The European School of Oncology came into existence to respond to a need for information, education and training in the field of the diagnosis and treatment of cancer. There are two main reasons why such an initiative was considered necessary. Firstly, the teaching of oncology requires a rigorously multidiscipli nary approach which is difficult for the Universities to put into practice since their system is mainly disciplinary orientated. Secondly, the rate of technological development that impinges on the diagnosis and treatment of cancer has been so rapid that it is not an easy task for medical faculties to adapt their curricula flexibly. With its residential courses for organ pathologies and the seminars on new techniques (laser, monoclonal antibodies, imaging techniques etc.) or on the principal therapeutic controversies (conservative or mutilating surgery, primary or adjuvant chemotherapy, radiotherapy alone or integrated), it is the ambition of the European School of Oncology to fill a cultural and scientific gap and, thereby, create a bridge between the University and Industry and between these two and daily medical practice. One of the more recent initiatives of ESO has been the institution of permanent study groups, also called task forces, where a limited number of leading experts are invited to meet once a year with the aim of defining the state of the art and possibly reaching a consensus on future developments in specific fields of on cology."

The epididymis has great significance in the reproductive biology of the male and it is gaining recognition as an organ worthy of study in its own right - where the secretory and absorptive activities of one tissue (the epithelium) profoundly modify the function of another (the spermatozoon). Apart from cases of epididymal agenesis or physical blockage, however, it is not yet known to what extent mal functions of the epididymis contribute to "unexplained" male infer tility, but its importance as a target for antifertility agents in the male is now widely appreciated. This monograph evolved from two lectures on epididymal func tion given at the National Research Institute for Family Planning, Beijing and the Sichuan Provincial Family Planning Research Insti tute, Chengdu, China in 1983. In order to stress for this audience the central importance of the epididymis in fertilisation, and so highlight its potential for attack by antifertility agents, the talks attempted to put the epididymis in reproductive perspective by stressing the func tional development of the sperm cells during their sojourn in the epididymis, rather than merely listing the changes observed in them."

Einzigartig umfassender evidenzbasierter Leitfaden fur Geburtshilfe und Gynakologie. Evidence-based Obstetrics and Gynecology richtet sich an Geburtshelfer, Gynakologen und angehende Facharzte. Der Schwerpunkt liegt auf der klinischen Praxis in den Bereichen Diagnostik, Untersuchung und Management. Der erste Abschnitt behandelt die evidenzbasierten medizinischen Verfahren fur beide Fachrichtungen. Im zweiten und dritten Abschnitt werden die wesentlichen Erkrankungen erlautert. Dabei beleuchtet jedes Kapitel die besten verfugbaren Behandlungsoptionen nach evidenzbasierten Kriterien. Die Kapitel folgen im Aufbau der EBM-Methodik, nach der sich die relevanten klinischen Fragen aus dem jeweiligen Fall ergeben. Evidence-based Obstetrics and Gynecology beschreibt ausfuhrlich abnorme Vaginalblutungen, Eileiterschwangerschaften, Unterleibsschmerzen, Infektionen des unteren Genitaltrakts, Verhutung und Sterilisation, Erkrankungen der Brust, urogynakologische und endokrinologische Erkrankungen, Unfruchtbarkeit, Pubertat und vorzeitige Pubertat, zervikale Dysplasie und Infektionen mit HPV, Gebarmutterhals-, Vaginal-, Gebarmutter- und Eileiterkrebs, Behandlungsverfahren vor einer Empfangnis, pranatale Behandlung und Diagnostik, Medikamente und deren Dosierung wahrend der Schwangerschaft, Komplikationen bei Schwangeren, chronische Hypertonie, Diabetes mellitus, Schilddrusenerkrankungen, neurologische Erkrankungen, psychische Erkrankungen, UEbertragung in der Schwangerschaft, Komplikationen beim Foetus, Praeklampsie u.v.m. - Das erste Fachbuch, das sich evidenzbasiert mit Geburtshilfe und Gynakologie in der klinischen Praxis beschaftigt. - Die evidenzbasierte Medizin ist ein uberzeugender Ansatz fur dieses mit vielen Risiken verbundene Fachgebiet. - Herausgeber ist ein fuhrender Experte aus den USA, der sich fur die evidenzbasierte Medizin engagiert.

The first few months of any pregnancy are of supreme importance to the success of that pregnancy. This statement is so obvious as to be almost a platitude, yet it must be said that no aspect of pregnancy has been more neglected in the human than the first three months. Little is known of the morphological changes that occur at that time and our knowledge of the mechanisms that control this vital stage of pregnancy is almost non-existent. The explanation for this neglect of what is an obvious area for study is the difficulty of obtaining normal material. It is rare to have material to study from a healthy first trimester pregnancy and the study by Hertig and Rock!l) of early conception found by chance in hysterectomy speci mens must be unique. The information that we do have about early pregnancy is mostly gained from animal studies or single miscarriages in humans. Chromosomal defects are common but are not an explanation for the majority of recurrent miscarriages. Obstetricians have hypothesised many causes for this condition and have deve loped numerous metQods for treating it, but the studies have been poorly con trolled so that our understanding of the cause(s) has not advanced. Treatment of women with a history of recurrent miscarriage by paternal leuco cyte infusion (immunotherapy) may be yet another form of treatment that is hailed as a new advance only to be rejected when subject to rigorous testing.

Various scientific evaluations taken from these chapters were presented during the international symposium, 'Carcinoma of the Cervix, ' which was held from September 4-7, 1980 in Kiawah Island, Charleston, South Carolina, U.S.A. An international selection of research investigators have contributed reviews designed to be informative to medical, graduate and post-graduate students, as well as clinicians, oncologists and investigators working in the area of female carcinoma. An attempt has been made to provide a total coverage of current progress in carcinoma of the cervix. In particular, the following major areas are included: Epidemiology, Histology & Histochemistry, Ultra structure, Physiology & Biochemistry, Genetics & Cytogenetics, Immunology, Diagnosis, and Patho physiology & Complications. Major changes have occurred in incidence and mortality rates for carcinoma of the cervix in the past decade. Mass screening programs and their ability to detect earlier stage diseases have attributed to a reduction in invasive diseases. Most cervical cancers could be prevented by an extension of cytologic screening programs in high risk areas. Greater resources must be provided to reach high risk areas in order to prevent the occurrence of cervical cancer."

Due to the introduction of molecular and cellular biology approaches, our understanding of ovarian physiology has reached a new level during the last few years. The present volume provides a new perspective on the ovary from molecular and cellular to whole organ levels, from non-mammalian and rodent to human levels and from paracrine, neuroendocrine and endocrine levels as well. These papers represent the proceedings of the Ninth Ovarian Workshop sponsored by Serono Symposia, USA, July 9-11, 1992 in Chapel Hill, North Carolina.

The original series, Advances in Prostaglandin Research, edited by Sultan M. M. Karim, was published by MTP Press in three volumes in 1975 and 1976. A glance at those books illustrates the progress that has been made since then. The thromboxanes were mentioned twice (first publication 1975) and prostacyclin not once (first publication 1976); leukotrienes were only on the horizon. The amazing generation of research data in the last 10-15 years has given new, broad insights into many areas, including asthma, inflammation, renal, cardiovascular and gastrointestinal diseases and in reproduction, and has led in some instances to real clinical benefit. This series, Advances in Eicosanoid Research, reflects the current understanding of prostaglandins , thromboxanes and leukotrienes. The aim is to provide an introductory background to each topic and the most up-to-date information available. Although each book stands alone, the eicosanoids cut across many boundaries in their basic actions; selected chapters from each book in the series will provide illuminating and productive information for all readers which will advance their education and research. In the production of this series, I must acknowledge with pleasure my collaboration with editors and authors and the patient endeavours of Dr Michael Brewis and the staff at MTP Press. KEITH HlLUER University of Southampton England ix Preface This book is an appraisal of areas in human reproduction where eicosanoid studies (prostaglandins, leukotrienes and thromboxanes) are contributing to physiological and pathological awareness and clinical advances.

Publication of this monograph acknowledges great strides made in research on the zona pellucida during the past decade or so. The body of work presented testifies to a resurgence of interest in the zona pellucida, prompted largely by a renewed appreciation of its unique properties and its important functions during early mam malian development. It is gratifying to realize that the zona pellucida has at last achieved a well-deserved attention. Whereas extracellular coats of nonmammalian eggs have been studied intensively for many years, the zona pellucida by comparison, has until now taken a back seat. Fortunately, the research presented here signals an end to this situ ation. Many of the difficulties inherent in working with relatively small amounts of material have been overcome, paving the way for application of a wider variety of experimental approaches to the zona pellucida by a larger community of investigators. Hopefully, this monograph will serve as a catalyst in this regard. As revealed in these pages, application of contemporary experi mental methodologies has had significant impact on both pure and applied research on the zona pellucida. For example, modem im munological approaches have been used to assess molecular fea tures of zona pellucida structure and function, as well as to evalu ate the zona pellucida as a potential contraceptive target antigen."

The introduction of prostaglandins into clinical practice has been one of the most important advances in obstetrics and gynaecology in recent years. During the last decade obstetricians have become familiar with these drugs for inducing labour and for terminating second-trimester pregnancy. Within the last year their use has been extended, in association with antiprogestin, to first-trimester termi nation. Although the effectiveness of prostaglandins in these pharma cological roles is clear, their full potential has still to be explored, and much remains to be learned about their physiology. Prostaglandins playa central role in the initiation of labour. Further clarification of this role could lead to improvements in preventing or treating preterm labour, which still remains the most important cause of perinatal mortality in this country. Prostaglandins are also inti mately involved in the mechanism of menstruation. More detailed understanding of this role should lead to more effective treatments for menorrhagia and dysmenorrhoea. These substances also playa part in the mechanism of implantation, and further research in this area may lead to more effective therapy for infertility.

Starting in 1986, the European School of Oncology has expanded its activities in postgraduate teaching, which consisted mainly of traditional disease-orientated courses, by promoting new educational initiatives. One of these is the cloister seminars, short meetings intended for highly qualified oncologists and dealing with specific, controversial aspects of clinical practice and research. Another is the institution of permanent study groups, also called task forces, where a limited number of leading experts are invited to meet once a year with the aim of defining the state of the art and possibly reaching a consensus on developments and treatment in specific fields of oncology. This series of ESO Monographs was designed with the specific purpose of disseminating the results of the most interesting of the seminars and study groups, and providing concise and updated reviews of the subjects discussed. It was decided to keep the layout very simple in order to keep costs to a minimum and make the monographs available in the shortest possible time, thus overcoming a common problem in medical literature: that of the material being outdated even before publication. Umberto Veronesi Chairman, Scientific Committee European School of Oncology Table of Contents How to Read this Monograph F.CAvALLI ......... . 1 Experimental Strategies for Studying the Development of Breast Cancer with Special Reference to Steroid Hormones, Growth Factors and Oncogenes R.J.B. KING . . . . . . . . . . . . . . . . . . . . . . . . .. . . . 5 . . .

This series of volumes dealing with reproductive health care has as its primary objective the improvement of the quality of human reproduction. The of knowledge and new technology give us opportunities as never explosion before to accomplish this end. The Editor has brought together contributors who are outstanding scientists from around the world. A number of the authors have personally made significant contributions to our body of knowledge in reproductive medicine. Bringing all this information together in an easily readable format is a great service. This is essential reading for all concerned with the control and improvement of human reproduction and the correction of its many deficits. xv P'art I Physio-anatom-ical Parameters 1 Uterine microvasculature and spontaneous abortion M. TAKADA In the implantation and subsequent development of a fertilized ovum, its integrity is most significant. However, with maternal local factors, i.e., unsatisfactory uterine conditions, implantation may not succeed even if the integrity of the fertilized ovum is excellent; if implantation is made, the maturation of the fetoplacental unit following implantation is disturbed, which leads to abnormalities in fetal development or to miscarriage. Thus, the uteroplacental unit, as well as the fetoplacental unit, plays an important role in the establishment and maintenance of pregnancy. Among the mechanisms of the utero placental unit, most significant is the physiological mechanism of the uterine microvasculature and its correspon dence to gestation. In particular, homeostasis of simultaneous cooperative development of the uterine wall and the placenta is most important."

by Dr. Donald L. King The past decade has seen the ascent of ultrasonography to a preeminent position as a diagnostic imaging modality for obstetrics and gynecology. It can be stated without qualification that modern obstetrics and gynecology cannot be practiced without the use of diagnostic ultrasound, and in particular, the use of ultrasonogra phy. Ultrasonography quickly and safely provides detailed, high resolution images of the pelvic organs and gravid uterus. The quality and quantity of diagnostic information obtained by ultra sonography far exceeds anything previously available and has had a revolutionary impact on the management of patients. High resolution static images permit the intrauterine diagnosis of fetal growth retardation and fetal abnormalities. In addition to tradi tional images, newer dynamic imaging techniques allow observa tion of fetal motion, cardiac pulsation, and respiratory efforts. The use of ultrasonography for guidance has greatly augmented the safety and utility of amniocentesis. One of the great virtues of diagnostic ultrasound has been its apparent safety. At present energy levels, diagnostic ultrasound appears to be without any injurious effect. Although all the availa ble evidence suggests that it is a very safe modality and that the benefit to risk ratio is very high, the actual safety margin for its use Vll as yet remains unknown. As a consequence, practitioners are urged to limit its use only to those situations in which genuine clinical indica tions exist and real benefit to the patient is likely to result."

Extensive basic research and clinical trials have in some aspect of reproductive physiology, gyne been conducted on inert and medicated intrauterine cology, or family planning. There is in this volume devices. In the last decade, substantial progress has an attempt to provide a total coverage of current been made in understanding the modes of action progress in medicated intrauterine devices. The and the physiological mechanisms of IUDs - pro volume is intended for a broad readership, includ gress resulting from modern techniques and in ing physicians, medical workers, medical personnel, strumentation in microanatomy, immunology, pa and administrators in family planning. It is hoped thology, endocrinology, biochemistry and biophy that this volume will serve as a stimulus to basic sics. Such studies, however, are scattered in such a scientists and clinicians concerned with intrauterine wide spectrum of journals that the clinician and devices to intensify their research toward better family planner can hardly keep up to date with the contraceptive techniques. advances. An attempt is made in this volume to coordinate physiological and clinical parameters. Little is September 1980 known about the possible role of diet, diseases and environmental factors. E. S. E."

The motive to prepare this volume on antibiotics for the physician caring for women was based upon the editor's perception that the subject matter had never been fully developed for the obstetrician-gynecologist. Most textbooks of infectious disease have a small section devoted to antibiotics, which has little relevance for the physician caring for post-operative or post-partum infections. Basic antibiotic pharmacology is described and there is a reflex prohibition of antibiotics for the pregnant woman. Correctly, the reader assumes that the authors themselves do not care for women with bacterial infections of the pelvis. Recent texts in infectious disease in obstetrics gynecology have been little better. Although the focus has been more clini cally oriented, space requirements have too often kept the discussions at a superficial level. A total focus upon antibiotics in this volume eliminates the restraints of space in prior publications. The greatest reward in my task as editor of this volume is related to the quality of the individual authors. They range from former students, to con temporary colleagues, to respected peers in infectious disease. Since the quality of this volume is related to the sum total of the individual chapters, I wish to comment about each of the contributors. Philip Mead from the University of Vermont is an old friend, who brings to the question of prophylactic antibiotics, his wide clinical experience and encyclopedic knowledge."

The aim of this book is to transmit the message that asphyxia is the major cause of infant mortality in the ne asphyxia-if severe, caus onatal period. The sequelae of ing cerebral palsy; if mild, leading to MBD to seizures are all potential risks. It is important to make young physicians and nurses aware of this complication of the birth period, how to avoid it, and how to treat it. Facilitating such awareness is the chief purpose of this book. Alberto Lacoius-Petruccelli New York 7 Contents 1. Asphyxia: Definitions, History, and Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 2. Occurrence in Utero, at Birth, and after Delivery ................................. 17 3. Physiopathology of Asphyxia and Its Staging .................................. 21 4. Work-up and Treatment in the Newborn: Delivery Room, Nursery, and Perinatal leU 25 5. Mechanical Ventilators .................... 31 6. Prognosis ................................ 37 7. Brain Asphyxia and Hemorrhage ., ........ 51 8. Types and Stages of Fetal Anoxia: Anoxic, Anemic, Stagnant, and Histotoxic ......... 57 9. Embryonic and Fetal Periods .............. 65 10. The Placenta: Origin and Functions ........ 77 9 CONTENTS 10 11. Fetal Circulation 87 12. Placental Insufficiency or Dysfunction ..... ."

This is a unique book in that it brings together the two key investigative techniques in Gynaecology and Obstetrics, namely ultrasound and endoscopy. So often in the past they were regarded by their exponents as rival techniques but it is now recognised that they are complementary to each other. Consequently future trainees in endoscopy should become efficient in transvaginal sonography and vice versa. Ultrasound can be used to study the morphology of the pelvic organs such as the endometrium, myometrium and ovaries, and being non-invasive, safe and convenient can be repeated as often as is deemed necessary to monitor changes over time; for example in the investigation of the infertile woman the development of the dominant follicle, the maturation of the endometrium and the formation of the corpus luteum can be documented throughout the menstrual cycle while growth of ovarian cysts can be precisely measured to determine the need for surgery. A seldom-mentioned strength of the ultrasound examination is its interactive quality, for example by performing abdominal palpation during the scan, the mobility of the uterus and ovaries can be assessed. Also the images as they appear can be shown to the patient to aid understanding. Ultrasound can also determine function and the use of Doppler has been used for example to access endometrial receptivity, follicular maturity and the likelihood of malignancy in the endometrium or ovary.

This volume represents the Proceedings of the World Conference on Embryo Transfer, In Vitro Fertilization and Instrumental Insemination held on September 24-27, 1980 in Kiel, West Germany. Professor Dr. L. Mettler and Dr. H. H. Riedel of Frauenklinik der UniversiUit in Kiel were the local co chairpersons, who contributed very richly to the program. Basic research, clinical trials, preparation of manuscripts, editorial assistance and presentation of results were generously supported by the following institutions and organizations: Kulturministerium des Landes Schleswig-Holstein Medizinische FakuItat der Christian-Albrechts-UniversiUit, Kiel Wayne State University School of Medicine; Detroit, Michigan, USA C. S. Mott Center for Human Growth and Development; Detroit, Michigan, USA Universitats-Frauenklinik und Hebammenlehranstalt; Kiel, West Germany Serono GmbH; Freiburg, West Germany Hutzel Hospital; Detroit Medical Center; Detroit, Michigan, USA Deutsche Gesellschaft fUr Gynaekologie und Geburtshilfe; West Germany Deutsche Gessellschaft zum Studium der Fertilitat und Sterilitat; Sektion Andrologie Thanks are also due to Aponti GmbH (5000 Koln 21), Bayropharm GmbH (5000 Koln 80), Deutsche Lufthansa (5000 Koln), Organon GmbH (8024 Oberschleissheim), Winthrop GmbH (6080 New Isenburg), and Wisap GmbH (8029 Sauerlach), for financial assistance. Sincere appreciation and gratitude are due to the contributors who meticulously prepared their chapters; to Ms Jackie Mucci for editorial skills and assistance, and Ms. Jackie Smieska for editorial help. Thanks are also due to Dr. H. D. Brackebusch for his assistance during the conference; to Ms. E. Seiss for her secretarial assistance; and to Mr."

The Fourth International Congress on the Menopause was held in Lake Buena Vista, Florida, USA in October - November 1984. It was different from the previous meetings held under the auspices of the International Menopause Society in three respects: the duration of the Congress was extended to five days, plenary sessions were held on each day, and the scope of the subject matter was expanded to provide a total or holistic overview of the subject - hence the theme for the Congress 'Climacteric Medicine and Science: A Societal need. ' In recent years there has been an increased interest in the menopause and middle year aging by scientists and clinicians in fields as diverse as anthropology, urodynamics, nutrition and exercise physiology, while 'newer' issues in clinical medicine, such as osteoporosis prevention and management, attracted specialists in nuclear immaging techniques and internal medicine. Over 120 invited speakers plus numerous contributors to the free communication, special lectures and the poster sessions provided a virtual cornucopia of information on the menopause, that has indeed brought a newer perspective to a subject previously the domain of a single specialty, the gynecologist, and dominated by a single therapy, estrogen replacement.

This collection of papers on different aspects of gynaecological oncology is taken from the proceedings of the Second International Conference on Gynaecological Cancer held in Edinburgh in Sep tember 1983. An attempt has been made to include topical material of interest and importance to all gynaecologists, both with and without specific oncological experience, and it is confidently expected that radiotherapists and general surgeons will also find much of value within these pages. Much of the material has been updated prior to its transfer to the printers, and authors have tried where possible to provide workable rather than tiresomely comprehensive bibliographies. Our sincerest thanks are directed to our other colleagues on the Organising Committee, namely Professors J. Carmichael, W. Duncan and J. F. Smyth and Doctors 1. Duncan, J. R. B. Livingstone, R. H. Nalick, T. J. O'Brien and E. Petrilli for their invaluable assistance on both sides of the Atlantic with the organisation ofthe above conference, to Dr. R. H. Kerr-Wilson for his help with, and sometimes translation of, the original proofs, and to our constantly overworked and uncomplaining secretaries Joann Little and Mary Hall."

This volume contains all the invited papers, symposium contributions and workshop reports of the 7th International Congress of Human Genetics, held in West Berlin from September 22 to 26, 1986. The organizers of this congress made sure to gain the cooperation of the leading scientists in the field from all over the world. These contributions therefore document the enormous progress made in human genetics research in recent years. The volume covers a wide range of topics, from analysis of the human genome to basic mechanisms, diagnosis and therapy of hereditary diseases, and to distribution of normal and pathological genes and DNA variation in human populations. Ethical issues raised by modern developments are discussed thoroughly. The volume is a must for all scientists and medical doctors working in human genetics research, its teaching and practical applications.

In vitro fertilization has resulted in an estimated 4000-5000 births in the world. The procedure has been accepted in Europe, America and Australia and several hundred IVF clinics are operating successfully. The newer procedures of GIFf, embryo freezing and donor oocyte IVF have become established and are dealt with in several chapters. GIFf has become the procedure of choice for patients with infertility of unknown origin. Oocyte freezing represents an important new technology which is being developed. The routine IVF procedure has improved slightly; variation in results can be reduced by quality control of laboratory and clinical techniques. Male factor infertility has been dealt with by IVF in mild and moderate cases, but newer techniques will be required to deal with severe problems in the male. Most countries have accepted that the straightforward IVF pro cedure is ethical. Limitations concerning the use of donor oocytes and embryo experimentation exist in some religions and countries; legal control of the new reproductive technologies ranges from the passage of statutes to no control at all. Many countries are still considering the need for legislative control. The text endeavours to indicate new areas of importance and to guide those organizing services as to how to introduce newer technolo gies.

ENTERING ON A CREATIVE AND ENTERPRISING PROJECT, DRS. DIZEREGA and Rodgers have taken an innovative look at the peritoneum. They have provided an interesting, informative, and stimulating text about an organ that is rarely considered independently-usually being thought of only as a part of other organs or organ systems. The peritoneum is an active membrane that serves as both a secretory organ and a structure that modulates diffusion and osmosis. Both of these important functions are described in great detail. The text is divided in classic fashion. The authors first examine the peritoneal anatomy from both macro and cellular viewpoints, during which exploration it becomes clear that what appears simply to be a lacy covering over abdominal organs actually is a complex structure. Fur thermore, during the discussion on its embryologic development the au thors make comprehensible the complexity confronting the student of the peritoneum. The authors then proceed to the practicalities associated with this im portant organ. To surgeons, for example, the key to the peritoneum is understanding the organ's repair mechanism, as it is adhesions formed on the peritoneal surfaces that interfere with the surgeon's hope of success."

Conceptual advances in the biological sciences are marked by the applica tion of new techniques and experimental strategies. Nowhere has this ge neric principle been more apparent than in the study of testicular cells, as judged by the evolution of themes presented at the Testis Workshop over the past 23 years. Like its predecessors, the 1995 Testis Workshop was structured to offer fresh insights and approaches for understanding the mechanisms of spermatogenesis and steroidogenesis. The chapters pre sented in this book emphasize three aspects of testicular cell function: first, the molecular analysis of the cell cycle; second, examination of the cell cycle, including the function and identification of specific macromolecules that direct the proliferation and differentiation of germ cells; and third, the development of Leydig cells and the role of specific macromolecules in the formation of testicular steroids. Each chapter is based on a lecture presented at the XIIIth Testis Work shop held on March 30 to April 1, 1995, at the Radisson Plaza Hotel in Raleigh, North Carolina. The selection of topics reflects the recommenda tions of the workshop'S organizing committee. Sincere thanks are due to the speakers who agreed to lecture and prepare chapters."