1976 Albert Lasker Public Service Award

Smallpox eradication

Smallpox, mankind's most feared and devastating infection, has, over the centuries, killed, blinded, and scarred countless millions, and frequently has changed the course of history itself.

The war against this deadly, contagious viral disease began in England in 1796, when Edward Jenner gave the first vaccination to an eight-year-old boy.

Today, smallpox has been wiped out in all except one country in the world, and there the disease is almost conquered.

This historic achievement—accomplished within the past ten years—involved the mobilization of personnel supported and directed by the World Health Organization, to work at the request of individual governments throughout the world. A global network was organized for surveillance, research, and laboratory capabilities. Conferences at national, regional, and grassroots levels were held to implement strategies. Dedicated health worker teams were dispatched to the most remote and inaccessible villages throughout the world, to search out and isolate cases, and to vaccinate contacts. In short, every weapon in the armament of modern science and public health services was employed in this war against an international and insidious enemy.

While surveillance must continue for the next two years to insure that the eradication of smallpox is permanent, we salute this historic milestone as one of the most brilliant accomplishments in medical history.

We hope that it will provide an example of how, with coordinated international effort, many of the other health problems that afflict mankind can be successfully attacked.

For the inspiration and unparalleled example of the dedicated workers around the world who have labored tirelessly to seek and contain, one by one, each of the thousands of smallpox outbreaks—and have now practically succeeded—this Special Albert Lasker Public Health Service Award is given.

World Health Organization

Acceptance remarks by Donald Henderson, 1976 Lasker Awards Ceremony

Not two years ago, cases of smallpox such as these from India and Bangladesh were numbered in the tens of thousands. These cases are of average severity—many were much more severe. The death rate varied from 15 to 30 percent, depending primarily on the age of the patient and his nutritional status; medical care could offer little but supportive therapy since there is no known treatment for smallpox. However, on 16 October last year, the last known case occurred in Asia—the last case of variola major, the severe form of smallpox. The patient, a three-year-old girl, Rahima Banu, lives on Bhola Island, Bangladesh.

This left then but one endemic country—Ethiopia. There, a much milder form of smallpox prevailed which caused death in only one percent of those afflicted. Beginning last autumn, resources were increasingly diverted from Asia to Ethiopia and assisted by contributions from the USA, the program was greatly intensified. Villagers in the infected areas were trained to search for cases and to vaccinate. For supervision, additional Ethiopian health officers and sanitarians were deputed to the program and the number of WHO epidemiologists was increased. Helicopters were deployed to facilitate supervision and to assist in the search for the remaining infected foci. The endemic areas steadily decreased until at last, on 9 August, Ethiopia's last known case occurred in a three-year-old Somali nomad girl living in the southern Ethiopian desert.

However, our jubilation was short-lived, for in late September a focus of five further cases was unexpectedly discovered in Mogadishu, the capital of Somalia. The cases were among Somali nomads recently arrived from Ethiopia. The cases resulted from importation from one of Ethiopia's last outbreaks. Containment was rapid and thorough. As of today, 57 days have elapsed since Nura Sheikh Yusuf, a 30-year-old Somali woman, developed smallpox.

But the search for additional cases is continuing. More than 1200 Ethiopian, Somalian, and international staff are searching throughout the country, and nearly 150,000 health workers have continued to search in other countries. No further cases have been found. We cannot yet say with certainty that the last human case of smallpox has occurred. However, as each day passes it becomes increasingly probable that Nura Sheikh Yusuf represents the last case in the chain of transmission of a disease which goes back more than 4000 years—a disease which over the centuries has again and again altered the course of history.

One must date the beginning of this campaign to a day 180 years ago when Dr. Edward Jenner first showed that an individual inoculated and infected with material from a disease of cattle, called cowpox, was protected from smallpox. The discovery was the more remarkable since this occurred long before the germ theory of disease had been propounded. For vaccination, the cowpox virus was propagated then by a method of arm-to-arm inoculation—the material being taken from the developing pustule of the person inoculated in order to inoculate others. With continuing passage of the virus in this manner, the virus changed in character but it is thought that the antecedent of today's vaccine virus was cowpox virus.

Jenner's discovery was enthusiastically acclaimed and the cowpox virus, within a decade, was distributed around the world. Smallpox then was universally prevalent; as with measles, virtually everyone eventually contracted the disease; death rates were well in excess of 20 percent and smallpox was the chief cause of blindness in Europe. No disease then or now, year in and year out, wrought such havoc or was so greatly feared.

Although vaccination came to be widely practiced in Europe, North America, and in many other parts of the world, the difficulties in assuring consistently an adequate supply of vaccine through arm-to-arm transmission of virus were formidable. As the virus is readily destroyed by heat, little vaccination was performed in the tropical areas where health services were negligible and communication impossible.

In the late 1800s, vaccine virus started to be propagated by inoculation of the flank of a cow and with greater quantities of vaccine available, aided by the development of the refrigerator which served to preserve it, smallpox became less and less of a problem in the developed world. However, smallpox was still so widely prevalent in 1926 that the Swiss delegate said that year, "Smallpox has, in reality, no place in an international convention. It is not a pestilential disease in the proper sense of the term: it is, in effect, a disease that exists everywhere. There is probably not a single country of which it can be said that there are no cases of smallpox." And as recently as 1938, the United States alone recorded 15,000 cases.

By 1950, extensive vaccination programs had eliminated smallpox from Europe and North America. That year the Pan American Health Organization decided that a campaign should be conducted throughout the Americas to eradicate the disease from the Western Hemisphere. The emphasis of the program was mass vaccination with assistance being given to national laboratories to produce a freeze-dried vaccine which would be stable under extremes of temperature. The results were encouraging if not spectacular, and over the next eight years, smallpox was eliminated from Mexico, Central America and several South American countries.

Meanwhile, the subject of what should be done by WHO in smallpox control was debated annually at the World Health Assembly. Finally, in 1958, the Soviet Union proposed that a global smallpox eradication campaign be undertaken under WHO auspices. The following year, after considerable debate and many misgivings, this was decided by the Assembly. It was intended that each endemic country should give priority to the program and that voluntary donations be provided to assist in the effort. During the succeeding seven years, a number of countries undertook mass vaccination programs and a few became smallpox-free. But assistance to the program amounted to less than $100,000 per year, and those few countries which did succeed in eliminating smallpox were besieged by importations of the disease from neighboring countries.

A coordinated effort with greater financial support was clearly required. But with WHO's other eradication program—that for malaria—proving to be an increasing disappointment, there was little enthusiasm for providing yet more funds for the eradication of smallpox—an objective which most frankly stated to be an idealistic dream, not a practical goal. However, after extended, often acrimonious debate, $2.5 million was voted by the Assembly for the program. The echo of Kennedy's assertion that a man could be landed on the moon within ten years was reflected in the proposal that the target for eradication be ten years. The intensified program began in January 1967.

In theory, the global eradication of smallpox appeared to be a straightforward proposition—man being the only host, with no human carriers and with a highly effective vaccine being available. Most important, smallpox by 1967 had been eliminated from a number of developing countries—in brief, a practical demonstration that the proposition might be feasible.

During the first years of the program, enthusiasm for smallpox eradication was severely tempered by widespread skepticism that eradication of smallpox or any other disease could be achieved, given the limited resources and considerable problems of the developing world. Illustrative of these difficulties were those encountered only two years ago in Bihar State, India, the epicenter then of the epidemic in Asia. At the height of the problem the northern part of the State was swept by floods, the southern part had such severe drought that famine relief programs were launched, train services throughout India were suspended for weeks by strike, civil disorder periodically erupted requiring virtual imposition of martial law and finally, the medical staff itself went on strike for higher wages. But through all of these problems and more, a remarkable group of international and national staff, again and again, adapted, rebuilt and readjusted to cope with the most impossible problems.

Techniques employed in implementation of the program are difficult to summarize succinctly as the strategy and tactics constantly evolved as new techniques and new approaches were tried in one area and, when successful, modified and applied in other areas. No two programs are or have been identical, and the changes in as little as six months in a given program are often considerable.

When the program began, the broader strategy called for a 2-to-3 year systematic mass vaccination program throughout each country in an effort to reduce smallpox incidence to less than five cases per 100,000. This we felt would give sufficient time to develop a reporting-case detection system and would bring smallpox incidence to a sufficiently low level so that the remaining foci could be eliminated by containment of each outbreak. Soon after the program began, there was a fortuitous delay in delivery of supplies to Eastern Nigeria. This, coupled with an energetic adviser, CDC's Dr. Bill Foege, served immediately to upset the planned strategy. Bereft of supplies to begin the mass campaign, he proceeded to organize a reporting system and containment vaccination in areas where outbreaks were occurring. As each patient was detected, he was isolated, all his contacts and then the village where he lived were vaccinated and a search was begun to find the source of his infection so that other infected areas could be dealt with similarly. By the time sufficient supplies had arrived in Eastern Nigeria to undertake the mass campaign, he couldn't find smallpox. Assessment at that time showed that less than half the population had recent or old vaccination scars. These findings were soon replicated in other countries of Western Africa and subsequently in Indonesia and Brazil. These observations precipitated the first of a number of modifications in strategy. It became clear that under most circumstances, smallpox spread much more slowly than most had thought, much slower than measles or influenza, for example. Usually, one person infected not more than two to five others. Further, it was found that smallpox was rarely widely dispersed over large areas. Rather, the disease concentrated in clusters of villages or in one area of a town. Intensive efforts could thus be focused on discrete problem areas. In brief, it soon became apparent that elimination of smallpox by a surveillance-containment approach was a far more feasible proposition even in highly infected areas than had originally been envisaged. Accordingly, the development of this component of the program was given first priority.

Data gathered through surveillance showed also that smallpox in a previously vaccinated person was uncommon—in Asia, 80 percent or more of all cases were occurring among those with no vaccination scar. In Africa and South America, more than 95 percent of cases occurred in persons who had never been vaccinated. And, thus, primary vaccination became the watchword. These were the first of the early major changes.

A further major change related to vaccination technique. In 1967, as we began the program, the jet injectors replaced the traditional but less effective scratch techniques in Western Africa and South America. But the jet injectors brought in their wake a host of problems related to repair and spare parts. Fortuitously, in late 1967, Wyeth Laboratories were completing field trials of the ingenious bifurcated needles for multiple pressure vaccination. We tested these to determine if an easily taught multiple-puncture technique would be effective. With this technique, the needle, holding approximately .02 milliliters of vaccine between its two prongs, is held at a right angle to the skin. Fifteen rapid punctures are then made. The technique proved to be better than expected. Even when frank bleeding was produced—an old taboo in vaccination—take rates were superb and less than one-fourth as much vaccine was required for vaccination. We redesigned the needle, making them shorter and of a stronger steel so that they could be re-used literally hundreds of times. To date, more than 49 million have been distributed to countries throughout the world.

The third and last of the significant initial developments was an insistence on the universal and uniform application of internationally certified, potent, and stable freeze-dried vaccine. Soon after the program began, agreements were reached with laboratories in Canada and the Netherlands to test batches of vaccine used in the program. The results in 1967 were nothing short of appalling. It was found that virtually no vaccine then in use in the endemic countries met accepted standards of potency and stability. In some samples of vaccine, in fact, no virus could be detected. Our $2.5 million budget, if used in toto, was insufficient to purchase the 250 million doses of vaccine required each year for the program. And thus the decision was made to purchase no vaccine whatsoever but, rather, to provide equipment and consultants to selected laboratories in the developing countries to make at least the more populous self-sufficient. Until such production could be developed, donations were sought and obtained from more than 25 countries, but in the early years, most vaccine—over 140 million doses annually—came from the Soviet Union. Now, more than 80 percent of the vaccine in use in the formerly endemic countries is produced in the developing world and many are donating the vaccine to others—such donors include Kenya, India, Guinea and Brazil. Most important, all vaccine used in the program since 1970 has met accepted international standards of potency and stability.

By December 1967, the end of the first year of the program, a first provisional assessment of the problem was possible. That year, some 43 countries had reported cases of smallpox but it appeared that 33 were endemic—cases occurring in the rest of the countries being attributed to importations. That year, 131,000 cases of smallpox were notified. Early studies to ascertain the completeness of reporting revealed that at most one case in twenty was being reported, but later observations showed that one case in one hundred was more accurate. Thus, it is probable that some 10–15 million cases of smallpox occurred in 1967. By 1969, programs, albeit of varying quality, were underway in all countries except Ethiopia and, in 1971, the Ethiopian program began.

During the succeeding four years, substantial progress was made so that in 1971, the number of countries reporting cases of smallpox had decreased from 43 to 17. By December 1971, only nine were considered to be endemic. In the 20 countries of western and central Africa to which the USA was providing support, the last case occurred in Nigeria in June 1970, six months earlier than had been expected. In eastern Africa, endemic smallpox was limited to Ethiopia, the late starter; to southern Sudan, where civil war had precluded a program being undertaken; and to Botswana, which had been re-infected almost coincident with the last cases of smallpox in South Africa. Brazil's last case had occurred in January of 1971, Indonesia's occurred in April 1972. On the subcontinent of Asia, however, progress was disappointing. The importance of surveillance-containment measures was not appreciated. Throughout Pakistan, northern India and Bangladesh, case detection was grossly inadequate, reporting systems were antiquated and outbreak containment, when attempted, was poorly executed. Health authorities were discouraged and support was limited. Efforts to control smallpox, including a ten-year-old mass vaccination campaign in India, had seemed to have little impact; and with other health programs such as malaria and family planning yielding disappointing results, there was everywhere a sense that smallpox was inevitable—to be controlled as best one could.

The key to a breakthrough came during the 1972–1973 smallpox season. Major outbreaks were discovered in a southern district of India in what was believed to be an extensive, virtually smallpox-free area. A district comprises a population of about two million persons. District staff knew of the outbreaks but had concealed them until their discovery by a WHO epidemiologist pursuing the source of infection of a case in another state. Rapid containment was critical. To achieve this, all health staff were mobilized for a house-by-house search for cases throughout the district. Two weeks of preparation were followed by a search which was completed in only one week and which, by independent assessment, was surprisingly thorough. Numerous unknown outbreaks were discovered and rapidly contained. The district became free of smallpox in a matter of weeks. Until then, it had not really been appreciated how many health staff are deployed in India nor how readily they could be mobilized to undertake a planned series of activities. The experience in this one district was successfully replicated on a statewide basis during the spring of 1973.

In the summer of 1973, it was decided to extend throughout India the approach of monthly searches extending over seven days and involving most, if not all, health staff. Extensive preparation followed. The first search occurred in October. The results were both encouraging and appalling. The State of Uttar Pradesh, with its population of 95 million people, had been reporting 100–300 cases per week. The first search in October revealed over 7,000 cases. But even these figures understated the problem. Independent assessment later showed that only 50 percent of the villages reported as searched had actually been visited. Improvements on this framework of case detection were made almost monthly thereafter. Special assistance was made available by the Government of Sweden. House-by-house search replaced a village-by-village search; between searches, special surveillance teams contacted persons at markets and schools to detect rumors of cases; an increasingly substantial reward was publicized to be paid to the person who reports a case and to the health worker receiving the report. Containment measures were steadily made more stringent. Special containment books were prepared which required listing and vaccinating every person in the village and all those for one mile around to ensure none were missed. House guards were hired locally to stand 24-hour guard to vaccinate all visitors and to prevent the patient from leaving the house. With improvement in notification, the number of reported cases sky-rocketed. In 1974, more than 218,000 cases were eventually reported—the highest total of cases since 1958. Newspapers reported the disaster in detail and more than one wrote an obituary of the global eradication program. Those involved with the program, however, felt that we had, at last, the key to eradication on the subcontinent.

Of the five Asian countries still endemic in 1971, Afghanistan became free in 1972 and Pakistan's last case occurred in October 1974. Nepal, plagued by more than a hundred importations from India, recorded its last case in April 1975.

In July 1974, we adopted a new unit of measurement to assess progress—the "infected village." A village (or ward in a city) was declared to be infected and entered on a list when one or more cases occurred. The village remained on the list until six weeks had elapsed since the last case and until an epidemiologist had certified through special search that transmission had been stopped.

India recorded over 7,000 villages in July 1974; the number fell to the 300–350 range by November. The last known case occurred on 24 May 1975.

In Bangladesh, optimism ran high in late 1974 as the number of infected villages reached 91. Unhappily, almost all were situated precisely in an area heavily afflicted by a famine which had followed the most devastating floods in decades. Hundreds of thousands of beggars, some infected with smallpox, began moving rapidly to all points of the country and despite heroic efforts, it was impossible to stem the tide. Smallpox spread as we had never before observed it. One memorable beggar, during two days in a market place, infected 52 persons in 18 villages. The final blow fell in January when the government without warning bulldozed the slums of Dacca, displacing 500,000 people. What had been small, reasonably well contained outbreaks in Dacca became dozens of satellite outbreaks scattered across the country. In mid-February, a more intensive program began. A peak of 1280 infected villages was reached in late April. But a highly effective program materially aided by the epidemiologist's best friend—the end of the high transmission season—rapidly decreased incidence.

On 16 October, there occurred the last case in Bangladesh—in fact, the world's last known case of variola major. Following this 12,000 health workers, supervised by nearly 100 international and national epidemiologists, have repeatedly searched the country house by house as they have in India and Pakistan. No cases have been found. Although search activities are continuing and will continue until two years after the occurrence of the last case, it now seems highly improbable that further cases will be found.

Ethiopia alone then remained a problem. Why? The program there did not commence until 1971, two years later than in any other endemic country. Again, it was malaria eradication which cast the shadow. Almost 11,000 workers and most of the country's health resources were engaged in a program which was obviously in serious trouble. Another eradication program they did not want. Finally, in 1970, national authorities agreed that the country would make available some 20 sanitarians if WHO would bear all other costs. We enlisted the help of 35 volunteers from the USA, Japan and Austria, and, with more hope than expectations of success, commenced a program. Seventy staff are few indeed to deal with a country which is more than twice the size of New England, New York, Pennsylvania and New Jersey combined. A country wherein half the population of approximately 25 million persons lives more than a day's walk from any sort of road and in houses scattered across the terrain, not in villages. A country in which health services are among the world's least developed. A country in which civil disorder was not infrequent, as isolated rural people resisted any sort of central authority.

And there were other problems. With little vaccination being given anywhere, variolation was often practiced as a protective measure against smallpox. In such areas extending over half the country, resistance to accepting vaccination was high. Communication facilities are few. And over the past two years, with the civil war in Eritrea, there have been problems in obtaining petrol and shortages of a variety of commodities. I could continue but perhaps this is enough to provide a sense of the magnitude of the problem. Operations were initially concentrated in the southwest of Ethiopia to protect smallpox-free areas in adjacent African countries and in Eritrea, where a network of health facilities permitted an active program with little additional manpower. During the first year, the number of registered cases rose from 700 to 26,000. But even then, I doubt we actually recorded more than one case in ten of those which actually occurred. Gradually however, province after province became free of smallpox until early last year; only 5 of the 14 remained infected. At that time, with additional funds at last made available, we were able to extend operations by recruiting and training local villagers. The numbers of staff rose from less than 100 to more than 1000. Helicopters were brought in to support the operations. Between January and July, the number of infected villages gradually rose as previously inaccessible areas were placed under surveillance. In early July, the total of infected villages reached 144, but since that time, the number fell steadily, if irregularly. Finally, this summer, a last small flurry of outbreaks occurred among nomads in the vast famine-stricken Ogaden desert. Control of the outbreaks was impeded by serious floods in the only major river in the area, the Wabi-Shebale, as roads and airplane landing-strips were washed away. But one by one the outbreaks were brought under control and search operations extended further and further across the area. The last of the known outbreaks occurred on 9 August in the nomadic village of Dimo, located more than 2.5 days' walk from the nearest market, isolated in the trackless scrub desert which extends over tens of thousands of square miles.

Seven weeks elapsed with no further cases being discovered. But on 23 September we were rudely shocked by a cable from Mogadishu, the capital of Somalia, reporting two cases of laboratory confirmed smallpox. The first case had occurred on 30 August—the last on 23 September. All patients were reported to have traveled separately by different routes and had only recently arrived in Mogadishu, fully 300 kilometers from the border. We calculated that there were at least two missing generations of cases, but where? Nearly 400 Ethiopian and Somali workers fanned out along every route traversed by the cases. Mogadishu itself was searched house by house.

Since then, specially planned, intensive search operations have been conducted throughout the most recently infected areas. In other provinces, teams have continued to search systematically once every two to three months through all villages, the markets and the schools, in an effort to detect evidence of existing or recent smallpox spread. None has yet been found…. But the search goes on.

By no means does this signify the end of the program. We cannot relax our efforts until we are completely satisfied that transmission has been interrupted. As much as 8 months have elapsed in recently endemic countries during which no cases were found, only to discover that unsuspected transmission was still occurring. Thus, on the advice of a WHO expert committee, it was decided that not less than 24 months of intensive search must continue after the last case (or fully three times the 8-month period) and then an international commission, after a full review of the program, must be satisfied that activities have been sufficiently intensive to detect smallpox if it had been present. International commissions have thus far certified the eradication of smallpox in the Americas in August 1972, in Indonesia in April 1973, and in 15 countries of Western Africa in April 1976. Hopefully, the last commission will be able to be convened in September 1978 to formally declare that eradication has been achieved in the last endemic area.

While eradication campaigns have been in progress in each of the countries, we have naturally been concerned as to whether or not smallpox might once again emerge from some unknown animal reservoir, from old scabs lying dormant or from some other source. The best evidence to suggest that this will not occur is the fact that during the past 10 years, no case of smallpox has occurred in the increasingly vast smallpox-free world which could not be traced to specific importations from known endemic areas. However, 23 illnesses closely resembling smallpox have been detected in Africa. All cases have occurred in remote villages in the tropical rain forest. Monkeypox virus has been documented as the cause for each either by virus isolation or serology. The virus, whose reservoir is not known but is probably rodents rather than monkeys, is related to but virologically different from smallpox. Most important, its capacity to spread in humans appears to be close to nil.

Hopefully, at this time, variola virus remains only in research laboratories. Laboratory infections due to smallpox are uncommon. Only two, possibly three, episodes are known. The virus is simply not that infectious. However, a program has begun in cooperation with governments and research laboratories to register all laboratories retaining stocks of variola virus. When this is done, a meeting of laboratory directors will be convened to draw up specific recommendations for laboratory safety to assure that there is no accidental escape of the virus. So far, reports have been received from all but a few of the 179 countries and areas, and 38 laboratories are presently registered as retaining stocks of variola virus. Hopefully, this number may soon be reduced to less than ten.

Frequently asked is the question, what has all of this cost? By 1978, when the last international commission has met, the total international investment, including bilateral assistance and donations provided through WHO, both in the form of cash and as vaccines and personnel, will be about $96 million or an average cost of about $8 million each year. The endemic countries have themselves spent perhaps twice this amount, but few have spent much more than what they had previously been spending year after year in a never-ending struggle to control the disease.

With confirmation of eradication, vaccination everywhere will be able to be stopped. The savings are considerable. A study in the USA in 1969 showed that in the USA alone some $150 million was being spent each year in smallpox vaccination, in hospital care for those experiencing complications and for quarantine measures. Worldwide, the costs are perhaps $1 billion annually.

Were the smallpox eradication campaign to be assessed purely in terms of cost-effectiveness ratios, it would clearly be regarded as having been a worthwhile investment. Illustrative is the fact that the United States will have recouped in 2.5 years all that it has contributed to WHO since 1948. All bilateral assistance from the USA for smallpox eradication will have been recovered in 56 days. As one delegate to the World Health Assembly observed, had the Organization never undertaken any other activity, its existence would be fully justified.

Of greater importance, however, are the implications which this program bears for the future in providing an example of how much can be achieved and for so little when there is a willingness on the part of all governments to pool their efforts in a clearly defined effort and an international organization able and willing to accept the challenge of carrying it out. More than 150,000 national staff have worked closely with more than 600 WHO staff and consultants from 51 countries under the most impossible of conditions; voluntary donations have been received from 43 countries and many private sources—and the list of contributors embraces those in the developing world—such as India, Kenya, Guinea, Uganda and Nigeria, to mention but a few; teams from neighboring countries have crossed hitherto sacrosanct national borders to cope with common problems; necessary research has been willingly undertaken as a cooperative effort by scientists across the world—from the USA, Netherlands, UK, Canada, Soviet Union, Bangladesh, India, and Japan.

In the previously endemic countries, the results have been gratifying. For many nascent health services, it has provided a needed sense of confidence which achievement can bring; it has dramatized the impact which preventive medicine can have and the potential for delivery which is implicit even with existing health staff when there is careful planning, management and motivation; and, not least of all, the potential of a United Nations organization in orchestrating such an effort.

Although the end of smallpox is clearly in sight, I believe the achievement must be viewed in perspective as but a small step in shifting our focus from curative medicine for the few to preventive medicine for all.