Forensic antiepileptic drug levels in autopsy cases of epilepsy.

A 1-year retrospective coroner-based forensic examination of causes of death among persons with a history of epilepsy was conducted at the Allegheny County Coroner's Office to evaluate the phenomenon of sudden unexplained/unexpected death in epilepsy (SUDEP), a diagnosis of exclusion. All cases at the Coroner's Office from January 1, 2001 through December 31, 2001, were examined. Review of a total of 1200 autopsied deaths revealed 12 cases with a past medical history of seizure disorder on the death certificate, which listed seizure disorder as the immediate cause of death or contributory cause of the death. Of the 7 men with seizure disorders, 5 were categorized as definite SUDEP and 2 as possible SUDEP. Of the 5 women with seizure disorders, 2 were listed as definite SUDEP, 2 as possible, and 1 as non-SUDEP because the convulsive seizures developed from a grade II glial tumor. Postmortem findings were evaluated for 11 cases; 1 body was decomposed. Toxicological screens were carried out on blood, bile, urine, and eye fluid for all 12. Antiepileptic drug (AED) levels detected in postmortem toxicological analysis were examined. AED levels were determined in 7 cases. Four of 7 had subtherapeutic AED levels, 2 had therapeutic levels, and only 1 victim of SUDEP had levels above the therapeutic range. Five cases had no detectable AED levels. AED levels at autopsy were either absent or subtherapeutic in 9 of 10 SUDEP cases, findings consistent with the likelihood of poor AED compliance. Subtherapeutic levels of AEDs may be a risk factor for SUDEP that could contribute to increased interictal and/or ictal epileptiform activity with associated autonomic dysfunction leading to disturbance of heart rate, heart rhythm, and/or blood pressure.

A new goldfish model to evaluate pharmacokinetic and pharmacodynamic effects of drugs used for motion sickness in different gravity loads.

This paper proposes a new goldfish model to predict pharmacodynamic/pharmacokinetic effects of drugs used to treat motion sickness administered in differing gravity loads. The assumption of these experiments is that the vestibular system is dominant in producing motion sickness and that the visual system is secondary or of small import in the production of motion sickness. Studies will evaluate the parameter of gravity and the contribution of vision to the role of the neurovestibular system in the initiation of motion sickness with and without pharmacologic agents. Promethazine will be studied first. A comparison of data obtained in different groups of goldfish will be done (normal vs. acutely and chronically bilaterally blinded vs. sham operated). Some fish will be bilaterally blinded 10 months prior to initiation of the experiment (designated the chronically bilaterally blinded group of goldfish) to evaluate the neuroplasticity of the nervous system and the associated return of neurovestibular function. Data will be obtained under differing gravity loads with and without a pharmacological agent for motion sickness. Experiments will differentiate pharmacological effects on vision vs. neurovestibular input to motion sickness. Comparison of data obtained in the normal fish and in acutely and chronically bilaterally blinded fish with those obtained in fish with intact and denervated otoliths will differentiate if the visual or neurovestibular system is dominant in response to altered gravity and/or drugs. Experiments will contribute to validation of the goldfish as a model for humans since plasticity of the central nervous system allows astronauts to adapt to the altered visual stimulus conditions of 0-g. Space motion sickness may occur until such an adaptation is achieved.

Role of veterinary medicine in public health: antibiotic use in food animals and humans and the effect on evolution of antibacterial resistance.

Veterinary public health is another frontier in the fight against human disease. The veterinary public health scope includes the control and eradication of zoonoses, diseases that are naturally transmitted between vertebrate animals and man. These diseases pose a continuous hazard to the health and welfare of the public. More than 100 diseases are categorized as zoonoses, including salmonellosis. It is important to understand how antibiotics are used in humans and in food animals and how these uses affect the evolution of antibacterial resistance. Appropriate use of antibiotics for food animals will preserve the long-term efficacy of existing antibiotics, support animal health and welfare, and limit the risk of transfer of antibiotic resistance to humans. An understanding of the epidemiology of antimicrobial resistance allows development of preventive strategies to limit existing resistance and to avoid emergence of new strains of resistant bacteria. Risk assessments are being used by the Center for Veterinary Medicine at the U.S. Food and Drug Administration as regulatory tools to assess potential risk to humans resulting from antibiotic use in food-producing animals and to then develop microbial safety policies to protect the public health. The veterinary public health scope, in addition to the control and eradication of zoonoses, also includes the development and supervision of food hygiene practices, laboratory and research activities, and education of the public. Thus, it may be seen that there are many ways in which veterinary medicine plays a very important role in public health.

Evaluation of student achievement and educational outcomes.

Development of problem-solving skills is vital to professional education as is factual recall. Student mastery must be measured to document student achievement requiredfor completion of educational requirements and professional certification. These measurements also help determine if the educational process is meeting its goal of helping students develop critical cognitive skills for therapeutic problem solving. Testing student growth in the ability to solve problems is less understood. Stressing integration of information across disciplines to derive answers is also important. Test items should resemble the real-world task that students are expected to master. Thatisreallythe essence of content validity, which means faculty should be biased toward presenting information that way. This article is based on a symposium presented at the annual meeting of the American College of Clinical Pharmacology in September 1996. Symposium goals were to define purposes and uses of student evaluations by type and format, including application of techniques that improve evaluation, precision, and validity. Technical applications of computer-based learning and evaluation of problem-solving skills are described. Actual experience with evaluation of problem solving in the curriculum is discussed. The process by which a medical school developed and implemented an evaluation system for a new problem-based curriculum is presented, followed by a critique of the successes and problems encountered during the first year of implementation. Criteria that a well-constructed evaluation program must meet are explored. The approach and philosophy of national standardized testing centers are explained.

Lessons learned from the past: a guide for the future of clinical pharmacology in the 21st century.

This article is a documentary of the history of the American College of Clinical Pharmacology (ACCP) and the Journal of Clinical Pharmacology. The history of the college and of the journal is presented as summarized by a few of the many leaders who played key roles in the growth of the profession of Clinical Pharmacology. Together, the college, the journal, and all clinical pharmacologists working in academia, industry, CROs, or government in many different subspecialty areas of the discipline contribute to the advancement of clinical pharmacology, the development of new drugs, and to an improved quality of life for mankind. Achieving leadership in health care in an era of change requires actions to be dynamic and flexible. Leaders must be capable of self-development and self-education. Leaders must examine challenges from top to bottom and build on the leadership foundations of vision, courage, and knowledge. Strong leaders are needed for the future of clinical pharmacology to address the rapidly changing environment for health care givers and the challenges faced by those working in drug development or training new leaders. One lesson from the past, from the professional life of Harry Gold, is that it is very important to convey the excitement of the field of clinical pharmacology and to pass on this excitement and knowledge base to those currently leading the educational process necessary to keep clinical pharmacologists in the forefront of the medical arena of today and tomorrow. The college became an instrument for change in the field of clinical pharmacology. Forward thinking efforts of the college did not allow stagnation. All founding leaders of the college were possessed of a dream of "what could be and what should be." Two points should be emphasized: the importance of teaching teachers how to teach and the importance of forming national networks, such as the college, to concentrate on the role of teaching students. Today's students are the leaders of tomorrow. The training of any given student in the field of clinical pharmacology continues over many years and requires the effort of many qualified mentors. The ACCP continues to prepare for the changing demands of a new millennium. The college responded to three challenges: (1) utilization of new technologies consistent with contemporary trends; (2) identification of new member services; and (3) dissemination of a position paper defining the philosophical foundations of the college. The basic tenant of the college remains the same today as it has been over the years: provide a multidisciplinary educational environment to have a broad appeal to the membership interested in clinical pharmacology.

Clinical pharmacology of antiepileptic drug use: "clinical pearls about the perils of patty".

This Clinical Pharmacology Problem Solving (CPPS) Unit is for use with fourth- or fifth-year pharmacy students and third- or fourth-year medical students during conferences held when they are taking either a rotation in Neurology or Clinical Pharmacology. It may also be used for house staff teaching of residents in Neurology, Pediatrics, Internal Medicine, and Family Practice and fellows in Clinical Pharmacology. This material was prepared for a Teaching Clinic in Clinical Pharmacology taught by Claire M. Lathers, PhD, FCP, Hugh J. Burford, PhD, FCP, and Cedric M. Smith, MD, FCP, and sponsored by the American College of Clinical Pharmacology, September 19-20, 1992, Washington, DC. This workbook includes: (1) an introduction to the Clinical Pharmacology Problem Solving (CPPS) Unit; (2) the learning objectives of the clinical simulation; (3) a pretest; (4) four clinical episodes occurring over many years in the life of a patient; (5) answers to the pretest; (6) a posttest; (7) answers to the posttest.

Experience-based teaching of therapeutics and clinical pharmacology of antiepileptic drugs. Sudden unexplained death in epilepsy: do antiepileptic drugs have a role?

The contents of this paper have been written to be used in a teaching program specifically designed for medical postgraduate education of resident physicians and fellows in training interested in the clinical pharmacology of antiepileptic drugs and their role in the treatment of epilepsy and/or in the prevention of sudden unexpected death associated with this disease. With some modifications, such as a specific lecture to provide an overview of the numerous concepts presented in the text, the article could be used when teaching fourth-year medical students. The format of the paper is a combination of didactic review and eight case reports in a self-learning format. A quiz for self-assessment is included at the end of the article (see Appendix). This material was covered in part in the 1992 Board Review Course for Clinical Pharmacology sponsored by the American College of Clinical Pharmacology. The format or setting of instruction for this material could include small learning groups composed of 10 to 15 students. When used in combination with other topics prepared in similar formats, this could become a take home course for those preparing to take the Boards in Clinical Pharmacology. Each instructor could select specific publications from the reference list for assigned readings depending upon the material emphasized by the instructor. The questions included at the end of the text could be used as either a closed or an open book quiz to assess student learning.

Presidential address. American College of Clinical Pharmacology has provided a variety of educational opportunities.

At the current time, the College is in an excellent position to support the educational needs of its growing membership. The fund balance has increased over the past few years and is continuing to increase during the current year. The unprecedented speed of changes in the health care environment in which all clinical pharmacologists are now working necessitates that the American College of Clinical Pharmacology continually examine and update its Strategic Plan and Long Range Goals to allow all of its members to keep abreast of these changes. As hospitals, medical schools, and other allied health colleges address the need for economic accountability, as educators in medical and pharmacy and other schools encounter state and federal reductions in financial assistance to students, and as new roles are developed for the clinical pharmacologists working within the professions of medicine, pharmacy and allied health specialties, the College must maintain its role as a leader for all clinical pharmacologists. The success of the College will be directly related to the effort invested by all of the committee members and chairpersons, the Board of Regents, the Officers of the College, and most of all, the membership. During the next two years, I look forward to working with the entire membership to encourage growth of the College.

Use of lower body negative pressure to assess changes in heart rate response to orthostatic-like stress during 17 weeks of bed rest.

This study examined the heart rate response to lower body negative pressure (LBNP) during 17 weeks of horizontal bed rest to estimate the development and duration of orthostatic instability elicited by this model for space flight. Based on data from Skylab, the authors hypothesized that orthostatic (LBNP) instability would appear during the first 3 to 4 weeks, and would then remain constant for the duration of bed rest. Heart rates of four healthy adult male subjects were monitored at rest and during LBNP for 1 week of ambulatory control, 17 weeks of horizontal bed rest, and 5 weeks of recovery. The LBNP protocol consisted of 10 minutes of control (atmospheric pressure) and 5 minutes each at 5, 10, 20, 30, 40, and 50 mm Hg decompression, followed by a 10-minute recovery period; this protocol was repeated weekly to document the progressive changes in heart rate response to LBNP. Lower body negative pressure was terminated early if symptoms compatible with the onset of syncope occurred. Throughout the study, heart rate was unchanged at 5, 10, and 20 mm Hg, but it increased at 30, 40, and 50 mm Hg LBNP. During the pre-bed rest period, peak heart rate was 97 +/- 10 beats/min (mean +/- SE), occurring at 50 mm Hg for all four subjects. After 3 days of bed rest, all monitored heart rate responses, including values after release of LBNP, were only slightly elevated (NS) above pre-bed rest level. Peak heart rate was 118 +/- 21 beats/min at 50 mm Hg decompression (NS; N = 3).(ABSTRACT TRUNCATED AT 250 WORDS)

Summary of lower body negative pressure experiments during space flight.

This paper summarizes the lower body negative pressure experiments performed in space, beginning with the experiments conducted on Skylab, because this program provided the most cardiovascular physiology data for United States space flight. Data obtained during studies of lower body negative pressure for use as a countermeasure after months of Russian space flight are also presented. Lower body negative pressure experiments conducted aboard Space Shuttle flights provide data about the deadaptation response of the cardiovascular system to orthostatic stress occurring during periods of zero gravity, and about protection against postflight orthostatic intolerance. Data obtained using Russian and American lower body negative pressure devices indicate that, when a crew member stands, as opposed to being supported by a seat or saddle as in the American device, there may be a slight detrimental effect in terms of the cardiovascular response to this orthostatic stress. Comparison of heart rate and blood pressure response to entry and landing of the Shuttle indicate that, although lower body negative pressure is a different stress and is applied in a different manner, the maximum heart rates during lower body negative pressure are reached at approximately the same point that the maximum heart rates are reached during entry and landing. Thus, the use of a lower body negative pressure stress in flight is a fairly good predictor of the cardiovascular response to the actual entry and landing of the Shuttle.

Cardiovascular responses to standing: effect of hydration.

Many astronauts experience intolerance to orthostatic stress after space flight, despite the ingestion of salt tablets and water equivalent to 0.9% saline just before their return to Earth. Previous research indicates that the ingestion of 1.07% saline solution increased plasma volume more than did 0.9% saline. Therefore, the authors hypothesized that the 1.07% saline would be more effective in reducing orthostatic stress during standing. In this study, six men (22-47 years) performed a 5-minute "stand test" (5 minutes supine followed by 5 minutes standing) under four hydration conditions: 1) hypohydrated (HYPO, 20 mg intravenous [IV] Lasix), 2) euhydrated (EU), 3) rehydrated with 1 L 0.9% saline 2 hours after Lasix, or 4) rehydrated with 1 L 1.07% saline. Stand tests were done 4 5 hours after rehydration. Plasma volume was reduced 10% after Lasix, and was restored by both rehydration solutions. When subjects stood, their diastolic pressure, mean pressure, heart rate (HR), and peripheral resistance increased (P < .05), and their stroke volume (SV), cardiac output (CO), and thoracic fluid (TF, by impedance cardiography) decreased (P < .05). Systolic arterial pressure (SBP) increased when subjects stood after saline, but decreased if subjects were HYPO or EU (P < .05 for 1.07% versus HYPO and EU). Heart rate (HR), another indicator of orthostatic stress, did not differ among hydration states. During the last minute of the stand test, TF was greater if subjects had fluid countermeasures. Stroke volume, CO, and TF were significantly less during minute 5 of standing than during minute 3. Whether they would continue to fall in a longer stand test is not known. The results for SBP indicate that 1.07% saline may have advantages over 0.9% saline as a countermeasure to postspace-flight or postbedrest orthostatic intolerance.

The spectrum of syncope.

Syncope is a loss of consciousness and postural tone. Although arising suddenly from prolonged recumbency or returning from weightlessness to Earth's gravity can result in syncope from orthostatic or vasovagal effects, there are many other possible causes. These causes can be divided into several groups. Causes listed in the cardiovascular category, especially cardiac causes, are more likely to occur in the elderly; noncardiac causes are more common in the younger population. The cases described herein illustrate the often unexpected mechanisms of syncope in otherwise healthy individuals. Two of the cases emphasize the usefulness of prolonged combined EEG/EKG monitoring. The categories of loss of consciousness experienced by air crew members are reviewed. The most important screening tool in identifying the mechanism(s) of syncope is a detailed history emphasizing a search for underlying disease, the specific associated circumstances, and pre- and post-event symptoms. The type of diagnostic studies, i.e., cardiac or neurologic, undertaken should be based on the historical data. Seizures must be considered as a possible mechanism of otherwise unexplained loss of consciousness in nonelderly persons, including air crew members.

Cardiovascular responses to repetitive exposure to hyper- and hypogravity states produced by parabolic flight.

Physiologic changes to repetitive hyper- and hypogravity stresses occurring during eight to ten parabolas on NASA's KC-135 aircraft were studied. Hemodynamic responses in 11 subjects in 4 different postures (supine, standing, sitting, and semisupine Space Shuttle launch position) were determined using noninvasive impedance cardiography. Five seconds of heart rate, cardiac index, thoracic fluid index, stroke index, ejection velocity index, and ventricular ejection time data were averaged during four different gravity (g) states: 1.3g (before parabola onset); 1.9g (parabola entry); 0g (parabola peak); and 1.7g (parabola exit) for each subject. The standing position was associated with the largest changes in the cardiovascular response to hypo- and hypergravity. The thoracic fluid index did not indicate a headward redistribution during transition from a simulated launch position to weightlessness. Analysis of the eight to ten parabolas revealed that, in general, values obtained at 1.8g differed from 1.6g, 0g differed from 1.6 and 1.3g, and 1.6g differed from 1.3g. The factors of gravity, thoracic fluid index, and cardiac index exhibited significant differences that were most likely to occur between parabola 1 versus parabolas 6, 7, and 8, and parabola 2 versus parabolas 4 through 8. Only the parameter of thoracic fluid index exhibited significance for parabolas 3 versus parabolas 6 and 7.

Comparison of cardiovascular function during the early hours of bed rest and space flight.

This paper reviews the cardiovascular responses of six healthy male subjects to 6 hours in a 5 degrees head-down bed rest model of weightlessness, and compares these responses to those obtained when subjects were positioned in head-up tilts of 10 degrees, 20 degrees, and 42 degrees, simulating 1/6, 1/3, and 2/3 G, respectively. Thoracic fluid index, cardiac output, stroke volume, and peak flow were measured using impedance cardiography. Cardiac dimensions and volumes were determined from two-dimensional guided M-mode echocardiograms in the left lateral decubitus position at 0, 2, 4, and 6 hours. Cardiovascular response to a stand test were compared before and after bed rest. The impedance values were related to tilt angle for the first 2 hours of tilt; however, after 3 hours, at all four angles, values began to converge, indicating that cardiovascular homeostatic mechanisms seek a common adapted state, regardless of effective gravity level (tilt angle) up to 2/3 G. Echocardiography revealed that left ventricular end-diastolic and end-systolic volume, stroke volume, ejection fraction, heart rate, and cardiac output had returned to control values by hour 6 for all tilt angles. The lack of a significant immediate change in left ventricular end-diastolic volume, despite decrements in stroke volume (P < .05) and heart rate (not significant), indicates that multiple factors may play a role in the adaptation to simulated hypogravity. The echocardiography data indicated that no angle of tilt, whether head-down or head-up for 4 to 6 hours, mimicked exactly the changes in cardiovascular function recorded after 4 to 6 hours of space flight. Changes in left ventricular end-diastolic volume during space flight and tilt may be similar, but follow a different time course. Nevertheless, head-down tilt at 5 degrees for 6 hours mimics some (stroke volume, systolic and diastolic blood pressure, mean arterial blood pressure, and total resistance), but not all, of the changes occurring in an equivalent time of space flight. The magnitude of the change in the mean heart rate response to standing was greater after six hours of tilt at -5 degrees or 10 degrees. Thus, results from the stand test after 6 hours of bed rest at -5 degrees and 10 degrees, but not at 20 degrees or 42 degrees, are similar to those obtained after space flight.

Orthostatic hypotension in patients, bed rest subjects, and astronauts.

Orthostatic hypotension after even short space flights has affected a significant number of astronauts. Given the need for astronauts to function at a high level of efficiency during and after their return from space, the application of pharmacologic and other treatments is strongly indicated. This report addresses the clinical problem of orthostatic hypotension and its treatments to ascertain whether pharmacologic or physiologic treatment may be useful in the prevention of orthostatic hypotension associated with space flight. Treatment of orthostatic hypotension in patients now includes increasing intravascular volume with high sodium intake and mineralocorticoids, or increasing vascular resistance through the use of drugs to stimulate alpha or block beta vascular receptors. Earlier treatment used oral sympathomimetic ephedrine hydrochloride alone or with "head-up" bed rest. Then long-acting adrenocortical steroid desoxycorticosterone preparations with high-salt diets were used to expand volume. Fludrocortisone was shown to prevent the orthostatic drop in blood pressure. The combination of the sympathomimetic amine hydroxyamphetamine and a monoamine oxidase inhibitor tranylcypromine has been used, as has indomethacin alone. Davies et al. used mineralocorticoids at low doses concomitantly with alpha-agonists to increase vasoconstrictor action. Schirger et al used tranylcypromine and methylphenidate with or without a Jobst elastic leotard garment or the alpha-adrenergic agonist midodrine (which stimulates both arterial and venous systems without direct central nervous system or cardiac effects). Vernikos et al established that the combination of fludrocortisone, dextroamphetamine, and atropine exhibited a beneficial effect on orthostatic hypotension induced by 7-day 6 degrees head-down bed rest (a model used to simulate the weightlessness of space flight). Thus, there are numerous drugs that, in combination with mechanical techniques, including lower body negative pressure to elevate transmural pressure, could be studied to treat orthostatic hypotension after space flight.

Use of lower body negative pressure to counter symptoms of orthostatic intolerance in patients, bed rest subjects, and astronauts.

This report briefly discusses some aspects of autonomic cardiovascular dysfunction as related to changes in orthostatic function in patients, bed rest subjects, and astronauts. This relationship is described in normal individuals to provide the basis for discussion of parameters that may be altered in patients, bed rest subjects, and astronauts. The relationships between disease states, age, periods of weightlessness during space flight, and autonomic dysfunction, and their contribution to changes in orthostatic tolerance are presented. The physiologic effects of lower body negative pressure are illustrated by presenting data obtained in bed rest subjects and in astronauts. Finally, the usefulness of lower body negative pressure to counter symptoms of orthostatic intolerance in patients, bed rest subjects, and astronauts is discussed.

The effect of phenobarbital on autonomic function and epileptogenic activity induced by the hippocampal injection of penicillin in cats.

This study addressed whether penicillin-induced epileptiform discharges in the right hippocampus produced associated autonomic dysfunction. The study also examined the effect of phenobarbital on the heart rate and blood pressure changes that were induced by the epileptiform discharges. The delay in onset of epileptiform activity at the site of injection ranged from 1 second to 16 minutes, and consisted of interictal discharges or ictal discharges. With the onset of epileptiform activity, blood pressure and heart rate increased significantly from control (P < .05). Electrocardiogram alterations included: P-R interval changes; increased P-wave amplitude; QRS complex changes; T-wave inversion; and ST elevation. Phenobarbital 20 mg/kg intravenously suppressed the epileptogenic activity and depressed the blood pressure and heart rate below control (P < .05). In an additional series of experiments, penicillin G injected into the right hippocampus in five cats produced epileptiform activity and increased the blood pressure and the heart rate significantly from the control (P < .05). Phenobarbital (20 mg/kg, intravenously, and 40 mg/kg, intravenously) also prevented the penicillin-induced epileptiform activity. Phenobarbital (40 mg/kg, intravenously) reversed the effect of penicillin on the blood pressure and heart rate, to levels significantly below that of control (P < .05). Phenobarbital diminished both epileptiform activity and autonomic dysfunction. The autonomic dysfunction related to epileptiform activity induced by focal hippocampal administration of penicillin was similar to that induced by the intravenous administration of pentylenetetrazol.

Echocardiograms during six hours of bedrest at head-down and head-up tilt and during space flight.

Left ventricular end-diastolic volume increased after 4 1/2 to 6 hours of space flight, but was significantly decreased after 5 to 6 days of space flight. To determine the role of acute gravitational effects in this phenomenon, responses to a 6-hour bedrest model of 0 gravity (G; 5 degrees head-down tilt) were compared with those of fractional gravity loads of 1/6 G, 1/3 G, and 2/3 G by using head-up tilts of 10 degrees, 20 degrees, and 42 degrees, respectively. On 4 different days, six healthy male subjects were tilted at one of the four angles for 6 hours. Cardiac dimensions and volumes were determined from two-dimensional and M-mode echocardiograms in the left lateral decubitus position at control (0), 2, 4, and 6 hours. Stroke volume decreased with time (P < .05) for all tilt angles when compared with control. Ejection fraction (EF) at -5 degrees was greater than at +20 degrees and +42 degrees (not significant); EF at +10 degrees was greater than at +42 degrees (not significant). For the tilt angles of -5 degrees, +10 degrees, and +20 degrees, mean heart rate decreased during the first 2 hours, and returned to control or was slightly elevated above control (+20 degrees) by 6 hours (not significant). At the +42 degrees angle of tilt, heart rate was increased above control at hours 2, 4, and 6. There were no significant differences in cardiac output at any time point for any tilt angle.(ABSTRACT TRUNCATED AT 250 WORDS)