A Trfbute to Carl Djensssi: Reflections on a Remarkable Scientific Entrepreneur

Number 42 October 18,1982

There has been much said about the Djerassi is best known to the public for scientflc entrepreneur. Ordinarily the h~ contribution to the development of term is applied to the scientist who has the birth control pill. But research in con- been successful in business, One thinks traception is only one aspect of his multi- of Thomas Edison or Edwin Land, faceted career. He is one of the giants of founder of Polaroid, among others, But modern organic chemistry. Carl has been there are also scientific entrepreneurs in a leader in analyzing or “elucidating” the the academic community. Many Cur- structures of complex organic molecules rent Contents@ (G@’ ) readers fall into and in applying these discoveries to the this category so I will not belabor the synthesis of pharmaceutically important point. My reason for mentioning these compounds. He is also responsible for two meanings of scientific entrepreneur major advances in the methodologies is to emphasize that we rarely find both used by organic chemists. Analytical kinds in one person. To maintain a cred- techniques which he helped develop, ible academic existence one needs enor- such as optical rotatory dispersion, circu- mous dedication and energy. To func- lar dichroism, and mass spectrometry, tion in a scientifically oriented business are now among the most widely used you need these qualities as well as signifi- took in organic chemistry. cant managerial competence. That rare I first met Djerassi back in 1959. We combination of qualities is found in my were introduced by , friend . who refers to Carl as one of the “wonders I recently had the honor of speaking of nature. ”I In 1960, when lS1° began informally at a very unusual event. The publishing Index Chemicus@ (Z@), now numerous friends and collaborators of Current Abstracts of Chemistry and Djerassi attended a party celebrating the Index Chemicus” (CA C&IC@ ), Carl publication of his 1,000th paper. My ad- served on the editorial advisory board. lib comments on that occasion left me He also lent his enthusiastic support to somewhat frustrated. In the euphoria of our next project, Science Citation In- the moment I failed to state so many of dex” (SCP ). Carl became one of the the more relevant facts about his many first memberx of the edkorial advisory accomplishments that I wished I had board of CC/Space, Electronic & Phys- come prepared with an appropriate ora- icai Sciences, a predecessor of CC/ tion, which I now belatedly provide. PhysicaL Chemical & Earth Sciences Perhaps only Carl and his closest friends (CC/PC&ES). In addition to his profes- will understand the special sympathies sional advice and encouragement, Carl we share, not the least of which is his ap- has shared with me his friendship and preciation of art and humanistic studies. joie de vivre.

721 of industrial experience he grew restless and eager for a position in academe, but he could not find one. Then, in the spring of 1949, D jerassi received a call from chemist George Rosenkranz. Ro- senkranz was the director of a small Mexican company called Syntex, and he invited Djerassi to head a research team there.z The job was appealing in that it would allow Carl to continue his investi- gation into the chemistry of steroids. Steroids were of interest to Djerassi and others because of their complicated structures and their prominent role in regulating such physiological processes as reproduction, digestion, and calcium metabolism. As more and more was un- derstood about the function of steroids in the body, their importance as phar- maceutical agents increased dramatical- Carl Djerassi ly. Steroid chemistry had been the sub- ject of Djerassi’s PhD thesis, but at Ciba Djerassi was bo~ in Vienna in 1923. it was difficult to keep working in this His Bulgarian-born father and Austrian area. Company policy confined most mother were both physicians. After the steroid research to the laboratories at outbreak of World War II, he emigrated Ciba’s Swiss headquarters. to the US with only $30 in his pocket. He It is of interest to mention that during spent two semesters at a now defunct this period the work on steroid chemis- junior college in Newark, New Jersey, try was almost frantic. In fact, the back- before accepting a scholarship from log of applications at the US Patent Of- Tarkio College, a small school in Tarkio, fice was eventuaUy so large that the Missouri. He later transferred to Ken- Pharmaceutical Manufacturers Associa- yon College, Ohio, and graduated sum- tion financed a steroid literature coding ma cum laude before his nineteenth project. Eugene Garfield Associates, birthday. Our foreign readers should re- predecessor of 1S1, received the con- alize that most Americans graduate at tract to do this work in 1958. We encod- the age of 22. ed over 20,000 steroid compounds and At this point, he joined a research established a precedent for the widely team at the Ciba Pharmaceutical Com- used fragment coding system employed pany, Summit, New Jersey. Within a in the Index Chemicus Registry System@ year, he and hk co-workers developed (ICR.S” ) and other systems. one of the first successful antihista- At the end of the 1940s, much of the mines, tnpelannamine. This compound, excitement centered around the dis- marketed by the Ciba-Geigy Corpora- covery that a steroid hormone, corti- tion as Pyribenzamine, is still used to sone, could aUeviate arthritis symptoms. treat a variety of allergy symptoms. The chemical could be derived from In 1943, Carl enrolled in the graduate animal bile, but initially not in amounts program at the University of Wisconsin. large enough to be of use in treating this He earned a PhD in organic chemistry chronic, widespread disease. Scientists before his twenty-second birthday and around the world were racing to find a returned to Ciba. After four more years more practical method for synthesizing

722 cortisone. The team Djerassi was invited the kind described earlier were rarely to head at Syntex was in fact attempting performed, “Natural products,” or natu- to develop a new synthesis. Djerassi ac- rafly occurring organic substances, can cepted the job, and in 1951, his team be used as models for synthetic com- won the race. They found away to make pounds. However, many natural prod- cortisone relatively simply, using a ucts consist of molecules so large, com- readily available raw material, the Mex- plex, and delicate that relationships be- ican yam. 3 tween their structure and function—and That same year, Djerassi’s team syn- in some cases, the structures them- thesized another compound which re- selves—are often obscure. At the time ceived much less attention at the time. when Djerassi was beginning his career, They named it “norethisterone,” and it it was still not uncommon for a natural was to become the active ingredient in products chemist using traditional ana- the birth control pill. Today it is known lytical methods to spend a lifetime eluci- as norethlndrone. dating the structure of a single sub- The work began with the female stance.4 hormone progesterone. Among other It was to a persistent problem, the in- things, progesterone prevents women adequacy of physical methods available from ovulating during pregnancy, thus for assessing organic structures, that acting as a natural contraceptive. Djer- Djerassi now turned his attention. He assi’s team found that by making a very was offered a professorship at Wayne spectilc change in progesterone’s chemi- State University, Detroit, in 1952. The cal structure, they could increase its following year he and his colleagues potency eightfold. This “analog” or syn- began to investigate optical rotatory thetic version of progesterone was dispersion. strong enough to work when injected, Optical rotatory dispersion and opti- but it lost its potency when administered cal circular dichroism, which Djerassi orally. The Syntex group needed a and others developed a decade later, use chemical which would be absorbed by polarized light to take an “impression” of the oral route. A breakthrough came a molecule’s three-dimensional shape. when they “rediscovered” a compound Both techniques operate on a principle synthesized more than a decade earlier known as the “Cotton effect,” named for but largely ignored because of its ap- a nineteenth-century French physicist, parent lack of medicinal value.z It was Fran~ois Cottons Cotton observed that called ethisterone and its activity in the polarized light can undergo changes body was not udlke that of progester- when it passes through certain sub- one. Moreover, its activity persisted stances. Dj erassi was able to transform even when taken orally. Djerassi’s group thk phenomenon into a practical tool devised a way to make the same chemi- for analyzing molecular structures. He cal modification in ethisterone which found that many organic substances, they had earlier made in progesterone. notably those containing a carbonyl The result was synthetic noreth~terone, group, produced the Cotton effect, and which prevented ovulation, was orally that the intensity of the effect vaned active, and could be incorporated into a with the wavelength of the light. He pill.z graphed these changes as “Cotton effect It is, of course, more efficient to me- curves,” and determined that many mo- thodically rearrange molecules, enhanc- lecular structures produced their own ing or creating desirable chemical prop- distinctive curves. By using these curves erties, than it is to randomly synthesize as “fingerprints” of molecules, he could compounds for biological testing. But make comparisons between molecules until recently, specific manipulations of never before possible. The “stereochem-

723 ish-y” or three-dimensionality of un- ples. Djerassi provided information known structures could be deduced which had long been sought concerning from known structures and subtle dif- the biosynthesis of terpenoids. He did ferences between similar molecules this by determining the structure of discemed.b iresin, a key biosynthetic “missing link’ Optical rotatory dispersion and circu- between the lower and higher ter- lar dichroism measure two different penes.ls components of the Cotton effect. The Djerassi also grew interested, during former detects a rotation in the light the 1950s, in other classes of chemicals, waves. The latter measures a change in particularly the alkaloids and the macro- the way the waves oscillate, a transition Iide antibiotics. In 1956, he and J.A. from a strictly “back-and-forth” to an Zderic became the first investigators to elliptical motion. Both techniques have elucidate the structure of a macrolide opened new fields in organic chemistry.b antibiotic.b As the prefix “macro” sug- In addition to enormously speeding up gests, the macrolides are large ring com- the process of stereochemical elucida- pounds. Their size and complexity had tion, they have made it possible for impeded prior efforts to elucidate them. chemists to work with minute quantities Djerassi and his team established the of compounds they are examining. This structures of methymycin and neo- is important because many naturally oc- methymycin and helped to elucidate the curring organic chemicals are scarce. clinically important macrolide, erythro- Moreover, unlike the analytical tech- mycin. b One special feature of the mac- niques previously in use, Djerassi’s in- rolides is that they include the only anti- ventions made it possible for chemists to biotics effective against fungal dis- “see” how atoms are positioned in orders. space—or, in other words, establish During the 1950s and 1960s, much of their “absolute configuration. ” Thus, Djerassi’s work involved novel alkaloids chemists may effectively distinguish be- found in tropical plants. Alkaloids are a tween molecules which are mirror im- class of chemicals with a long history as ages of one another. Such distinctions hallucinogens, narcotics, poisons, and are crucial, Djerassi explains, because medicines. Their name comes from the mirror-image molecules may have en- fact that they are generally basic, or tirely different biological properties. For “alkaline. ” In this field, Djerassi saw example, the important hormones or promise in a new analytical technique amino acids are biologically active in called mass spectrometry. one mirror-image form, but totally inac- A mass spectrometer is essentially a tive in the others “sophisticated weighing machine. ”lb Although optical rotatory dispersion The substance under study, in gaseous and circular dichroism quickly became form, enters a chamber where its mole- part of the standard vocabulary of or- cules are broken into a variety of frag- ganic chemistry, some of the most im- ments through electron bombardment. portant discoveries involving them have Some of these fragments carry a charge been made in Djerassi’s laboratory .T-lx and thus can be deflected and focused During the 1950s much of this work in- by electric and magnetic fields. Heavy volved the elucidation of the structures particles will be deflected less than light of terpenoids. Terpenoids are a large ones with the same charge. Depending class of chemicals which include the on their masses and charges, fragments body’s essential oils, vitamins A, E, and will fall in predictable locations on a K, most perfumes, natural rubber, and photographic or electronic detector. lb the chemicals which are the precursors Up until the 1960s, mass spectrometry of cholesterol, to name only a few exam- had not been a very useful tool for chem-

724 ists elucidating organic structures. The “a major collaborative program on the reason was that under electron bom- use of computer ‘’ bardment, organic molecules would techniques in organic chemistry .’’22T2T merely “shatter into a confusing array of Their group developed a series of com- pieces. ” As was recently noted in Sci- puter programs which take raw data ence News, itwas a bit like “dksecting a from mass spectrometry and other phys- watch with a sledge hammer. ”lGWithout ical or chemical data and process it in a detailed knowledge of how these mole- ways which make it easier to analyze. cules were likely to split apart, it was dif- For instance, given the mass and charge ficult to identify fragments just on the of a particular fragment, a computer basis of their mass and charge. could create a fist of possible identities In 1961, Djerassi, who had been on for the fragment. Different programs the faculty of Stanford University for could produce similar lists on the basis of two years, began to develop mass spec- other criteria. Computers, as Djerassi trometry as a tool for structural elucida- points out, aflow chemists to examine al- tion. This involved looking for rules ternative structures in an “absolutely rig- which could be used to understand the orous way. “s One program, the Meta- fragmentation behavior of organic DENDRAL program,zT can even search molecules. He and his associates began for new rules concerning the fragmenta- by synthesizing hundreds of small tion behavior of complex molecules by “model” compounds, and bombarding working “backward,” or generalizing these with electrons. In this way, they from patterns found in spec~lc data, determined how different groups of thus further refining the technique of atoms, which normally make up seg- mass spectrometry. ments of organic molecules, responded In the past decade, Djerassi has em- to electron bombardment. 17They com- ployed the new analytical methods he pared these results with the fragmenta- helped develop to examine a group of tion patterns of more complex mole- exotic sterols found only in such marine cules and were eventually able to pro- animals as sponges and soft corals. The duce a comprehensive set of theories sterols produced by terrestrial organisms which could be used to interpret the include only cholesterol and a few simp- mass spectra of organic molecules. Their le variations. But a single marine or- work was crucial in making available a ganism may produce as many as 70 dif- technique which is now one of the two ferent sterols. zs “The question,” most widely used physical methods in or- Djerassi muses, “is what are these things ganic chemistry.b I remember the early doing in the ocean, and why are they days of Carl’s interest in mass spectrom- not in plants and animals on earth?”s etry because we considered the possibili- One intriguing possibility is that these ty of creating a new molecular weight in- sterols represent “missing links” which dex for ZC, to be derived automatically will tell us something about the evolu- from the molecular formula. Since that tion of celf membranes.zg It has recently time, some of Carl’s most important dis- been discovered that sterols help to coveries and influential publications] 7-Z3 maintain the integrity of cell mem- have been built on the earlier research, ~ranes, and are involved with regulating which made it possible for him to use their permeability. Prokaryotes, primi- and interpret mass spectral data. tive single-cefled organisms like bacteria During the past ten years, Djerassi has md blue-green algae, cannot manuf ac- continued his efforts to develop and re- :ure sterols as do eukaryotes. The abili- fine the toofs used for structural ehscida- :y to do so was probably a prerequisite tion. Together with Lederberg and Ed- ‘or the evolution of multicellular forms ward Feigenbaum, D jerassi undertook >f liie.’2g The presence of a host of novel

725 sterols in primitive aquatic animals may in miniature. The Zoecon group has also reveal how the first step in the evolution initiated studies of pheromones, chemi- of higher life forms took place. It may cals which insects secrete in order to also offer further insight into the communicate with one another. Phero- physiology of cell membranes.zg mones can attract insects to traps, which Up until 1972, in addition to the re- they mistake for females; can convince search which Djerassi did at Wayne them to emerge prematurely from hiber- State and Stanford, he also maintained nation and freeze; or can alarm them, hls affiliation with Syntex. He traveled to causing them to “run like crazy or drop Mexico when he was on sabbatical leave off the leaf” or whatever they may be from Wayne State, and continued to eating. m serve as a vice-president of Syntex until Djerassi believes these new pesticides 1959, when he accepted his professor- can help reduce the “chemical load” in ship at Stanford. A few years later, Syn- the environment.5 “Although we cannot tex moved its research headquarters to eliminate the chemicals in our environ- the Stanford Industrial Park and Djer- ment, we can have both fewer chemicals assi served as its president until 1972. and more exquisitely designed ones, ” That year he resigned from Syntex in says D jerassi. “I can think of no area order to devote his time outside the uni- where we can do this more effectively versity to Zoecon Corporation, a smalf than with pest control.” Insect-borne offshoot of Syntex which he helped to diseases, he points out, kill more people found. Zoecon, a company engaged in worldwide “than cancer, heart disease, developing “biorational” insecticides, or anything else we are worried about continues to receive much of Djerassi’s here.”s Much of the world’s food supply attention, as he is both the president and is also destroyed each year by insects chairman of the board. and other pests. The insect control agents being devel- In areas like pest control and birth oped at Zoecon are analogs, or near du- control, Djerassi has argued that the plicates, of naturally occurring insect problems of the less-developed coun- hormones. For instance, by modifying tries ought to be given more priority in the chemical structure of insect “juve- the scientific community. He feels that nile” hormone, Zoecon workers have safer and more effective technologies derived substances which can retard an are needed but are not being developed insect’s development. The result is for a number of reasons.sl In his most re- either the death of the insect, or its inef- cent book, The Politics of Contracep- fectiveness as a pest. Hormone analogs, tion,2 reviewed in CC,32 Djerassi ex- unlike other pesticides, can be made amines the web of economic and politi- quite specific in their action. They do cal factors affecting the fate of new tech- not kill the targeted insects’ natural nologies. In her review of the book, predators, nor do they persist in the en- Elizabeth B. Connell, Northwestern vironment, ~ Thus it appears that they University, Chicago, Illinois, writes, are remarkably free from adverse eco- “Only an individual with Djerassi’s di- logical effects. verse background—scientist, politician, In addition to hormone analogs which writer, and keen observer of the social stunt insects’ growth, there are others and bureaucratic scene—could have which can cause “insect mental retarda- produced a volume so vitalfy important tion,” A treated moth, for instance, and eminently readable. ”ss might continue to behave like a larva.~ One issue Djerassi confronts is that of Other analogs interfere with molting, government regulation. Our regulatory and still others cause insects to develop apparatus, as he points out, is geared

726 toward preventing risks, rather than en- Djerassi’s work on the methodology and couraging needed kinds of research. direction of research in organic chemis- There is no mechanism for taking ac- try has been enormous. This is consis- count of the price that society might tently reflected in our citation studies. In have to pay for letting certain technolo- our most recent study of the 1,000 most- gies go undeveloped. Since birth control cited authors publishing between 1965 is an urgent problem for the populations and 1978,3S he appeared as the 49th of the less-developed countries, the most-cited author, having received over price of our failure to innovate is paid 7,700 citations during these years. When most heavily by them. It is interesting to we did our 1976 study of the top 300 ponder Djerassi’s suggestion that if the scientists cited between 1961 and 1976, regulatory climate had been the same in we discovered that Djerassi’s citation the 1950s as it is today, the birth con- count for this period was over 11 ,000,M trol pill might still be a “laboratory higher than that of any other organic curiosity.”z (p. 85) chemist. As a senior researcher, Djerassi In addition to gearing investigations usually is named last when coauthoring a more toward the needs of the less-devel- paper. Nonetheless, his first author oped countries, Djerassi feels that the papers alone have been cited over international scientific community 10,000 times since 1961. When we pub- ought to provide more aid to researchers lish the 1955-1964 SCI we will have more in these countries. He has sponsored a data on the crucial 1950s. number of measures to increase the level The number of papers Djerassi has of scientific exchange between the in- published which can be regarded as clas- dustrialized and the nonindustrialized sics is remarkable in itself. Formerly, his countries. He served on, and for several most-cited paper was “The direct con- years chaired, the National Academy of version of steroidal AS-3/3-alcohols to A5- Sciences Board on Science and Technol- and A’t-3-ketones. “37 Several years ago ogy for International Development. The we invited Carl to write this up as a Cita- board has organized bilateral workshops tion Classic, but he declined because he in many countries of Latin America, felt that his 1961 article, “Structure and Asia, and Africa. the optical rotatory dispersion of Djerassi has also been a longtime par- saturated ketones,”9 was far more in- ticipant in the Pugwash Conferences on fluential. The citation data now agree Science and World Affairs.~ His pro- with Dj erassi’s assessment and thk is posal for a scientific exchange program, currently his most-cited paper. We are presented to a Pugwash Conference in pleased that his personal report on that 1967, resulted in the establishment of the milestone work appears on page 22 of International Center for Insect Physiol- th~ week’s issue of CC/X&ES.~ The ogy and Ecology (ICIPE) in Nairobi, paper is coauthored with Nobel chemist Kenya. This center is an outstanding ex- Robert B. Woodward, and is based on ample of effective international collabo- Djerassi’s initial work with optical ration. rotatory dispersion. It discloses the cor- Despite the attention he has received relation between the optical and struc- for his role in the development of the tural characteristics of sterols. birth control pill, and for his efforts to Another Citation Classic~ by Djerassi lessen the technological and economic is a book he coauthored with his post- gap between developed and less-devel- doctoral fellows Herbert Budzikiewicz oped countries, D jerassi feels that hk rind Dudley Wilfiams, entitled Mass most significant contributions have been Spectrometry of Organic Compounds.@ in basic research. Indeed, the impact of Since its appearance in 1%7, it has been

727 explicitly cited over 2,750 times. The rres a moderate teaclnng load. lMrmg book is based largely on conclusions the past few years he has been particu- which emerged from Djerassi’s experi- larly active in undergraduate teaching mental work with mass spectrometry. It by developing a series of policy courses outlines the theoretical basis of fragmen- taught as part of Stanfords innovative tation behavior of organic molecules. human biology program. Djerassi also wrote a book entitled Op- Carl’s penchant for inventing things tical Rotatory Dispersion: Applications has carried over into hk private life. Un- to Organic Chemistry,41 which has been fortunately, as the result of a skiing acci- cited over 1,200 times since its publica- dent, Carl has a fused knee. But, with tionin 1960. the help of a student, he designed a spe- Djerassi’s achievements have been cial ski boot which has enabled him to recognized with a long list of honors and continue his favorite sport. In addition awards. In addition to being awarded to skiing, Cad’s avocations include col- nine honorary doctorates, he is a mem- lecting both primitive and modern art ber of the US National Academy of Sci- (notably the works of Paul Klee), and at- ences, the American Academy of Arts tending every performance of the San and Sciences, and several foreign acade- Francisco opera. His love for travel and mies. outdoor sports culminated last year in a The American Chemical Society has three-week trek through the Himalayas honored him with many different in Bhutan, where his fused knee did not awards, among them the Award in Pure prevent him from climbing up to alti- Chemistry ( 1959), the Baekeland Medal tudes of 15,000-16,000 feet. (1959), the Fritzsche Award (1960), the It is a privilege to know and write Award for Creative Invention (1973), about someone with Djerassi’s range of and most recently (1982) the American interests and humanitarian concerns. Chemical Society’s Award in the Chem- His efforts to develop new technical istry of Contemporary Technological met hods for organic chemists, and his Problems. He afso received the Freed- desire to unstop administrative and reg- man Foundation Patent Award (197 1) ulatory bottlenecks, reflect two differ- and the Chemical Pioneer Award ( 1973) ent sides of his fierce commitment to of the American Institute of Chemists, productive science. Generations of and the Perkin Medal of the Society for chemists as well as the world’s popula- Chemical Industry ( 1975). At a cere- tion at large will benefit from his tireless mony at the White House in 1973, then intellect and from his capacity to share President Richard M. Nixon presented his discoveries and perspectives with Djerassi with the National Medal of others. Science. Djerassi was inducted into the I look forward to following Carl’s National Inventors Hall of Fame in 1978. work in the future. Maybe, he jokes, he That same year he was the first recipient wifl change h~ name and begin publish- of the Wolf Foundation Prize. As we will ing another 1,000 papers. This would be explain in a future essay, this is one of an impressive feat. There is actually a the most remunerative and prestigious record of one scientist, entomologist awards in science today. Theodore Dru Alison Cockerell (1865- In addition to his duties directing proj- 1948), who published over 3,904 items. ects at Zoecon, Djerassi has a full On the other hand, the eminent re- schedule as a Stanford faculty member. searcher Lord Kelvin published “only” Even though formally on a half-time ap- about 650 papers. Of course, it is diffi- pointment, he supervises the research cult to measure the quality and import in work of approximately 20 graduate stu- the fields involved. The ability to publish dents and postdoctoral fellows, and car- large numbers of papers varies from field

728 to field. In modem astronomy it is not like Djerassi. For instance, my friend feasible to publish a paper every week Alan L. Mackay, Birbeck College, Uni- for 20 years or more. Perhaps in ancient versit y of London, UK, recently brought times it was. Today, even proltilc mathe- to my attention the fact that the bibliog- maticians do not produce as many pa- raphy of the late Nikolai Vassilevich pers as do, say, life scientists. Within a Belov, Institute of Crystallography, field, however, according to Derek J. Moscow, USSR, includes approximately de Solla Price, there is generally a good 1,5fM publications.43 If any CC readers correlation between “the quantity and know of other authors who have pub- quality” of a researcher’s publications. lished, or are about to publish, their The most widely accepted explanation 1,000th paper, please let us know. When for this phenomenon is that successful we have completed publication of publication leads to further publication SC1 for 1955-1964 we will obtain a list of and lack of success tends to discourage the most prolific authors for the past 25 publication. The best researchers tend years. to be prolific publishers as well, and only rarely will their papers be “trivial and un- cited. ”42 There is a tendency to deni- ***** grate prolific scientists and lump them all together as though there were not considerable variation in the reasons why they are so prolific. My thanks to Patricia HelIer and We hope that this essay will be the first Kathleen Neil Schalch for their help in in a series of tributes to prolific scientists the preparation of this essay. 0158?tsl

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