 5 C &$ 3 0(!" 2/ 0 2N " 1 ) @@2 82/8 MPPP2+ (0,9µg/20µl), & C 15µg/20µl 60µg/20µl. ;15µg/20µl )MPP9+ &$3 <48448515:854 &.859&B?:! 4 5428! 22 855=5<:! 59842545 MNAC13 mab (0,9µg n=8; 1,875µg n=10; 3,75µg n=10; 7,5µg n=10; 15µg n=10; 30µg n=10; 60µg/20 µl n=9) * P<0.05, ** P<0.01,*** P<0.001 vs IgG (n=12) sc-injected mice (Fisher s PLSD). 59

C&) 22 )2.9µ3.Pµ 2.9µ3.Pµ+ " )../ 2F/@ [P.2F/+)../ 2F?@[P.P9/+6 2P 7 &) 3 <48 4 48515:85 4 2&& 58!! 58 59&B?:! 4; 8 4 5 4 28! 224<:! 59842545 F&(K α&&&$µfbkα&&&$µfb. " +,:- &.,59- " &% 0(!" 2/2N 15µg/topo, scelta in base ai risultati ottenuti con il dose/risposta (minima dose con massimo effetto), era in grado di generare un significativo decremento del licking sia nella prima fase) 22F 9/9/MPP9+) 22F 2@P9@ MPPP2+ 0(!"2/ ) 22@ 9?.. MPP9 22@?NFP MPPP9+ & 0(!" 2/ ( 3-1! R 7 60

&%3 8!! 5 859,15µg/20µl) vs somministrazioni ip (15µg/topo) 4 &.89<8&B? :! 4; 8del test della formalina. F0 &.F&(K F0 &.F0 HFI(($ HHFI((($ &. C&B 0(!" 2/ 2N )2µ3.Pµ+ )231+ 29 & )0(!" 2/ 2µ3.PµL0 231+ )&0(!"2/2µ3.PµL&2µ3.PµL02 31+) 98.?PF?MPPPP2+) 98. 2222/ MPPPP2+ D )& [PPP.?U && [PPPP.+.93129)[PP99.+ )[PPP29+ )9 31+)& MPPPP2&& MPPPP2+ D )[PP222+ 61

&B 3 8 59 4 &.! 82 488 2!! 88 8!! 5 8 4;98:8 &.8 59&B?:! 4; 845428! 4854 2µ3.Pµ)2.9931+29 & L*[N0(!"2/L[?& L0 2[?& L0.9[@& L0 9[F0(!"2/L0 2[? `[MPPP9``[MPPPP9```[MPPPP2 62

/.3 59<558 6 ( 3-1! 7-1!!7 7 220(!" 2/5C RC (-1! C ( 7 $ ( ) 2??.U O 2??8+! D ( ( 7 0(!" 2/ 22! 0(!"2/ 0 7 7 " 4 4-1!!7 7 * 7 0 I2N 0(!"2/0 6 7 )0 + 7 63

)O.PPP+ C 0 C 7 2 D 7 4 " 2N 0(!"2/ 0 6 7 0 7 ; 7 )+ )+ 29µ0(!"2/0 7 & ) :+ 4-1! 4-1! 7 0(!" 2/ 7 & 64

D - ; 0(!" 2/! 0(!"2/.931 6 7 *7-1! =1> )GTIZB.PP/+( 0 B ).PP8+ $ ( - 1!&7 ( )!.PP.+C ( & D -1! 65

!$C &*$).PP.+Y; B EB >:(UFF)/+2F?4@. "!$<")2?NN+=-: 4 B B >X(9P2PP/42P2P "!"* 0 ; )2???+ = 1 : 1! :4 :>X(2??FN@4?@?@ " *"!C ).PP2+=: :H4:: 0(!"2/ 4: 1! :>!":<":9@2/P@42/P? X*$*")2??.+ =& 4:: B >(8?F?/4F?N GGZB 0 ).PP/+=(4 : B ::>X(0 29./)F+.P@9,.PN9 0 B -*).PP8+ =;E B 4 4 <.L:>(2.9)8+2P.?4/@ O <B 0*O <(A0 ).PPP+=-& )$+ 1:$&$&& :$!>X&2F89/2/49/2N O "X*4 <0 6 )2??8+=(B ::::>(F./.@4//2 66

$3 ""&. 2&& $&3894< :! " 2 )" $ C " &:+ /948P * E )..L2K" + )FP] +3 2.! -?PP28PP C =" $;&&!*>)!&(_ 2?N/2F2P?422P+ )C22F3?. " ; NF3FP?3;;" + & 7 * + 4( 22)" 2?NN+ )0 + ".PP8U + 4-1!0(!" 2/)" 2???+ )0 +".PP2U+ & )& *&0!+ 0 & -!+8 /89F 0 220(!" 2/9P3 - <+ N / 8 9 F@ N? 2P 0 0(!" 2//P@P322@P3 67

" L + C <)<T H2?NN+ )8PP 31+ " / ) F3P+ 2 & & 6 ) * 2???+ : )<+ & C 7 ) + C 3 ) +% 2P (!+ /28 <+ /2 4 68

7!(% I! 6 4 C* $3 5< A-32&&&. &! 0(!" 2/22 9Pµ3 2? ).2?.2F?8U MPPPP2+ ) F2? 92N2U MPPPP2+ ) 2N2? /P9UMPPPP2+ &03! 85<69898,/:-488.88)4&.42&&4854 $(µ18:8 F%K2&&F&(K &.F$ & 0(!"2/22*)2?+89F 69

0(!" 2/ 22 6 0(!" 2/ 4-1! < AA- "&. & < N 0(!"2/ /P @Pµ3 (.P 0(!" 2//Pµ3)/4F 22@ 2P?. [ P/PP.+ @ ) 22@ 98288MPPPP2+ C 0(!" 2/)@P µ3+ )8+ ) 2.2 N@9@.MPPPP2+ (3! 85<69898A-B58!! 5 8:,.&(-4&..(%(µ18:8! 98<4=85998 F&& &..(FB &.%(F& &2?/2)..N 9P82F MPPPP2+ 4-1!! 70

)2.+ & )..N.8PP MPPPP2+ ) 29.N 2F2/FMPPPP2+ ) /P.N 8N89MPPPP2+ $.3 59<558 & ( 3-1! * ( 7 & 4-1!) + ( ; C )+! $ 4B 4. ( * ( 3-1! & * 7 4( 3-1! 71

! C (0!!0!!<! 7 *(" ( U 7 6 D 7 ) + 8 N! 7 * 0(!" 2/7 2@K D 7 ". ( 7 => & 7 R 72

C C0(!" 2/ -1!! =0 ( 7 D 5> 0(!" 2/ * ).P+ D 2?* ( => -1! 0(!" 2/ 76 C ).PP/+ (! 4-1!3( " 0(!" 2/322 73

295 "!$<")2?NN+=-: 4 B B >X(9P2PP/42P2P "!"* 0 ; )2???+ = 1 : 1! :4 :>X(2??FN@4?@?@ " *"!C ).PP2+=: :H4:: 0(!"2/ 4: 1! :>!":<":9@2/P@42/P? C!" S I0 CB X</ ).PP/+ Y" B >((U2N8)2+.?94/P/ 74

)3 & 4( 224-1!0(!" 2/A -1! ( & &R 0(!" 2/ 22 0(!" 2/ 2N7 0(!" 2/7 0(!" 2/ 22 0(!" 2/! D D 7 * 3 ( 3U C => 7 7 % 75

D 5C & C C ; 4( 3-1! & 76