The State of the World’s Antibiotics in

2018

Ella Pringle LectureRoyal College of Physicians of Edinburgh

Ramanan LaxminarayanTwitter @CDDEP

!"# $%&'#%()*)+,-.(#*)#%*)*-'#/0%12/*2(#,-2#+3%(,+(-)#',*-)#4,2(#*-#%(2&.*-'#+3(#5&%2(-#06#*-6(.+*0&)#2*)(,)()

!"#$%#&'"#($))$*+,"#"'#-./0#-$*1'20%#10%$%".&"#"'#30&$*$,,$&#$&#"40#,.2'1."'15#25#063'%$&7#"40-#"'#*'&*0&"1."$'&%#&'"#%+))$*$0&"#"'#/$,,#"40-8#.&(#"40#%.-0#"4$&7#4.%#'**.%$'&.,,5#4.330&0(#$&#"40#2'(59

!"#$%&'#()*"#+,&-.)/012

!"#$%&'()*'&+,-()./00

!"#$%&'()$*+$,-*./%(+$0%(1$2('1((+$3444$&+/$3453

670&+$('$&.8$#9:8$345;

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

"#$%&'()#%&*+,-#%&.,-%,%/%0.0#,)#'#*',11'0.2'-*33*)1450%6',)#.3.-&*+.,1',7%)#0'.)'8,1,9.

850.-$, %#',1:'.(/#%012/3 4'" ;<=>Trends in antimicrobial resistance in bloodstream infection isolates at a large urban hospital in Malawi

!"#$%&#$'()*+,-+.$"/+"* 0#12(3456

Northern Regions

Free State

Western and Northern Cape

Eastern Cape

KwaZulu-Natal

Northern Regions

Free State

Western and Northern Cape

Eastern Cape

KwaZulu-Natal

2011 2012

2013 2014

Resistance rate

No data

Northern Regions

Free State

Western and Northern Cape

Eastern Cape

KwaZulu-Natal

Northern Regions

Free State

Western and Northern Cape

Eastern Cape

KwaZulu-Natal

15-25% 26-32% 33-36% 37-40% 41-43%

!"#$%&'()())*+,#*-.*+,!"#$#%&'(")%*)*+&($,,$')-./0123

!""#$"%&'()&(*+(,,!-(./012(34

!""#$"%&'()&(*+(,,!-(./012(34

!"#$%&'(&$)&!"#$%"&'( )*+",-.*&+,-./

!"#$%#$&'#"()*)+,-$).#$/"&01#2$&3$"#(+()*,4#$0#4*5(#$&3$2#*(5"#2#,)$0+*(6

!"#$%"&"# '()*+,-./

!"#$%&'()*("+,-"%(./01231#1'%(%+45#%'(,6%+3,*,%6(',+2%(,+3&)6"23,)+()*(*,&'3(./01231#(1+3,$,)3,2'(

!"#$%&'"()'!"#$%&*'+$,-./$.01'+.01'2$.01'3%#1'45651

!"#$%&'$()"*$+",-.)%#-)/"#.-)'0)0-"0%$-.)/'$1)#-.'.$%0$)'02-+$'"0.

!"#"$%& '()!"*+%,-." /()'0,1"*.23#" 45()6&7&*,".)8()'-."$" 8/9):;<;9)=7&>,?@27-)2A)B2-,@,C&)D322>)?+3@+7&)"$>)>&"@.-)"*2$%)$&2$"@&-)0 ,@.)-+-B&?@&>)$&2$"@"3)-&B-,-),$)")@&7@,"7#).2-B,@"3()'0"$1"E F"$1"$,"9)G'H)=&>,"@7,?-)<;I)JK9

<LK

MN

JOK

<M<

K<

MM

:J

;

<;

:;

J;

L;

M;

O;

H+3@ +7 & P7 "*) Q&"?@ , 2$ /8G5 'Q8R

!"#$%&'()

*#+#,"$"+

=2- ,@ ,C&

S&%"@ ,C&

!"#$% %&'()*+,-./"&+$!*+0123

!"#$%&"'"("&)*+)",)!"&-*+.)/012

Absolute risk reduction (ARR) of infection with antibiotic prophylaxis in common surgical procedures and blood cancer chemotherapy in the

USA

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

Number of additional infections per year in the USA under a 30% decreased efficacy of antibiotic prophylaxis

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

!"#$%&'()*%+,)%-.,&+%/-*

! !"#$#%&$#%'(%)*++*,-%./$0#$*#.%*-%+,12*-3,)#%3,/-4$*#.%#&3"%5#&$! 676%)*++*,-%./$0*3&+%.*4#%*-8#34*,-.%,$%99:.%;<%=#$%>??%=$,3#@/$#.A%B&C,/4%&%4"*$@%,8%&++%"#&+4"3&$#%&..,3*&4#@%*-8#34*,-.! 99:.%&$#%4"#%+#&@*-0%3&/.#%,8%*-8#34*,-%*-%.#44*-0.%1*4"%+*)*4#@%$#.,/$3#.! D,$4&+*45%$&4#%8$,)%99:%E&4#.%,8%),$4&+*45%8$,)%./$0*3&+%.*4#%*-8#34*,-.%&$#%FG%*-%4"#%H9%&-@%C#41##-%I%&-@%(?G%*-%+,12*-3,)#%3,/-4$*#.! J#41##-%K??L???%&-@%&%)*++*,-%@#&4".%8$,)%99:.%#&3"%5#&$%1*4"%&-%*-3$#&.*-0%-/)C#$%3&/.#@%C5%$#.*.4&-4%=&4",0#-.7%

!"#$" %&'"()'*+,$-.+-(-/0'123&$"(+")'4-5'6789

!!" #$%$&'($&)*+,%(-&.($&)/,-%$&'(-)),%%(0*(-&0$1$*0$)%(-/,(%-2$&'(3$2,%(4-305*6'5(3-)7(*8(-)),%%(%0$33(7$33%(+*/,(9,*93,(05-&(-&0$1$*0$)(/,%$%0-&),:(160(-/,(&*0(-('**.(%61%0$060,(8*/(9613$)(5,-305

!"#$%&'"()*'+%"+%+)"&%)+$'((),"-.&)/'((%&+)'0)*%1%(.2'03)#.40$&'%+)5%#"4+%).6)("#/).6)"##%++)$.)"0$'5'.$'#+

!"#$%&'(&)(*+,(-*'.&)(/001

!"#$%#&'%('%#)*+,-%./%#,$+0+.$+1)2

!"#$%&%"%'()*+(&,,"-&./%&*-0(&-)'1%&*-(1*-%+*2(/-3(4/%'+5$/-&%/%&*-

South Asia

!"#$%&%"%'()*+(&,,"-&./%&*-0(&-)'1%&*-(1*-%+*2(/-3(4/%'+5$/-&%/%&*-

Sub-Saharan Africa

!"#$ %&'()'#*+','-./* 0'%(1'233456789:877;:846+

!"##$%&'(#"%()&(&**&#+$,&-%,"'$,&(.$'&"'&(#"/'&.()0(1%&/23#3##$($%(#4$5.6&%(/%.&6(+73(.&#5$%&.($%(+4&(89(:3'+(:%&/23,"##$%"+$3%

!""#$%&'"&()*+&,-%.'/0$%,'-&,-&1222&'-&3-%,4,'%,$&5.#6$.,5%,'-6&3-/&374083%'.9&$3.#&:,6,%6

!"#$%&'%()*%+&,-('.-/0%1223

!""#$%&'"&()*+&,-%.'/0$%,'-&,-&1222&'-&3-%,4,'%,$&5.#6$.,5%,'-6&3-/&374083%'.9&$3.#&:,6,%6

!"#$%&'%()*%+&,-('.-/0%1223

45'-6-#'-/%7.&0/.-7'-#50%(''.-6$'(6)&%'#%(/$'&%#'-'-0%8&,-(%,&/.&(0&,%9.#8%:1;;%'#%<11%7.&0/.-7'-#50%7&.%:222%7&.0#5=>&(.0%? (%;:@AB%.&,$/'-#5@

Antibiotic consumption is increasing in developing countries...

Source: Based on data obtained under license from IMS Health MIDAS ™ (January 2005-December 2010); IMS Health Incorporated. All Rights Reserved.

0

5000

10000

15000

20000

25000

BRAZIL, RETAIL INDIA, RETAIL VIETNAM, RETAIL NORWAY, RETAIL USA, RETAIL

Sta

nda

rd U

nits

pe

r 100

0 p

op

ula

tion

Per capita total antibiotic use, retail sector, 2005-2010

2005

2006

2007

2008

2009

2010

!"#$%"&%'()$)#()*&*#'+,-.()#'&$/&*#,'(0/1&2333423567&

8)") 97&:";)'&;(&%"7&<=>?&@#)153753ABC.'%+75A5A2D6556

!"#$%"&%'()$)#()*&*#'+,-.()#'&$/&*#,'(0/&)'*#-1&*"%++)2)*%()#'3&4555645789&

:)")&;9&<"1)'&1(&%"9&=>?@&A#)375975BCD.'%+97B7B4E8778

!"#$%&'(&)*+,-.*/&01*234(&-5&61,3.137

!"#$%$&#$'('&")*+,#$&"(-.#/(0&-(123)4(5623)7864(."9(5623)756(&0(#:/(0&*-(+&)#7'&")*+/9(#:/-.,/*#$'(';.))/)(&0(."#$%$&#$')($"(<<<)(,/-(=4>>>($":.%$#."#)(,/-(9.?@(

A$;$ B@(C;/$"(/#(.;@(DE!F(9&$G=>@=>HIJ,".)@=H=HKLM==M

!"#$%&'(&)*+,-.*/&01*234(&-5&61,3.137

!"#$%$&#$'('&")*+,#$&"(-.#/(0&-(123)4(5623)7864(."9(5623)756(&0("/:(."9(;.)#7-/)&-#(."#$%$&#$')($"(<<<)(,/-(=4>>>($"?.%$#."#)(,/-(9.@A(

B$;$ CA(D;/$"(/#(.;A(EF!G(9&$H=>A=>IJK,".)A=I=ILMN==N

!"#$%&'(&)*+,-.*/&01*234(&-5&61,3.137

Antibiotic use per capita by income in selected countries, 2010

Source: Van Boeckel et al. 2014 (based on IMS MIDAS) and World Bank 2015

Carbapenem retail sales in selected countries, 2005–2010 (per 1,000 population)

Source: Laxminarayan et al. 2013 (based on IMS MIDAS)

*An IMS grouping of Benin, Burkina Faso, Cameroon, Côte d’Ivoire, Gabon, Guinea, Mali, Republic of the Congo, Senegal, and

Togo

!"#$%&$'())(*+,$-./0$1*2"3"(2"4$4(*.-)52"(*$"*$0"66/7/*2$7/#"(*.$(6$'8"*1$3,$4+1..$"*$9:;;$1*0$9:;<&

!"#$%"&'()*(+,-.(/*(0"-.(12*()-.(3*(3$,(4!(56789:(+'&.;#(-.;(<-==&'.#(%>(-.=,?,%=,@(@%.#"A<=,%.(,.(B$,.-C#(=&'=,-'D($%#<,=-E#F(G-#&;(%.(-(H(D&-'(#"'I&,EE-.@&(J,=$(#-E&#('&@%';#*(6788K678HL(M4N3(NOP(86586:F(&78Q7R8SL($==<#FTT;%,L%'UT87L8R98TV%"'.-EL<%.&L78Q7R8S$==<FTTV%"'.-E#L<E%#L%'UT<E%#%.&T-'=,@E&W,;X87L8R98TV%"'.-EL<%.&L78Q7R8S

!"#$%&'&( )$'*+(%,-$'./"*.-')#&"*&0.12.3456.*-')&.-,.7"*."%%#$8&0.9$#.+*&.-'.:'0-".-'.;<3<

!"#$%" &'(")*(+),# -#. /,0*(1234

Carbapenem consumption in the hospital sector in selected European countries, 1997–2013

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

!"#$%&'()&*%+*"#,-(',".,/#+*0*)&"1*/2(,*(,)"00"#

!"#$%&'()'%*+',%&-()'./+'0122

!"#$%&'()'* '+$"*,$-"#('+$.#/ 012,$3456

!"#$%&'$(#)(*+$,($)$-#.$/0,1#0$*%$)+2,3,*2,4$4*+('562,*+

!"#$%&"'()*")+,&)-"*+&.)/+(+&0)*0)"&(1$2)3&1#&4+$2)31&.*4+&.)52)("+*5*6+*4)0($&0).(+(

!"#$%&&' &()*#)+', -"'( ."/0 1023)4566

Hospital use of carbapenems is rapidly growing

0

10

20

30

40

50

60

70

VIETNAM, HOSPITAL CHINA, HOSPITAL NORWAY, HOSPITAL USA, HOSPITAL

Sta

nda

rd U

nits

per

100

0 p

opul

atio

n

Per capita total carbapenem use, hospital sector, 2005-2010

2005

2006

2007

2008

2009

2010

Source: Based on data obtained under license from IMS Health MIDAS ™ (January 1999-December 2010); IMS Health Incorporated. All Rights Reserved.

!"#$%&'()*+,#)-"'()-,"#*"*'.,"*-,(/()0

!"#$%"&%'%("%$("()*&#+&,#"(-)(.

!"#$%"&'("$()*+(,-./(0123(

!!!"# $%&'(%)#*+#,-.&/&*.&0#1)(#%(2,.(#.*#&-0(-.&'()#,-3#/(4,'&*%#*+#5,.&(-.)6#547)&0&,-)6#54,%8,6#5,7(%)#,-3#4(,2.40,%(#&-).&.1.&*-)"

!"#$"%&'$()*+,)-./(&#&0"(

! !"#$%&'$()*+"#$,(#*,-+,.#"#$/(%

!"#$%&'&()*&+,&-...

!"#$%$&'()*+$,-"($'#."*%"%($'*//.&/.$*+"(/."%#.$0$',

!"#$%&'%(')*+',-.-'/.+'0123

4%*)("5%'(6'(7%'8"&9('76:&'68')'9%99"6#+'(7%')$;:9(%$'6$$9'&)("69'68')#("<"6("='>&%9=&"<"#?'"#'(7%'86:&(7'76:&'@)9'2A0B'CDEF'G/+'2A2HI2A32J

!"#$%&'()*+,-+&%.-#

!!"#$%$&#$'()*+,)*)(-%(#$#-#,).&+)$".,'#$&")'&"#+&/! 0".,'#$&")'&"#+&/)$()&.#,")"&#)'&12,"(*#,3

!"#$%&'()*+,-)%./'01')"2)1"#$3+1%,+"0/4)1"#$3+1%,+"0/)*'&')%//"1+%,'()*+,-)%)!"#$%&' -+5-'&)1"0,&+.6,+"0)#%&5+0)$'&)$%,+'0,)*+,-)$&+7%,')+0/6&%01')89::);:<)7/ 9=>);<>?)%0()%)!&'(#$-+5-'&)1"0,&+.6,+"0)#%&5+0)$'&)$%,+'0,)*+,-)@'(+1%&')89<>A;)7/ 9=BBC?D

! "#$#%&$'#()#$*+$#%&)(,-.$//0$12034$,(#5&6#'$7&)&$(+&8)59&$(6:$%(:$6*);(9$7%5#&$89**:$<&99$<*=6#'>

! ",,)*,)5(#&$<=9#=)&'$7&)&$<*99&<#&:$+)*;$?2/$1@A34$,(#5&6#'.$(6:$/@0$1@B34$7&)&$6&C(#5D&>$

! E-$#%&$@#%$:(-$*+$#%&)(,-.$F/>@3$*+$&;,5)5<(9$(6#5;5<)*85(9'$7&)&$&'<(9(#&:.$/F>@3$7&)&$6())*7&:$*)$:5'<*6#56=&:.$(6:$GG>?3$7&)&$=6<%(6C&:>$

! H())*756C$*)$:5'<*6#56=(#5*6$7('$;*)&$95I&9-$7%&6$<=9#=)&'$7&)&$<*99&<#&:$(#$#%&$'#()#$*+$#%&)(,-$(6:$6*$56+&<#5*6$7('$6*#&:$*6$(6$565#5(9$)(:5*9*C5<(9$'#=:->

!"# $%&'(')&'*+,-.+'%+/%'0/1+-.*&)2+'-+'%*2./-'%3+31)(/114+'%+2.-5)%-.+&)+&6.+&2.0.%7),-+32)8&6+'%+7.0/%7+9)2+/%'0/1+52)&.'%#+

:./%86'1.+/%&'(')&'*+0/%,9/*&,2'%3+'-+.;5.7'&'%3+&6.+/**,0,1/&')%+)9+2.-'-&/%*.+3.%.-+'%+&6.+.%<'2)%0.%&#

!!""##$$%%&&'' (())''**++,,''**((----..//,,''(())''..--**001100((**0022&&''&&((33%%''44(($$33%%4400%%,,''..$$,,''55&&,,%%''00--''..//$$00225533**55$$,,

!"#$%&'()*'+),-.*/'0%'1%&0$'$%&'230%$'04'4".'.)'0%5*"$4"'.6)'.)'4"7"%'()-&'8".6""%'9:::'$%&'9:;:

!"#$%&'((

!"#$%&'(#)*+#,-./0-#1."2345)6."#.7#0--#0")64618./60-2#6"#7..9#0"640-2#:02#+2)640)+9#0)#&'&(&%;#)."2

<8.=+1)+9#).#8+01*#$%%($'>#)."2#/?#$%'%

@0"#A.+1B+- +)#0-(#!"#$%"$ $%&C

!"#$%&'()'* '+$"*,$!"#$%"$ -./0

! !"#$%&'"()*+,#-"(&-(&./-($&0 12344&#"()&-(&24567

! 89444&#"()&":&$(#-;-"#-')&<='><#<?&;@&/*+$(&$(?&$(-+$%)&0 +*'/&":&#/-)&<(#<><?&-(#"&#/<&><'<-A-(B&<(A->"(+<(#&:"%%"C-(B&A$>-"*)&C$)#<C$#<>&#><$#+<(#)&-(#"&8D&>-A<>&;$)-()&":&./-($

E/$(B&<#&$%7&F(A G'- !<'/7&2458&

!"#$%&'('&")*+,-'.)")')"/0+123+'44'*5+60)0&)06+789+-.",-0+405"5)'.&0+#0.05+':;.#+'<<+;=+)$0+='4:+5':(<05>+)$0+);(+?@+A3B5+C0".#+0.4"&$06+79D%=;<6+E:06"'.F+-(+);+DG>HHH%=;<6+E:'I":-:F+&;:('406+J")$+)$0"4+405(0&)"/0+'.)"C";)"&%=400+:'.-40+;4+5;"<+&;.)4;<5K

!"#$%"&%'&()*&!"#$%&"'(")*+,-(*+).,/(%01(2)$#(0*&+,-.

!"#$%&'%()%*+, -./ (+0%12&34%5667

!!""##$$%%&&''%%(())**((&&""++,,--,,))++,,##(($$%%'',,''++&&""##%%((..%%""%%''&&//))""..(('')),,00''((##))0000%%##++%%11((&&++((**,,22%%(('',,++%%''((,,""((3344%%((55%%++44%%$$00&&""11''((**$$))//66778899((++))((::9999;;<<

!"#$$%&'%#(%)"* +,- .&,/0%1232

Antibiotic consumption in livestock, top ten countries 2010–2030 (projected for 2030)

!"#$%&'()'* '+$"*,-$./01-$2345

!"#$%&"'"("&)*+)",-)./01)2*34'+-)5678

!"#$%&'()('*+",$%&'(#-.+/-$+&#.'.+0,"+0"#$%&,$+0(1+(-&%"",$+2*+",3#)(-1+45!.+

!"#$%&"'"("&)*+)",-)./01)2*34'+-)5678

!" #$%&'()'(*%(+,%-(.'/'0.'1$%.2+%-($,+34

MMaakkee bbeetttteerr uussee ooff eexxiissttiinngg aannttiibbiioottiiccss

!"#$%&'()*+%,-&(.&/0)++%*,+(12

FFiinndd nneeww aannttiibbiioottiiccss

!"#$%&'()*+%,-&(.&/0)++%*,+(12

!"##$"%$%&'#($)&*+$,'-.#$&*/'+0#+#$,'-.$/"#(#

!"#$%&'()*+(,"-.%/(,&$01&%2.3&(45567((89812&9(:$";()*+(<"9&-(="$;#-8$/7()*+(>-.?.%8-(@#.9&-.?&0(8?9(<8?8A&;&?2(!%.&?%&0(:"$(*&8-2BC0(455D(E?2&$?82."?8-(F$#A(,$.%&(E?9.%82"$(@#.9&(G0-.9&(%"#$2&0/'(F83.9(*&/;8??H

!"#$%&'"$()*$+&,"$,"#&%$+)--#,./$,"#$(00%$+&,"$,"#&%$-&1#.

Developed world cost per course of therapy

De

ve

lop

ed

wo

rld

De

ve

lop

ing

wo

rld

Supplier

Pfizer

GSK

Ortho-McNeill

Bayer

Roche

Pfizer

Roche

GSK

IDA

Eli Lilly

Oscient

various

Branded product only

Generic product available

Price/full course of therapy

Notes: *Chloramphenicol is not available in developed world—price is therefore estimated. †Ceftriaxone and ciprofloxacin may be available in some tertiary settings in developing world.Source: The Medical Letter (2006), Disease control priorities in developing countries, Lancet (2006), Expert

interviews.

$1,500

$1,480

$666.80

$223.30

$16

$11

$5*

$3.60

$103

$39

$121

$145

$144.8

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

-.'/%#)*)&%&+,

01)(+23%41)(

!21+42%51'()&,

6")&%#%&+,7)&8%,'()*+,

93#%1'(43+&)8%#0+21'8:8#)&+,

;'81%#)*+,<#:8%4+42)*+,

=()&%5#:8%,)*+,>+&)8)##)&,

1930s 1940s 1950s 1960s 1970s 1980s 1990s 2000s

!"#$%&'()*%+*,'-*$./##'#*%+*/,0"1"%0"$#

!!""##$$%%""&&$$''(())''&&$$**''++&&,,""--..""//00((11""++%%''2200334455''4400((**""&&44''++)),,$$00''++''%%((&&44''%%++44!!""##$$%%&&''(())**$$++&&))$$,,''--)),,..$$##//$$00))$$11''2211

!!!"#$%&'()$*++,&##&+$%-$.*,)&$,&/&(0$,&'(1&#02&(0$'($(31&.$2&/4*('#2$+&1&.352&(0$

!!

!"#$"%#&'()&'*"+,",#,-*./,0/10"/,.+-%+(1#2+/&"(&/**'*"+,"/&&"34/*'*"#$"0'5'&#3%',.

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

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

!"#$!"%!!"%%!"%$!"%"!"$&!"$'

!"$(!"$)!"$"!"('!"(*

'&&&'&&#'&&$'&&)

+,-./0123456750383--3069230/:-;8/63456<5=>1-/6=/?306<>-/?12=>5038/-@5A?18;8-3056B18?/-3456 CDE308/6123456 C+A?5=A/:?12306F-;8/=5=A3456G3.12;8306H3A?/323431I/-56J,30/-/056@?325A>/=?32

KL1I/-3430/056E3=/=5=A3456F-;8;-8;8-30567-5,?/2,A3-306

6')('7'/*(0$)*5$'($7',#0$'(0,3+8/0'3($37$(&9$*(0'2 '/,3%'*.$/.*##&#!!!

,$*-)(.#/012#0*3+4#5$#6-*3+7#89:;(#<1<(-4#=91-&1<-$>();+4#?$2&1@#1@2#?(@+9184#51;*-(#?(A:(8+#6-*3#6:+)$A(-B4#0CD#E@1'B+:+

67"8'/1"0'5'&#3%',."9/3

!"#$%&'($'%#)#*+,-#$.'+/'$#0'1$.(2(+.(3&

!"#$%&'($'%#)#*+,-#$.'+/'$#0'1$.(2(+.(3&

!"#$%&#'(#)&*#+)$,-,.$,/0#+112.3&4#-&$*&&)#(567#+)4#87759#8'#:;<=>#*&2&#*,$%42+*)#&,$%&2#-&/+?0&#."#$.@,/,$A#.2#B+/C#."#D+2C&$9#/.D1+2&4#*,$%#+#(<=#*,$%42+*+B#2+$&#".2#.$%&2#$%&2+1&?$,/#/+$&E.2,&0#:!?$$&20.) &$#+B#87(<>

!"#$%&"'"("&)*!"#$%"$)*+,-.

!"#$%&"'"("&)*!"#$%"$)*+,-.

!"#$"%&'$()*+,)"$-)."%&/&+%&#(0).()1,+1+($2)/3)45675)."2)89):.3)$"#+;,.<$)"$-)2,;<)2$'$=+1:$"%)/;%)2+">%)&:1.#%)&"#$"%&'$()*+,);(&"<)2,;<().11,+1,&.%$=3

!"#$%&'()*+%,-&(.&/0)++%*,+(12

!"#$%&'()*+%,-&(.&/0)++%*,+(12

! 3#1+%*4(50#$%,! 6*(74(+41,! 8)(*)"&,%9,49$! /-974(+41,

!!""##$$##%%&&''((""))&&**++,,--..

!"#$%&'()%'*+++,-$$%.,/)0

Thank you