rss rsr ss r - - PowerPoint PPT Presentation
rss rsr ss r tt r t
❇✐♦st❛t✐st✐❝s✱ ❯♥✐✈❡rs✐t② ♦❢ ❈♦♣❡♥❤❛❣❡♥✱ ❉❡♥♠❛r❦
✶ ✴ ✹✺
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✺ ✴ ✹✺
✻ ✴ ✹✺
✼ ✴ ✹✺
s❡① ❛❣❡ t✐♠❡ ❊✈❡♥t ❆❋ st❛t✉s ❢❡♠❛❧❡ ✻✺ ✸ ❉❡❛❞ ◆♦ ✵ ♠❛❧❡ ✽✵ ✹ ❈❡♥s♦r❡❞ ◆♦ ✵ ❢❡♠❛❧❡ ✺✵ ✹ ❈❡♥s♦r❡❞ ◆♦ ✵ ♠❛❧❡ ✺✻ ✻ ❆❋ ❨❡s ✶ ♠❛❧❡ ✾✶ ✼ ❆❋ ❨❡s ✶ ♠❛❧❡ ✻✵ ✼ ❉❡❛❞ ◆♦ ✵ ❢❡♠❛❧❡ ✾✶ ✽ ❉❡❛❞ ◆♦ ✵ ♠❛❧❡ ✽✼ ✾ ❆❋ ❨❡s ✶ ♠❛❧❡ ✺✺ ✶✶ ❆❋ ❨❡s ✶ ♠❛❧❡ ✼✽ ✶✹ ❈❡♥s♦r❡❞ ◆♦ ✵
❇❛s❡❧✐♥❡ t❛❜❧❡❄
❱❛r✐❛❜❧❡ ▲❡✈❡❧ ■♥❝✐❞❡♥t ❆❋ ✭♥❂✹✮ ◆♦♥✲❆❋ ❞❡❛t❤ ✭♥❂✻✮ ❛❣❡ ♠❡❛♥ ✭s❞✮ ✼✷✳✷ ✭✶✾✳✹✮ ✼✵✳✼ ✭✶✺✳✵✮ s❡① ❢❡♠❛❧❡ ✵ ✭✵✳✵✮ ✸ ✭✺✵✳✵✮ ♠❛❧❡ ✹ ✭✶✵✵✳✵✮ ✸ ✭✺✵✳✵✮
✽ ✴ ✹✺
s❡① ❛❣❡ t✐♠❡ ❊✈❡♥t ❆❋ st❛t✉s ❢❡♠❛❧❡ ✻✺ ✸ ❉❡❛❞ ◆♦ ✵ ♠❛❧❡ ✽✵ ✹ ❈❡♥s♦r❡❞ ◆♦ ✵ ❢❡♠❛❧❡ ✺✵ ✹ ❈❡♥s♦r❡❞ ◆♦ ✵ ♠❛❧❡ ✺✻ ✻ ❆❋ ❨❡s ✶ ♠❛❧❡ ✾✶ ✼ ❆❋ ❨❡s ✶ ♠❛❧❡ ✻✵ ✼ ❉❡❛❞ ◆♦ ✵ ❢❡♠❛❧❡ ✾✶ ✽ ❉❡❛❞ ◆♦ ✵ ♠❛❧❡ ✽✼ ✾ ❆❋ ❨❡s ✶ ♠❛❧❡ ✺✺ ✶✶ ❆❋ ❨❡s ✶ ♠❛❧❡ ✼✽ ✶✹ ❈❡♥s♦r❡❞ ◆♦ ✵
❇❛s❡❧✐♥❡ t❛❜❧❡❄
❱❛r✐❛❜❧❡ ▲❡✈❡❧ ■♥❝✐❞❡♥t ❆❋ ✭♥❂✹✮ ◆♦♥✲❆❋ ❞❡❛t❤ ✭♥❂✻✮ ❛❣❡ ♠❡❛♥ ✭s❞✮ ✼✷✳✷ ✭✶✾✳✹✮ ✼✵✳✼ ✭✶✺✳✵✮ s❡① ❢❡♠❛❧❡ ✵ ✭✵✳✵✮ ✸ ✭✺✵✳✵✮ ♠❛❧❡ ✹ ✭✶✵✵✳✵✮ ✸ ✭✺✵✳✵✮
✽ ✴ ✹✺
Calendar time
E O D E O O
Inclusion Statistical evaluation 2000 2005 2010 Study time (years)
E O D E O O
Inclusion 5 10
E D O = Event = Dead = Alive ✾ ✴ ✹✺
❛❢t❡r ✺ ②❡❛rs
❱❛r✐❛❜❧❡ ▲❡✈❡❧ ■♥❝✐❞❡♥t ❆❋ ◆♦♥✲❆❋ ❞❡❛t❤ ✉♥❦♥♦✇♥ ❊✈❡♥t✲❢r❡❡ ♥ ✵ ✶ ✷ ✼ ❛❣❡ ♠❡❛♥ ✭s❞✮ ✕ ✻✺✳✵ ✭✕✮ ✻✺✳✵ ✭✷✶✳✷✮ ✼✹✳✵ ✭✶✻✳✻✮ s❡① ❢❡♠❛❧❡ ✵ ✭✵✳✵✮ ✶ ✭✶✵✵✳✵✮ ✶ ✭✺✵✳✵✮ ✶ ✭✶✹✳✸✮ ♠❛❧❡ ✵ ✭✵✳✵✮ ✵ ✭✵✳✵✮ ✶ ✭✺✵✳✵✮ ✻ ✭✽✺✳✼✮
✶✵ ②❡❛rs
❱❛r✐❛❜❧❡ ▲❡✈❡❧ ■♥❝✐❞❡♥t ❆❋ ◆♦♥✲❆❋ ❞❡❛t❤ ✉♥❦♥♦✇♥ ❊✈❡♥t✲❢r❡❡ ♥ ✸ ✸ ✷ ✷ ❛❣❡ ♠❡❛♥ ✭s❞✮ ✼✽✳✵ ✭✶✾✳✷✮ ✼✷✳✵ ✭✶✻✳✻✮ ✻✺✳✵ ✭✷✶✳✷✮ ✻✻✳✺ ✭✶✻✳✸✮ s❡① ❢❡♠❛❧❡ ✵ ✭✵✳✵✮ ✷ ✭✻✻✳✼✮ ✶ ✭✺✵✳✵✮ ✵ ✭✵✳✵✮ ♠❛❧❡ ✸ ✭✶✵✵✳✵✮ ✶ ✭✸✸✳✸✮ ✶ ✭✺✵✳✵✮ ✷ ✭✶✵✵✳✵✮
✶✵ ✴ ✹✺
◮ ❊✈❡r② ♣❛t✐❡♥t ✇✐❧❧ ❡✐t❤❡r ❞✐❡ ❞✉❡ t♦ ❝❛r❞✐♦✈❛s❝✉❧❛r ❞✐s❡❛s❡ ♦r
◮ ✐♥ ❛ ✶✵ ②❡❛r ♣❡r✐♦❞ t❤r❡❡ t❤✐♥❣s ❝❛♥ ❤❛♣♣❡♥✿
◮ ❝❛r❞✐♦✈❛s❝✉❧❛r ❞✐s❡❛s❡✴♠♦rt❛❧✐t② ◮ ❞❡❛t❤ ✇✐t❤♦✉t ❝❛r❞✐♦✈❛s❝✉❧❛r ❞✐s❡❛s❡ ◮ ❛❧✐✈❡ ❛♥❞ ❢r❡❡ ♦❢ ❝❛r❞✐♦✈❛s❝✉❧❛r ❞✐s❡❛s❡
✶✶ ✴ ✹✺
◮ ❊✈❡r② ♣❛t✐❡♥t ✇✐❧❧ ❡✐t❤❡r ❞✐❡ ❞✉❡ t♦ ❝❛r❞✐♦✈❛s❝✉❧❛r ❞✐s❡❛s❡ ♦r
◮ ✐♥ ❛ ✶✵ ②❡❛r ♣❡r✐♦❞ t❤r❡❡ t❤✐♥❣s ❝❛♥ ❤❛♣♣❡♥✿
◮ ❝❛r❞✐♦✈❛s❝✉❧❛r ❞✐s❡❛s❡✴♠♦rt❛❧✐t② ◮ ❞❡❛t❤ ✇✐t❤♦✉t ❝❛r❞✐♦✈❛s❝✉❧❛r ❞✐s❡❛s❡ ◮ ❛❧✐✈❡ ❛♥❞ ❢r❡❡ ♦❢ ❝❛r❞✐♦✈❛s❝✉❧❛r ❞✐s❡❛s❡
◮ P❛t✐❡♥ts ✇❤♦s❡ st❛t✉s ❛t ✶✵ ②❡❛rs ✐s ✉♥❦♥♦✇♥ ❤❛✈❡ t❤❡ s❛♠❡
✶✶ ✴ ✹✺
◮ ❊✈❡r② ♣❛t✐❡♥t ✇✐❧❧ ❞✐❡ ❞✉❡ t♦ ❝❛r❞✐♦✈❛s❝✉❧❛r ❞✐s❡❛s❡ ◮ ✐♥ ❛ ✶✵ ②❡❛r ♣❡r✐♦❞ t✇♦ t❤✐♥❣s ❝❛♥ ❤❛♣♣❡♥✿
◮ ❝❛r❞✐♦✈❛s❝✉❧❛r ❞✐s❡❛s❡✴♠♦rt❛❧✐t② ◮ ❛❧✐✈❡ ❛♥❞ ❢r❡❡ ♦❢ ❝❛r❞✐♦✈❛s❝✉❧❛r ❞✐s❡❛s❡
◮ P❛t✐❡♥ts ✇❤♦s❡ st❛t✉s ❛t ✶✵ ②❡❛rs ✐s ✉♥❦♥♦✇♥ ❤❛✈❡ t❤❡ s❛♠❡
◮ P❛t✐❡♥t ✇❤♦ ❞✐❡ ✇✐t❤♦✉t ❝❛r❞✐♦✈❛s❝✉❧❛r ❞✐s❡❛s❡ ❤❛✈❡ t❤❡ s❛♠❡
✶✷ ✴ ✹✺
✶✸ ✴ ✹✺
◮ ❈❛s❡✿ ♣❛t✐❡♥t ✇✐t❤ ❝❛r❞✐♦✈❛s❝✉❧❛r ❞✐s❡❛s❡✴♠♦rt❛❧✐t② ❜❡❢♦r❡ ✶✵
◮ ◆♦♥✲❝❛s❡✿ ❡✐t❤❡r ♥♦♥✲❝❛r❞✐♦✈❛s❝✉❧❛r ♠♦rt❛❧✐t② ♦r ❛❧✐✈❡ ❢r❡❡ ♦❢
◮ ❈❛s❡✿ ♣❛t✐❡♥t ✇✐t❤ ❝❛r❞✐♦✈❛s❝✉❧❛r ❞✐s❡❛s❡✴♠♦rt❛❧✐t② ❜❡❢♦r❡ ✶✵
◮ ◆♦♥✲❝❛s❡✿ ❛❧✐✈❡ ❢r❡❡ ♦❢ ❝❛r❞✐♦✈❛s❝✉❧❛r ❞✐s❡❛s❡
✶✸ ✴ ✹✺
Years since inclusion Absolute risk 5 10 0 % 25 % 50 % 75 % 100 % Age 50 60 70 80 90
Cardiovascular disease/mortality
Years since inclusion Absolute risk 5 10 0 % 25 % 50 % 75 % 100 % Age 50 60 70 80 90
Non−cardiovascular mortality Hypothetical world: AUC(10yrs)=83.5 % Real world: AUC(10yrs)=68.9 %
✶✹ ✴ ✹✺
✶✺ ✴ ✹✺
◮ ❆ ❢❛st✲♠♦✈✐♥❣ ♦❜❥❡❝t ❤❛s ❛ ❤✐❣❤ s♣❡❡❞ ❛♥❞ ❝♦✈❡rs ❛ r❡❧❛t✐✈❡❧②
◮ ❆ s❧♦✇✲♠♦✈✐♥❣ ♦❜❥❡❝t ❝♦✈❡rs ❛ r❡❧❛t✐✈❡❧② s♠❛❧❧ ❛♠♦✉♥t ♦❢
✶✻ ✴ ✹✺
◮ ❆ ❢❛st✲♠♦✈✐♥❣ ♦❜❥❡❝t ❤❛s ❛ ❤✐❣❤ s♣❡❡❞ ❛♥❞ ❝♦✈❡rs ❛ r❡❧❛t✐✈❡❧②
◮ ❆ s❧♦✇✲♠♦✈✐♥❣ ♦❜❥❡❝t ❝♦✈❡rs ❛ r❡❧❛t✐✈❡❧② s♠❛❧❧ ❛♠♦✉♥t ♦❢
◮ ❆♥ ❡①♣♦s❡❞ ♣❡rs♦♥ ❤❛s ❛ ❤✐❣❤ ❤❛③❛r❞ r❛t❡ ❛♥❞ ✇✐❧❧ ❣❡t ❞✐s❡❛s❡❞
◮ ❆ ♥♦♥✲❡①♣♦s❡❞ ♣❡rs♦♥ ❤❛s ❛ ❧♦✇ ❤❛③❛r❞ r❛t❡ ❛♥❞ ✇✐❧❧ ❣❡t
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✶✼ ✴ ✹✺
✶✼ ✴ ✹✺
✶✽ ✴ ✹✺
✶✽ ✴ ✹✺
◮ ❚♦t❛❧ ❞✐st❛♥❝❡✿ ✺✵ ❦♠ ◮ ❚♦t❛❧ ❞✉r❛t✐♦♥✿ ✶✺✹✳✺ ♠✐♥✉t❡s
✶✾ ✴ ✹✺
◮ ❚♦t❛❧ ❞✉r❛t✐♦♥✿ ✺✵ ♠♦♥t❤s ◮ ❚♦t❛❧ ❛❜s♦❧✉t❡ r✐s❦✿ ✻✷✳✽✪
✷✵ ✴ ✹✺
◮ ❚♦t❛❧ ❞✉r❛t✐♦♥ ✇✐t❤♦✉t ❞♦♣✐♥❣✿ ✶✺✹✳✺ ♠✐♥✉t❡s ◮ ❚♦t❛❧ ❞✉r❛t✐♦♥ ✇✐t❤ ❞♦♣✐♥❣✿ ✶✹✵✳✺ ♠✐♥✉t❡s
✷✶ ✴ ✹✺
✷✷ ✴ ✹✺
◮ ❚♦t❛❧ ❛❜s♦❧✉t❡ r✐s❦ ♣r❡✈✐♦✉s ❛❣❡✿ ✻✷✳✽✪ ◮ ❚♦t❛❧ ❛❜s♦❧✉t❡ r✐s❦ ♦♥❡ ②❡❛r ♦❧❞❡r✿ ✻✻✳✹✪
✷✷ ✴ ✹✺
Relative Risks for Stroke by Age, Sex, and Population Based
MORGAM Project
Kjell Asplund, MD, PhD; Juha Karvanen, DSc(Tech); Simona Giampaoli, MD; Pekka Jousilahti, MD, PhD; Matti Niemela ¨, MD; Grazyna Broda, MD; Giancarlo Cesana, MD; Jean Dallongeville, MD; Pierre Ducimetriere, MD; Alun Evans, MD; Jean Ferrie `res, MD; Bernadette Haas, MD; Torben Jorgensen, MD; Abdonas Tamosiunas, MD; Diego Vanuzzo, MD; Per-Gunnar Wiklund, MD, PhD; John Yarnell, MD; Kari Kuulasmaa, PhD; Sangita Kulathinal, PhD; for the MORGAM Project
Background and Purpose—Within the framework of the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) Project, the variations in impact of classical risk factors of stroke by population, sex, and age were analyzed. Methods—Follow-up data were collected in 43 cohorts in 18 populations in 8 European countries surveyed for cardiovascular risk factors. In 93 695 persons aged 19 to 77 years and free of major cardiovascular disease at baseline, total observation years were 1 234 252 and the number of stroke events analyzed was 3142. Hazard ratios were calculated by Cox regression analyses. Results—Each year of age increased the risk of stroke (fatal and nonfatal together) by 9% (95% CI, 9% to 10%) in men and by 10% (9% to 10%) in women. A 10-mm Hg increase in systolic blood pressure involved a similar increase in risk in men (28%; 24% to 32%) and women (25%; 20% to 29%). Smoking conferred a similar excess risk in women (104%; 78% to 133%) and in men (82%; 66% to 100%). The effect of increasing body mass index was very modest. Higher high-density lipoprotein cholesterol levels decreased the risk of stroke more in women (hazard ratio per mmol/L 0.58; 0.49 to 0.68) than in men (0.80; 0.69 to 0.92). The impact of the individual risk factors differed somewhat between countries/regions with high blood pressure being particularly important in central Europe (Poland and Lithuania). Conclusions—Age, sex, and region-specific estimates of relative risks for stroke conferred by classical risk factors in various regions of Europe are provided. From a public health perspective, an important lesson is that smoking confers a high risk for stroke across Europe. (Stroke. 2009;40:2319-2326.) Key Words: blood pressure cholesterol cohort studies smoking stroke risk factors
he appraisal of stroke risk in populations or individuals is based on the recognition that all cardiovascular disorders are multifactorial in nature. The most widely used risk score statistical techniques.1 The Framingham stroke risk score has been used extensively when international and national guide- lines for cardiovascular prevention have been developed.
✷✸ ✴ ✹✺
✷✹ ✴ ✹✺
✷✺ ✴ ✹✺
◮ ❆ ❝②❝❧✐st ❝❛♥ ❤❛✈❡ ❛♥ ❛❝❝✐❞❡♥t ♦r ❣❡t ✐♥❥✉r❡❞✳
◮ ❛❢t❡r t❤❡ ❛❝❝✐❞❡♥t t❤❡ s♣❡❡❞ ✐s ③❡r♦✳
◮ ❚♦ ❡st✐♠❛t❡ t❤❡ ❝❤❛♥❝❡s ♦❢ ❛ ❝②❝❧✐sts t♦ ✇✐♥ ❛ r❛❝❡✱ ♦♥❡ ❤❛s t♦
✷✻ ✴ ✹✺
◮ ❆ ♣❛t✐❡♥t ❝❛♥ ❞✐❡ ✕ ❢r❡❡ ❢r♦♠ ❝❛r❞✐♦✈❛s❝✉❧❛r ❞✐s❡❛s❡✳
◮ ❛❢t❡r ❞❡❛t❤ t❤❡ ❤❛③❛r❞ r❛t❡ ♦❢ ❝❛r❞✐♦✈❛s❝✉❧❛r ❞✐s❡❛s❡✴♠♦rt❛❧✐t②
◮ ❚♦ ❡st✐♠❛t❡ t❤❡ r✐s❦ ♦❢ ❝❛r❞✐♦✈❛s❝✉❧❛r ❞✐s❡❛s❡✴♠♦rt❛❧✐t②✱ ♦♥❡
✷✼ ✴ ✹✺
✵
✵
❈❱❉ ❛t s
◮ ❈♦① r❡❣r❡ss✐♦♥ ❢♦r ❈❱❉ ❤❛③❛r❞✿
◮ ❈♦① r❡❣r❡ss✐♦♥ ❢♦r ♥♦♥✲❈❱❉ ❤❛③❛r❞✿
✷✽ ✴ ✹✺
✷✾ ✴ ✹✺
✸✵ ✴ ✹✺
Time Status 1 event−free event Ti
✸✶ ✴ ✹✺
Time Status
Ci event−free event?
✸✷ ✴ ✹✺
✶ ✻
✻
✶ ✻
✻
✻
✻ ✰ ✶ ✻ ✯ ✶ ✸✮
✻ − ✶ ✶✽
✻ − ✶ ✶✽
✻ − ✶ ✶✽
✸✸ ✴ ✹✺
Time Survival probability 20 40 60 80 0 % 25 % 50 % 75 % 100 % I II 6 6 6 4 4 4 4 4 4 2 1 Subjects: 1/6 1/6 1/6 + 1/18 ✸✹ ✴ ✹✺
Time Status Competing risk at time Ti 1 event−free Ti
✸✺ ✴ ✹✺
✶ ✻ ✶ ✻
✶ ✻ ✷ ✻
✷ ✻
✶ ✻ ✸ ✻
✸ ✻
✸ ✻
✸✻ ✴ ✹✺
Time Absolute risk 20 40 60 80 0 % 25 % 50 % 75 % 100 % II 6 6 6 4 4 4 4 4 4 2 1 Subjects: 1/6 1/6 1/6 ✸✼ ✴ ✹✺
✸✽ ✴ ✹✺
Years since inclusion Absolute risk 5 10 0 % 25 % 50 % 75 % 100 % Age 50 60 70 80 90
Cardiovascular disease/mortality
Years since inclusion Absolute risk 5 10 0 % 25 % 50 % 75 % 100 % Age 50 60 70 80 90
Non−cardiovascular mortality Hypothetical world: AUC(10yrs)=83.5 % Real world: AUC(10yrs)=68.9 %
✸✾ ✴ ✹✺
◮ ❧❡ss ♥♦♥✲❝❛s❡s ◮ ❣r❡❛t❡r ❝❡♥s♦r✐♥❣ ✇❡✐❣❤ts ❲
✹✵ ✴ ✹✺
◮ ❧❡ss ♥♦♥✲❝❛s❡s ◮ ❣r❡❛t❡r ❝❡♥s♦r✐♥❣ ✇❡✐❣❤ts ❲
✹✵ ✴ ✹✺
❈❱❉ ❈❛s❡ ✭❛❣❡✮ ◆♦♥✲❝❛s❡ ✭❛❣❡✮ ❖✉t❝♦♠❡ ❈♦♥❝♦r❞❛♥t ❲ ✺✻ ✹✸ ❛❧✐✈❡ ❨❡s ❂ ✶ ✺✻ ✺✸ ❛❧✐✈❡ ❨❡s ❂ ✶ ✺✻ ✻✵ ♥♦♥✲❈❱❉ ◆♦ ❂ ✶ ✺✻ ✽✶ ♥♦♥✲❈❱❉ ◆♦ ❂ ✶ ❆❯❈ ✺✵✳✵✪
❈❱❉ ❈❛s❡ ✭❛❣❡✮ ◆♦♥✲❝❛s❡ ✭❛❣❡✮ ❖✉t❝♦♠❡ ❈♦♥❝♦r❞❛♥t ❲✶ ✺✻ ✹✸ ❛❧✐✈❡ ❨❡s ❃✶ ✺✻ ✺✸ ❛❧✐✈❡ ❨❡s ❃✶ ✺✻ ✻✵ ♥♦♥✲❈❱❉ ❯♥❦♥♦✇♥ ✵ ✺✻ ✽✶ ♥♦♥✲❈❱❉ ❯♥❦♥♦✇♥ ✵ ❆❯❈ ✶✵✵✪
✹✶ ✴ ✹✺
❱❛r✐❛❜❧❡ ❯♥✐ts ❍❛③❛r❞❘❛t✐♦ ❈■✳✾✺ ♣✲✈❛❧✉❡ ❛❣❡ ✶✳✵✽ ❬✶✳✵✼❀✶✳✶✵❪ ❁✵✳✵✵✶ s❡① ▼❛❧❡ ✶✳✵✵ ✕ ✕ ❋❡♠❛❧❡ ✵✳✺✺ ❬✵✳✹✸❀✵✳✼✶❪ ❁✵✳✵✵✶ ❞❛②t✐♠❡❙❇P ✶✳✵✷ ❬✶✳✵✷❀✶✳✵✸❪ ❁✵✳✵✵✶
❱❛r✐❛❜❧❡ ❯♥✐ts ❍❛③❛r❞❘❛t✐♦ ❈■✳✾✺ ♣✲✈❛❧✉❡ ❛❣❡ ✶✳✵✾ ❬✶✳✵✼❀✶✳✶✵❪ ❁✵✳✵✵✶ s❡① ▼❛❧❡ ✶✳✵✵ ✕ ✕ ❋❡♠❛❧❡ ✵✳✽✾ ❬✵✳✻✻❀✶✳✶✾❪ ✵✳✹✸✺ ❞❛②t✐♠❡❙❇P ✶✳✵✶ ❬✶✳✵✵❀✶✳✵✷❪ ✵✳✷✼✽
✹✷ ✴ ✹✺
❱❛r✐❛❜❧❡ ❯♥✐ts ❍❛③❛r❞❘❛t✐♦ ❈■✳✾✺ ♣✲✈❛❧✉❡ ❛❣❡ ✶✳✵✽ ❬✶✳✵✼❀✶✳✶✵❪ ❁✵✳✵✵✶ s❡① ▼❛❧❡ ✶✳✵✵ ✕ ✕ ❋❡♠❛❧❡ ✵✳✺✹ ❬✵✳✹✷❀✵✳✼✵❪ ❁✵✳✵✵✶ ❞❛②t✐♠❡❙❇P ✶✳✵✵ ❬✵✳✾✾❀✶✳✵✷❪ ✵✳✻✹✸ ♥✐❣❤tt✐♠❡❙❇P ✶✳✵✷ ❬✶✳✵✶❀✶✳✵✹❪ ❁✵✳✵✵✶
❱❛r✐❛❜❧❡ ❯♥✐ts ❍❛③❛r❞❘❛t✐♦ ❈■✳✾✺ ♣✲✈❛❧✉❡ ❛❣❡ ✶✳✵✾ ❬✶✳✵✼❀✶✳✶✵❪ ❁✵✳✵✵✶ s❡① ▼❛❧❡ ✶✳✵✵ ✕ ✕ ❋❡♠❛❧❡ ✵✳✽✽ ❬✵✳✻✻❀✶✳✶✽❪ ✵✳✹✵✹ ❞❛②t✐♠❡❙❇P ✶✳✵✵ ❬✵✳✾✽❀✶✳✵✶❪ ✵✳✻✽✼ ♥✐❣❤tt✐♠❡❙❇P ✶✳✵✶ ❬✶✳✵✵❀✶✳✵✸❪ ✵✳✶✶✷
✹✸ ✴ ✹✺
✹✹ ✴ ✹✺
◮ ❆❜s♦❧✉t❡ r✐s❦s ✐♥ t❤❡ r❡❛❧ ✇♦r❧❞ ❛r❡ ❝♦♠♣❧❡① ♦❜❥❡❝ts ♦❢
◮ ❆❣❡ ✐s ❛ ✈❡r② ❣♦♦❞ ♣r❡❞✐❝t♦r ◮ Pr❡❞✐❝t✐♦♥s ♦❢ ❛❜s♦❧✉t❡ r✐s❦s ❛♥❞ r❡tr♦s♣❡❝t✐✈❡ ❛♥❛❧②s✐s ♦❢
◮ ❈❡♥s♦r❡❞ ♦❜s❡r✈❛t✐♦♥s ❞✐str✐❜✉t❡ ♣r♦❜❛❜✐❧✐t② ♠❛ss t♦
◮ ■♥ t❤✐s ✇♦r❧❞ t❤❡ r✐s❦ ♦❢ ❈❱❉ ❛❢t❡r ❞❡❛t❤ ✐s ③❡r♦
✹✺ ✴ ✹✺