Tuberculosis in the Republic of Cuba: its possible elimination

Tuhercle and Lung Disease (1994) 75.188-194 0 1994 Longman Group Ltd

Tuberculosis in the Republic of Cuba: its possible elimination E. Gonzalez*, L. Armas*, A. Alonsot *Group for Epidemiological Surveillance and Research on Acute Respiratory Infections and Tuberculosis and fDepartment of Statistics and Computation, Institute Pedro Kouri, Havana, Cuba S U M M A R Y. Setting: Tuberculosis elimination is a priority in most developed countries, although the

AIDS epidemic and drug resistance are a handicap in some of them. Tuberculosis is an even greater problem in developing countries. Objective: To evaluate the epidemiological situation in Cuba, the trend of new cases reported for 1979-91 by clinical category and age group is described. Design: A simple regression model was fitted to the time series data on ‘new case’ rates taken from the national surveillance system. The annual variation percentage was estimated. Results: From 1979-91 tuberculosis decreased by 59.5% (from 11.6- 4.7 per 105 persons per year). This decline occurred in ail age groups; 60% of new cases in 1991 were aged 45 years and over, of which 30% were aged 65 and over. Drug resistance of Mycobacterium tuberculosis strains (2.49% in 1989) remains uncommon and HIV infection (0.009% in 1991) is rare in the general population. Conclusions: The continuing steady decline of the number of new cases reported, in addition to the favorable trend of drug resistance and the low rate of HIV infection in the general population so far seem to indicate the real possibility of maintaining the effectiveness of the National Programme for Tuberculosis Control in the future, making it reasonable to formulate new strategies for the elimination of the disease. R l? S U M 8. Cadre: L’elimination de la tuberculose est Pun des objectifs principaux de la plupart des pays

industrialises, mCme si I’endemie du SIDA et la resistance aux drogues sont des problemes graves chez certains. La tuberculose est encore plus repandue dans les pays en developpement. Objet: Afin d’haluer la situation epidemiologique en Cuba, est d&rite ici l’evolution des cas nouveaux notifies 1979-91 selon la categoric clinique et le groupe d’age. SchtGna: Un modele de regression simple a CtCapplique aux donnees en serie temporelle des taux de ‘cas nouveaux’ obtenues du Systeme National de Contrble. A CtCestime le pourcentage annuel de variation. Rkwltuts: Dans la periode de 1979 a 91 la tuberculose a diminue de 59,5% (de 11,6 a 4,7 par an pour lo5 habitants). Cette baisse s’est produite dans tous les groupes d’lge ; en 1991 60% des cas nouveaux se trouvaient dans le groupe age de 45 ans et davantage, dont 30% Ctaient ages de 65 ans et davantage. La resistance aux drogues des souches de Mycobacterium tuberculosis (2,49% en 1989) demeure une condition hors du commun et I’infection par le VIH est rare (0,009% en 1991) dans la population g&&ale. Conclusion: La baisse progressive du nombre de cas nouveaux notifies, ainsi que la tendance favorable des taux de resistance aux drogues et le taux faible d’infection VIH dans la population g&t&ale jusqu’ici semblent indiquer la possibilite concrete de maintenir l’efficacite du Programme National du Controle de la Tuberculose dans l’avenir et de justifier la recherche de nouvelles strategies pour l’elimination de la maladie. R E S U M E N - Marco de referenciu:

La elimination de la tuberculosis es uno de 10s objetivos de la mayoria de 10s paises desarrollados, aunque el SIDA y el problema de la resistencia a las drogas es un inconveniente en algunos de ellos. La tuberculosis es un serio problema de salud sun mayor en 10s paises en desarrollo.

Correspondence to: Dr E. Gonzalez Ochoa, Institute Pedro Kouri, Autopista Novia de1 Mediodia Km 6 e/Carretera Central y Autopista National, Apartado Postal 601, Marianao 13, Ciudad de la Habana, Cuba. Paper received 4 August 1992. Final version accepted 5 July 1993. 188

Tuberculosis

in the Republic of Cuba: its possible elimination

189

Para evaiuar la situaci6n epidemiologica en Cuba, se describe la evolution de cases nuevos de tuberculosis notificados durante el period0 1979-91 segun la categoria clinica y el grupo de edad. Mktodo: Se aplico un modelo de regresi6n lineal simple a 10s datos en serie temporal de las tasas de ‘cases nuevos’ tomadas de1 Programa National de Control de la Tuberculosis. Se estimd ei porcentaje anual de variaci6n. Resultados: Desde 1979 hasta 1991 la tuberculosis disminuyo de 59,5% (de 11,6 a 4,7 por loj habitantes). Esta disminucion se produj6 en todos 10s grupos de edad ; el 60% de cases nuevos en 1991 tenia 45 aiios y mas, de 10s cuales el 30% tenia 65 arias y mas. La resistencia a las drogas de las cepas de Mycobacterium tuberculosis (2,49% en 1989) sigue siendo una situation poco comun y la infection con VIH es rara (0,009% en 1991) en la poblaci6n general. Conclusiones: La disminuci6n progresiva y sostenida de 10s cases nuevos, asi coma la evolution favorable de la resistancia a las drogas y la tasa baja de infection VIH en la poblacidn general hasta ahora, revelan la posibilidad de mantener la efectividad de1 Programa National de Control de la Tuberculosis en el futuro y lo ponen condiciones de plantearse nuevas estrategias para la eliminaci6n de esta enfermedad. Objetivo:

INTRODUCTION In the past IO-20 years tuberculosis

(TB) has been one of the worst controlled and managed health problems, although it is prevalent throughout the developing world. In industrialized countries TB is no longer considered a danger, since it now affects the poorest social groups, iA which are also those who have the least political influence. In some countries, TB patients coming from certain groups of the population’-’ become a handicap for the productive potential of society and to efforts to eliminate the disease. This situation has started to change, however, in industrialized countries,‘G’3 because of the deterioration caused by HIV infection. There is much evidence that the two diseases interact in an adverse, progressive situation.‘k24 At the same time scientific and technological progress in diagnostic techniques and chemotherapy regimens has encouraged scientists and health managers to apply these new approaches to the elimination of tuberculosis.25-29 Even in the disadvantaged social and economic conditions generated by the world economic crisis, the preventive and curative means available so far provide a set of effective measures for achieving acceptable results if they are introduced on a large scale.’ However, problems have recently emerged with the emergence of multidrugresistant strains of Mycohacterium tuberculosis within high risk groups, increasing the possibility of its transmission among HIV infected persons.2G3” Any review of the tuberculosis situation in Cuba must take into account the international and regional contexts. The Cuban National Tuberculosis Control Programme (CNTCP) has run throughout 3 historic stages:3sm36the first before 1959, the second from 1959-70 and the third after 1970. We will briefly refer to the major aspects of the third. In 1970 the CNTCP strategy was modified.“7 Casefinding based on bacteriological diagnosis and a new treatment policy consisting of fully supervised ambulatory treatment were introduced, and a standard chemotherapy regimen consisting of an initial phase of streptomycin (S), isoniazid (INH) and thiacetazone

(Tbl) 6 days per week for 4 weeks, followed by a second phase of S and H twice weekly for 48 weeks and a third phase of self-administered INH (300 mg daily), was administered. The effectiveness of this regimen in the routine conditions of the Primary Health Services (PHS) was 8492% sputum conversion.3hii This was used throughout the country from 197 I. The treatment was later adjusted, according to the findings of intemational research on anti-tuberculosis chemotherapy. to a 9-month regimen with an initial phase of S (I g for those aged up to 50 years and 0.5 g for those aged over .50), INH (300 mg), rifampicin (R) (600 mg) and pyrazinamide (P) (2 g), in a daily single dose for 8 weeks. followed by a second phase of intermittent treatment with S (1 g) and INH (750 mg) twice weekly for 28 weeks. R (600 mg) and INH (750 mg) were later introduced into the second phase. The impact of the CNTCP, with favourable decreasing trends in the periods 1964-70 and 1970--78 has previously been reported by Rodriguez’” and by Menendez et a1.3x The present article describes and analyses the trend of new cases of tuberculosis by age group for 1979-91, comparing expected and observed figures for the period. The aim of the TB control programme was to achieve a reduction of 5% or over in the annual rate of new cases.

MATERIALS AND METHODS Data were obtained from the notification system of the National Division of Statistics (NDS) and the publications of the National Division of Epidemiology (NDE) in the Ministry of Public Health (MPH).j” A new case of tuberculosis was defined and notified in all persons (diagnosed for the first time, or previously diagnosed but notified for the first time) in whom M. tuberculosis was identified by microbiology or histopathology. In children clinical diagnosis or diagnosis based on X-ray was accepted, even without bacteriological confirmation. Extrapulmonary tuberculosis was identified according to the methods used for diagnosis.

190

Tubercle and Lung Disease

The number of new cases divided into age group was obtained for 1979-91. Global and specific rates were calculated taking the population figures estimated by the NDS and data from the State Committee of Statistics, Census and Estimations. The trend up to 1992 was estimated by means of the simple linear regression procedure, with the value of the natural logarithm of the rates as dependent variable (In y=a+bx). The regression and determination coefficient calculations were acceptable, ranging from 0.6-0.9 for the former and 0.4-0.9 for the latter. The percentage of variation (reduction), the average annual variation and the geometric mean of the rates were calculated. An estimation of the annual rate of tuberculosis infection was calculated based on the average rate of bacilloscopy positive new cases in the last 5 years of the period evaluated, following the procedure described by Styblo,40 considering 85% of bacilloscopy positive patients among new cases of pulmonary tuberculosis. The reliability of the data was based on the national overall application of standard techniques and procedures to identify persons with prolonged respiratory symptoms such as cough and/or expectoration in the network of 400 PHC polyclinics and 400 Secondary Health Care (SHC) hospitals, where ambulatory treatment and hospitalization were administered in coordination with the National Hospital of Pneumophthisiology. Each polyclinic has a general clinical laboratory with the means of performing direct sputum examination by microscopy. 3 specimens must be collected from each person suspected of having TB; about 90% of specimens collected were sent for culture to the microbiology laboratories39 located in 32 municipality centers and 13 provincial centers for Health and Epidemiology and to the microbiology laboratories of 57 hospitals working in collaboration with the National Mycobacterium Reference Laboratory of the Pedro Kouri Institute,4’ according to the CNTCP network of bacteriological diagnosis for case-finding and treatment monitoring. The application of standard techniques and procedures to the diagnosis, recording and reporting of cases already mentioned makes

Table 1.

New cases of tuberculosis,

Year

Tuberculosis+ Rates Cases

1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991

1133 1136 833 815 765 705 677 653 639 513 581 546 503

11.6 11.6 8.5 8.3 7.7 7.1 6.7 6.4 6.2 5.9 5.5 5.1 4.7

this time series data consistent enough for periodic analysis. The Public Health Services cover more than 99% of the population. During the period evaluated there was no change in the definition of new cases of tuberculosis, nor in the other major guidelines of the CNTCP, and there had been a steady level in casefinding throughout the country.

RESULTS Tuberculosis notifications from 1979-91 declined from 1133 (11.6 per 100 000 population) to 503 (4.7 x 100 000), a decrease of 4.9% per year (Table 1). Pulmonary tuberculosis declined from 1022 (10.4 x 100 000 population) to 454 (4.2 x 100 000), a total reduction of 59.5% (4.9% per year). Extrapulmonary tuberculosis (0.12-0.18) decreased by 66% (7.7% per year). In the period 1979-84 notification of pulmonary and extrapulmonary tuberculosis decreased by 39% (7.7% per year) and 49% (9.5% per year) respectively, and in the period 1986-91 by 26.5% (5.3% per year) and 23.5% (4.7% per year), respectively. The geometric means of rates for the whole period and the 2 five-year periods of the time series for pulmonary tuberculosis and extrapulmonary tuberculosis were 9.3, 8.5 and 1.0 per 100 000 for the former and 6.4, 5.9 and 0.7 for the latter. During the period evaluated the rate of autopsies carried out throughout the country ranged between 45-68% of deaths. For 1990 this was 47.5% (31336/65941). 12 new cases of previously unidentified tuberculosis were diagnosed, 2.1% of total new cases reported and 0.04% of total autopsies (NDS unpublished data). Previously unidentified TB cases diagnosed only after death have averaged 10-15 per year. In age groups under 15 years there has been a noticeable decline in tuberculosis, particularly among those aged under 10 (Fig. 1). In the O-4 year age group this decrease has reached 91.6% (7.6% per year); in 1991 only one case was reported from this age group. In children aged 5-9 the TB rate has decreased by 85.7%

Cuba 1979-9 1*

ER

Pulmonary+ Cases Rates

ER

Extrapulmonary Rates Cases

10.76 10.03 9.35 8.71 8.12 7.57 7.06 6.58 6.13 5.72 5.33 4.97 4.63

1022 1064 734 718 688 631 607 562 568 534 514 495 454

9.52 8.9 8.33 7.78 7.28 6.81 6.37 5.95 5.57 5.2 4.87 4.55 4.25

111 126 99 97 77 71 77 91 71 79 67 53 49

10.4 10.3 7.5 7.3 7.0 6.4 6.0 5.5 5.5 5.1 4.89 4.64 4.24

*Rates per 100 000 population; ‘International Classification code (0.11); ICD code (0.12-0.18); ER = estimated rate.

1.2 1.3 1.0 1.0 0.7 0.7 0.8 0.9 0.7 0.7 0.63 0.5 0.46

ER 1.2 1.11 1.04 ,096 0.9 0.83 0.77 0.72 0.67 0.62 0.58 0.54 0.5

of Disease (ICD) code (0.1 O-O. 18); JICD

Tuberculosis

0 1979

1980

1981

1982

1983

1984

1985

1986

1987

in the Republic of Cuba: its possible elimination

1988

1989

1990

1991

191

1992

Years Fig. l-Estimated

rates of tuberculosis

in groups aged O-4 years old. Cuba 1979-92.

(7.1% annually) and by 90% (7.5% per year) in 10--14year-olds (Table 2). The decline was most rapid in the period 1979-84. ln young adults and adults the trend was also favourable, but particularly among the youngest (Fig. 2). In the group aged 15-19 new cases of tuberculosis fell by 85.7% (7.1% per year) and in those aged 20-24 by 72.9% (6.1% per year). Among those aged 2544 and 45-64 this was 66.4% (5.5% per year) and 64.0% (5.3% per year), respectively. The decline was considerably lower in the eldest group, aged 65 and over, at 57.2% (4.8% per year). Taking into account the high proportion of the population in this age group, its influence on the global percentage of reduction for the general population during this period is evident. The proportion of new cases aged 45 and over and 65 and over had increased in 1991 compared with 1979 (from 52.7% and 23.4%, respectively, to 60.6% and 29.6%) (Table 3). The estimated annual rate of tuberculosis infection for the years 1987-91 was between 0.08-0.09%, depending on whether the data was for pulmonary tuberculosis or tuberculosis. Even assuming a rate of new cases ranging between 5.8-6.0 the annual rate of tuberculosis infection would be 0.12%.

The goal of many developed countries has been to define tuberculosis elimination.‘2~29 This would be achieved when: (1) the incidence of the disease is less than 1 per million, or (2) the prevalence of tuberculosis infection in the general population is under 1%. The Advisory Committee for the Elimination of Tuberculosis for the USAl established this goal for the year 2010, with an interim target of a case rate of 3.5 per 100 000 by the year 2000. In the Netherlands29 it was pointed out that this could not be met within the next 3 decades, but that efforts were being made in that direction. Cuba is listed as a developing country, but in terms of prevention and health care as well as socially it is on a par with many industrialized counties. This is expressed in a low infant mortality rate (10.2 per 1000 live births in 1992) and a life expectancy of 75 years (from birth). On this basis a general health plan has been established to improve the health of the Cuban population by the year 2000,4* taking into account communicable diseases including tuberculosis. The current issue is to develop a rational approach to a strategy of elimination of tuberculosis in Cuba, which needs to take into account the following factors: (1) the

Table 2.

Rates of new cases of tuberculosis.

Age

Rates 1979

1984

1986

1991

1979-84 Red. (%)

Mean AV

Rates GM

198&91 Red. (%)

Mean AV

Rates GM

1979-9 1 Red. Meall (%) AV

Rates GM

1.2 0.7 1.0 5.6 10.7 14.3 22.8 38.1

0.1 0.1 0.6 2.5 3.9 7.2 1.2 21.5

0.1 0.6 0.1 1.3 4.2 6.3 24.1 24.1

0.1 0.1 0.1 0.1 0.8 4.8 16.3 16.3

91.6 85.7 40.0 55.4 63.5 50.0 68.4 43.6

18.3 17.1 8.0 11.0 12.7 10.0 13.7 8.7

0.4 0.3 0.5 2.9 6.4 9.7 16.0 32.2

0.0 83.3 0.0 38.5 30.9 23.8 33.9 32.4

0.0 16.6 0.0 7.7 6.2 4.8 6.8 6.5

0.0 0.0 0.3 I.5 3.8 5.1 10.2 21.1

91.6 85.1 90.0 35.7 72.9 66.4 64.0 57.2

0.0 0.0 0.4 2.1 4.x 7.0 12.9 25.9

o-4 5-9 IO-14 15-19 20-24 2544 45-64 65+

Red. (%) = Percentage

of reduction;

Geometric

DISCUSSION

mean and percentage

Mean A.V. = mean annual variation;

of reduction by age. Cuba 1979-91

Rates G.M. = Rates geometric

mean.

7.6 7.1 7.5 7.1 6.1 5.5 5.3 4.8

192 Tubercle and Lung Disease

1979

1980

1981

1982

1983

1984

1986

1986

1987

1988

1989

1990

1991

1992

Years Fig. 2-Estimated

rates of tuberculosis for population groups aged 15 years and over. Cuba 1979-92.

Percentage of new cases of tuberculosis by age, Cuba 1979, 1984, 1991

Table 3.

Age (years)

1979

1984

1991

O-4 5-9 lo-14 15-19 2S24 25-44 45-64 65+

1.0 0.8 1.0 5.0 7.1 32.4 29.3 23.4

0.2 0.2 1.0 4.0 5.5 26.8 33.4 34.2

0.2 0.2 0.2 1.6 6.8 30.4 31.0 29.6

current trend of the disease, (2) the probability of its association with HIV infection, (3) the emergence of multi-drug resistant M. tuberculosis and (4) health policy for tuberculosis control. There is clear evidence of a rapidly decreasing trend in the number and rate of new TB cases reported in 1991 (4.7 per 100 000). The mortality rate for the same year was 0.2 per 100 000,39 similar to the rates in Canada and the LJSA;43 the annual risk of infection, at 0.2%, was also in the same range as in Canada and the USA.43 The age distribution of new cases, with 60% aged 45 years and over and 30% 65 years and over, is characteristic of the evolution of tuberculosis in industrialized countries. In the 1980s tuberculosis incidence varied widely between the different countries in the American continent:43 <10/100000 in Canada, Cuba and the USA, 20 in the Bahamas and Venezuela, 30 in Argentina and Uruguay, 40-50 in Brazil, Chile and Mexico, >70 in El Salvador, Guatemala, the Honduras and Nicaragua and 100-200 in Bolivia and Haiti. In 1988 the incidence rate of bacteriologically confirmed cases of TB was 7.2/ 100 000 in the former German Democratic Republic4 and a tuberculosis incidence rate of 58.3/100000 was reported in Barcelona, Spain in 1988;45 and in Czechoslovakia the incidence of bacteriologically confirmed cases was 12.5/100 000 in 1989.46

In the USA the tuberculosis incidence rate decreased from 53/100 000 in 1953 to 9.4/100 000 in 1984; the number of new cases reported declined by an average of almost 5% per year. In Cuba the decline over the period 1979-91 also reached an annual average of almost 5%. However since 1984 in the USA the trend of morbidity has changed; in 1990 the incidence rate was 10.3/ 100 000, an increase of 9.4% over the 1989 rate and of 15.5% over the 1984 rate. In 1987 the USA case rate was 9.3/100 000,4’ indicating a reversal of the trend from 1984-90. In Cuba, however, no change was observed in the declining trend of TB incidence; on the contrary there was a large drop from 1987-91. Given the role of AIDS in the aggravation of the incidence of tuberculosis and vice versa,‘k24 this subject must be analyzed in the formulation of an elimination strategy for tuberculosis. In countries with a low prevalence of tuberculosis infection in those aged 15-49, the probability of an increase in new cases of TB is 10w,2~ and therefore the transmission of AIDS in such infected persons would be small, giving rise to the suggestion that HIV infection would not have a great influence on TB elimination in such countries. This is a question that will need to be addressed in the near future. Cuba can be considered a low prevalence country for tuberculosis; similar arguments can thus be made as regards the possible adverse effects of HIV infection. As the rate of new cases of tuberculosis is rapidly declining in the age group 15-55, the risk of dual infection by HIV and M. tuberculosis is minimal. The annual risk of infection estimated for this group in 1991 depends on that calculated 40 years before and on the mean annual diminution during that period. Within the routine conditions of the CNTCP the cure and relapse rates are 98% and ~2% respectively, with a very low (0.2%) rate of absconders from treatment (NDE unpublished data). The risk of HIV infection in the general population of Cuba was 0.009% (183/2 149 065) in 199139 and no TB-

Tuberculosis

positive cases were confirmed among AIDS patients before 1991 (Pedro Kouri Institute AIDS clinic - unpublished data), making the association of AIDS and TB very uncommon. In a Pan-American Health Organization (PAHO) report up to 10 September 199247 the rate of AIDS cases per million of population in 1991 was 327.7 in the USA, 56.4 in Canada, 82.2 in Brazil, 80.3 in Mexico and 4.3 in Cuba for men, and 47.0 in the USA, 3.1 in Canada, 15.6 in Brazil, 10.8 in Mexico and 1.3 in Cuba for women. The rates are 75 times higher in men and 35 times higher in women in the USA than in Cuba, and despite this the annual risk of tuberculosis infection is the same in both countries. Multidrug-resistant (MDR) tuberculosis as an emerging problem in the USA has been discussed recently.3k34 As a complex problem it may be associated with several factors:” (1) immigration of tuberculosis patients from regions with a high prevalence of MDR strains, (2) inappropriate treatment regimens prescribed by different groups of private and public health physicians, (3) patients who do not comply with appropriately prescribed regimens. These factors are considered satisfactorily answered in Cuba: the small number of immigrants, mainly students from Africa, Latin America and Asia are screened for infectious disease on entry, those suspected of having tuberculosis being tested accordingly, and adequate standard TB treatment regimens are wellsupervised, with satisfactory compliance by the patients. However these factors are only minor obstacles to the elimination of TB, since they can easily be solved with good TB control and management.48 A combination of the above factors, added to HIV infection, is increasing amongst the socially disadvantaged groups of industrialized countries and the general population of developing countries. The transmission of MDR strains among high risk population groups demands particular attention, particularly to monitor the different features of this phenomenon. In Cuba 8.6% of primary resistant M. tuhevculosis strains were reported in 1981, and 6% in 1982.4” In 1987 reported primary resistance was 3.2%, in 1988-89 it was 2.7% and in 1991 2.4%.50,51 Surveillance of drug resistant strains in Cuba reveals a decreasing trend corresponding with the favourable results of the chemotherapy programme during the period evaluated. No MDR strains have so far been identified. To maintain the positive trends in the notification of new cases of tuberculosis and the low probability of interference by HIV infection, TB control techniques could be reformulated along the lines of those in other countries.27 The programme policies need to be reoriented towards better case-finding, which at present is being carried out mainly by family doctors in the PHC clinics, in collaboration with the polyclinic laboratories. In recent years the new generations of physicians, as in other developed countries, have been inclined to regard tuberculosis as obsolete as it is no longer common, giving rise to delayed diagnosis due to lack of familiarity with the disease. This problem could also present itself among laboratory technicians for the same reasons. Thus it is

in the Republic of Cuba: its possible elimination

193

important to give ongoing training to both PHC and SHC staff in TB diagnosis and surveillance. Cuban health policy requires that TB be kept at the 1970s levels, and focal surveillance and preventive chemotherapy will play an important role. Surveillance of high risk groups will be an important task for family doctors and general hospital staff in collaboration with the Infectious Disease Division of the Municipal and Provincial Centers of Health and Epidemiology. Special priority must be given to improving the quality of bacteriological techniques for diagnosis, with more frequent and direct supervision, and the introduction of new diagnostic techniques. It is clear that intensive support for the CNTCP is important in order to achieve these results with a view to total eradication of the disease. Looking at the favourable situation of trends in tuberculosis infection and morbidity, the low rate of HIV prevalence and AIDS cases, the relative rarity of drugresistant M. tuberculosis strains and the comprehensive support of the Ministry of Health for improving the health of the Cuban population by the year 2000, the elimination of tuberculosis in the first half of the next century is a definite possibility.

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35. 36.

37.

38.

39.

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41.

42

43 44

45.

46 47.

48. 49.

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