München, Techn. Universiẗat, Diss., 2004.

A enterite necrótica causada por Clostridium perfringens é, comprovadamente, um grande problema para frangos de corte, seja sob a forma clínica ou subclínica , com elevados prejuízos produtivos. Em perus, não está claramente identificada a influência deste patógeno sobre os resultados produtivos, e provavelmente por razões econômicas, o volume de pesquisa nesta área é limitado. Em dois experimentos consecutivos, conduzidos em granjas experimentais diferentes, e sobre cama nova e reutilizada, perus de 14 dias, sem medicação com anticoccidianos, foram inoculados, a partir de uma amostra de campo patogênica, com uma superdosagem de aproximadamente 1 x 1010 UFC/ml de Clostridium perfringens, tipo A; bactéria anaeróbica Gram positiva, que compõe a microflora intestinal dos perus. Lesões necróticas severas, com grande destruição da mucosa intestinal, foram observadas após o 4º dia de inoculação. Nos dois experimentos, a resposta dos perus à infecção foi diferente da descrita em frangos de corte. A mortalidade foi muito baixa ou nula e a recuperação das aves, independente da medicação utilizada, foi rápida com pouco ou nenhum comprometimento zootécnico. Escores das lesões histológicas foram desenvolvidos, para tentar correlacionar as lesões macroscópicas com as lesões microscópicas, mas a correlação foi baixa. Frente ao alto desafio observado, não foi possível avaliar adequadamente a ação do antimicrobiano utilizado. As respostas frente aos desafios de Clostridium perfringens nos perus, aparentam ser diferentes em relação às observadas em frangos de corte, sendo necessária cautela ao extrapolar padrões de uma espécie para outra. O uso de critérios subjetivos nas avaliações podem comprometer a tomada de decisão em relação aos tratamentos e as respostas esperadas. / Necrotic enteritis caused by Clostridium perfringens represents a major challenge in broilers, causing clinical or sub clinical diseases, and results in important economic losses for the poultry industry. In turkeys, however, the importance of this pathogen is not clearly defined, and there are few studies assessing its effects on the performance of turkeys, most probably for economic reasons. In two consecutive trials, conducted in two experimental farms, 14 day old turkey poults were reared on new and reused wood shavings litter, without any anticoccidials in the feed, and were inoculated with an overdose of approximately 1x1010 CFU/ml of a pathogenic field sample of Clostridium perfringens type A. This Gram positive anaerobic bacterium is a normal inhabitant of the gut micro flora in the enteric tract of turkeys. Severe necrotic lesions, with major damage to the intestinal mucosa were observed on Day 4 after inoculation. In both trials, the response to the turkeys to the clostridial infection was clearly different from what is described in the literature for broilers. The mortality rate was very low or inexistent, and the birds in all treatments groups recovered very fast, with little or no impact on performance results. An attempt was made to establish a pattern to correlate histological lesion scores with macroscopic and microscopic lesions, but the resulting correlation was very low. Considering the high level of challenge induced in both trials, it was not possible to evaluate in activity of the antibiotic in proper terms. The response of turkeys to a high level of challenge with Clostridium perfringens seems to be different when compared to what is observed in broilers under similar experimental conditions, and caution should be applied when using the same diagnostic methods for different species. The use of subjective criteria to assess and describe the lesions can lead to erroneous treatments decisions and misinterpretation of the responses to treatment.

A enterite necrótica causada por Clostridium perfringens é, comprovadamente, um grande problema para frangos de corte, seja sob a forma clínica ou subclínica , com elevados prejuízos produtivos. Em perus, não está claramente identificada a influência deste patógeno sobre os resultados produtivos, e provavelmente por razões econômicas, o volume de pesquisa nesta área é limitado. Em dois experimentos consecutivos, conduzidos em granjas experimentais diferentes, e sobre cama nova e reutilizada, perus de 14 dias, sem medicação com anticoccidianos, foram inoculados, a partir de uma amostra de campo patogênica, com uma superdosagem de aproximadamente 1 x 1010 UFC/ml de Clostridium perfringens, tipo A; bactéria anaeróbica Gram positiva, que compõe a microflora intestinal dos perus. Lesões necróticas severas, com grande destruição da mucosa intestinal, foram observadas após o 4º dia de inoculação. Nos dois experimentos, a resposta dos perus à infecção foi diferente da descrita em frangos de corte. A mortalidade foi muito baixa ou nula e a recuperação das aves, independente da medicação utilizada, foi rápida com pouco ou nenhum comprometimento zootécnico. Escores das lesões histológicas foram desenvolvidos, para tentar correlacionar as lesões macroscópicas com as lesões microscópicas, mas a correlação foi baixa. Frente ao alto desafio observado, não foi possível avaliar adequadamente a ação do antimicrobiano utilizado. As respostas frente aos desafios de Clostridium perfringens nos perus, aparentam ser diferentes em relação às observadas em frangos de corte, sendo necessária cautela ao extrapolar padrões de uma espécie para outra. O uso de critérios subjetivos nas avaliações podem comprometer a tomada de decisão em relação aos tratamentos e as respostas esperadas. / Necrotic enteritis caused by Clostridium perfringens represents a major challenge in broilers, causing clinical or sub clinical diseases, and results in important economic losses for the poultry industry. In turkeys, however, the importance of this pathogen is not clearly defined, and there are few studies assessing its effects on the performance of turkeys, most probably for economic reasons. In two consecutive trials, conducted in two experimental farms, 14 day old turkey poults were reared on new and reused wood shavings litter, without any anticoccidials in the feed, and were inoculated with an overdose of approximately 1x1010 CFU/ml of a pathogenic field sample of Clostridium perfringens type A. This Gram positive anaerobic bacterium is a normal inhabitant of the gut micro flora in the enteric tract of turkeys. Severe necrotic lesions, with major damage to the intestinal mucosa were observed on Day 4 after inoculation. In both trials, the response to the turkeys to the clostridial infection was clearly different from what is described in the literature for broilers. The mortality rate was very low or inexistent, and the birds in all treatments groups recovered very fast, with little or no impact on performance results. An attempt was made to establish a pattern to correlate histological lesion scores with macroscopic and microscopic lesions, but the resulting correlation was very low. Considering the high level of challenge induced in both trials, it was not possible to evaluate in activity of the antibiotic in proper terms. The response of turkeys to a high level of challenge with Clostridium perfringens seems to be different when compared to what is observed in broilers under similar experimental conditions, and caution should be applied when using the same diagnostic methods for different species. The use of subjective criteria to assess and describe the lesions can lead to erroneous treatments decisions and misinterpretation of the responses to treatment.

A enterite necrótica causada por Clostridium perfringens é, comprovadamente, um grande problema para frangos de corte, seja sob a forma clínica ou subclínica , com elevados prejuízos produtivos. Em perus, não está claramente identificada a influência deste patógeno sobre os resultados produtivos, e provavelmente por razões econômicas, o volume de pesquisa nesta área é limitado. Em dois experimentos consecutivos, conduzidos em granjas experimentais diferentes, e sobre cama nova e reutilizada, perus de 14 dias, sem medicação com anticoccidianos, foram inoculados, a partir de uma amostra de campo patogênica, com uma superdosagem de aproximadamente 1 x 1010 UFC/ml de Clostridium perfringens, tipo A; bactéria anaeróbica Gram positiva, que compõe a microflora intestinal dos perus. Lesões necróticas severas, com grande destruição da mucosa intestinal, foram observadas após o 4º dia de inoculação. Nos dois experimentos, a resposta dos perus à infecção foi diferente da descrita em frangos de corte. A mortalidade foi muito baixa ou nula e a recuperação das aves, independente da medicação utilizada, foi rápida com pouco ou nenhum comprometimento zootécnico. Escores das lesões histológicas foram desenvolvidos, para tentar correlacionar as lesões macroscópicas com as lesões microscópicas, mas a correlação foi baixa. Frente ao alto desafio observado, não foi possível avaliar adequadamente a ação do antimicrobiano utilizado. As respostas frente aos desafios de Clostridium perfringens nos perus, aparentam ser diferentes em relação às observadas em frangos de corte, sendo necessária cautela ao extrapolar padrões de uma espécie para outra. O uso de critérios subjetivos nas avaliações podem comprometer a tomada de decisão em relação aos tratamentos e as respostas esperadas. / Necrotic enteritis caused by Clostridium perfringens represents a major challenge in broilers, causing clinical or sub clinical diseases, and results in important economic losses for the poultry industry. In turkeys, however, the importance of this pathogen is not clearly defined, and there are few studies assessing its effects on the performance of turkeys, most probably for economic reasons. In two consecutive trials, conducted in two experimental farms, 14 day old turkey poults were reared on new and reused wood shavings litter, without any anticoccidials in the feed, and were inoculated with an overdose of approximately 1x1010 CFU/ml of a pathogenic field sample of Clostridium perfringens type A. This Gram positive anaerobic bacterium is a normal inhabitant of the gut micro flora in the enteric tract of turkeys. Severe necrotic lesions, with major damage to the intestinal mucosa were observed on Day 4 after inoculation. In both trials, the response to the turkeys to the clostridial infection was clearly different from what is described in the literature for broilers. The mortality rate was very low or inexistent, and the birds in all treatments groups recovered very fast, with little or no impact on performance results. An attempt was made to establish a pattern to correlate histological lesion scores with macroscopic and microscopic lesions, but the resulting correlation was very low. Considering the high level of challenge induced in both trials, it was not possible to evaluate in activity of the antibiotic in proper terms. The response of turkeys to a high level of challenge with Clostridium perfringens seems to be different when compared to what is observed in broilers under similar experimental conditions, and caution should be applied when using the same diagnostic methods for different species. The use of subjective criteria to assess and describe the lesions can lead to erroneous treatments decisions and misinterpretation of the responses to treatment.

Zum Studium des prophylaktischen Einflusses ausgewählter antibiotischer Leistungsförderer [Avilamycin (10 ppm), Avoparcin (15 ppm), Virginiamycin (20 ppm)] und ionophorer Antikokzidia [Monensin (100 ppm), Narasin (70 ppm)] sowie des metaphylaktischen bzw. therapeutischen Einsatzes von Tylosin [Tylan 0,5 g/l H2O] auf das Auftreten und die Ausprägung der Clostridium (Cl.) perfringens-Enterotoxämie (CPE) wurden Untersuchungen an insgesamt 33 Versuchsgruppen mit 825 Broilerküken durchgeführt. Die Erkrankung konnte mittels intraduodenaler Inokulation einer Vollkultur Cl. perfringens Typ A (ATCC 3624) sicher reproduziert werden. Die Morbiditätsrate betrug in allen infizierten Gruppen 100 %. An klinischer Symptomatik zeigte sich hauptsächlich profuser wässriger Durchfall. Schwerere Störungen, Apathie und Anorexie, waren selten und in allen beobachteten Fällen vom schnellen Tod des betreffenden Tieres begleitet. Allgemein fiel auf, daß die infizierten und nicht medikamentierten Tiere schneller und länger erkrankten. Bei infizierten und unmedikamentierten Tieren ergab sich eine Mortalitätsrate von 16 bis 36 %, in den medikamentierten Gruppen maximal 8 %. Tylosin zeigte eine sehr gute metaphylaktischen bzw. therapeutische Wirkung. Die Lebendmasseentwicklung betrachtend, konnte Avoparcin unter den Leistungsförderern beste Ergebnisse erzielen. Ähnliche Resultate wurden in den Kombinationsgruppen [Avilamycin plus Monensin oder Narasin] bzw. mittels Narasin erreicht. In absteigender Reihenfolge zeigten Avilamycin, Virginiamycin und Monensin eine geringere leistungsfördernde Wirkung. Die Bestimmung fäkaler bzw. ileozäkaler Clostridienkonzentrationen lebender, respektive verendeter Hühner erbrachte nur wenige und relativ unbedeutende statistisch gesicherte Korrelationen zu anderen Ergebnissen. Es konnten keine Zusammenhänge zwischen Erregerzahl und Lebendmassezunahme, bzw. Todesursache, aufgedeckt werden. Die Resultate aus allen Versuchen zusammenfassend, müssen den Kombinationen von Avilamycin mit Narasin bzw. Monensin beste Effekte hinsichtlich einer positiven Beeinflussung CPE-bedingter Morbidität, Mortalität und Lebendmasseverluste bescheinigt werden. Tylosin war in der Lage, die Verlustzahlen durch CPE rasch zu senken. Für die Ausprägung kompensatorischer Effekte hinsichtlich der Lebendmasseverluste unter der Infektion muß mit einer größeren Zeitspanne gerechnet werden. Die Polyether und auch Avilamycin sind als Futtermittelzusatzstoffe für die europäische Geflügelhaltung zugelassen. Durch die ständige Kokzidiosebedrohung in den Hühnerbeständen kann auf einen prophylaktischen Einsatz antikokzidieller Futtermittelzusatzstoffe momentan nicht verzichtet werden. Es ist zu vermuten, daß es durch den simultanen Einsatz von Polyether und Leistungsförderer zu einer positiven Beeinflussung der schädigenden Wechselwirkungen von Kokzidien und Cl. perfringens im Darm kommt. Bei vorhandener Empfindlichkeit der Eimerien sollte dies sowohl die Bekämpfung von CPE als auch von Kokzidiosen begünstigen. Der positive Eindruck von Avoparcin spielt, bedingt durch das europaweite Verbot, momentan für die Praxis keine Rolle. Die Entwicklungstendenzen auf dem Sektor antibiotisch wirksamer Futtermittelzusatzstoffe, eng verknüpft mit der bakteriellen Resistenzproblematik, werden in der Arbeit ausführlich diskutiert. / Investigations with 825 chickens in 33 trials were performed in order to find out the prophylactic effect of selected antibiotic growth promoters [avilamycin (10 ppm), avoparcin (15 ppm) virginiamycin (20 ppm)] and polyether ionophore antibiotics [monensin (100 ppm), narasin (70 ppm)] on the incidence of Clostridium (Cl.) perfringens enterotoxemia (CPE) in chickens as well as the therapeutic resp. metaphylactic influence of tylosin [Tylan 0,5 g/l H20]. The enterotoxemia could be reproduced regularly by intraduodenal infection with high numbers of vegetative cells of Cl. perfringens type A (ATCC 3624). The morbidity rate always reached 100 %. In spite of a profuse and watery diarrhoea the chickens normally showed no further considerable disturbances of the general status. Apathy or anorexia were rather rare and immediately followed by Exitus letalis of the related chickens. It was striking that the infected and non-medicated broilers contracted the disease more quickly and for a longer time. The mortality rate among the infected and non-medicated animals was 16 to 36 %, among the medicated groups max. 8 %. Tylosin showed a considerable metaphylactic effect in decreasing CPE mortality. The avoparcin group showed the best weight gain among the growth promoters, comparable to the results by means of the combinations [avilamycin + monensin or narasin] or narasin only. Decreasingly avilamycin, virginiamycin and monensin were less successful. Analysing the faecal resp. ileocecal quantities of Cl. perfringens adduced only a few statistically guaranteed correlation with other results. There was no causal connection between numbers of Cl. perfringens and life weight development. It was impossible to discover a numerical threshold of germs responsible for the death of the chickens. Summarising all the results of the entire attempts the combinations of avilamycin and narasin resp. monensin were the most effective concerning the reduction of morbidity, mortality and life weight losses by CPE. By application of tylosin it was possible to stop the mortality rate quickly. But it needs more time to achieve reductions of the CPE related weight losses. The two polyethers and also avilamycin are still admitted in the European Union. Currently an abandonment of anticoccidial feed supplements seems to be impossible due to the present danger of coccidiosis in poultry. By means of monensin/narasin plus avilamycin the adverse health effects of interactions of both pathogens should be reduced. Presupposing susceptibility of the coccida this should be a notable contribution to a better controlling and to the prevention of CPE and coccidiosis, too.

Orientador: Valquíria Cação Cruz-Polycarpo / Resumo: A administração de ácidos orgânicos em dietas de frangos de corte pode influenciar os microrganismos e as condições do trato gastrintestinal. Para tanto, conduziu-se um experimento no qual foram utilizados 840 pintos de corte machos da linhagem Cobb®, distribuídos num delineamento inteiramente casualizado, com sete repetições e 30 aves por boxe. Os tratamentos foram: T1- dieta basal - sem inclusão de aditivo (DB) - aves não desafiadas; T2- dieta basal - sem inclusão de aditivo(DB) - aves desafiadas; T3- DB + ácidos orgânicos- aves desafiadas; T4- DB + antibiótico e anticoccidiano - aves desafiadas. Os ácidos orgânicos foram um blend composto de ácido lático (40%), ácido propiônico (5%) e ácido butírico (1%). Os frangos foram desafiados por inoculação via oral aos 11 dias de idade com Eimeria acervulina, E. máxima e E. tenella. Aos 10, 14 e 21 dias foram realizadas colheitas de sangue de aves previamente identificadas para as análises imunológicas: níveis de eritrócitos, leucócitos circulantes, proteínas totais, glicose, albumina, hematócrito, hemoglobina e contagem total de leucócitos. Os dados de desempenho foram avaliados nos períodos de 1-7,1-14, 1-21 e 1-42 dias.Com os dados de desempenho aos 42 dias, evidenciou-se a eficiência do tratamento controle negativo (sem desafio) e antibiótico + anticoccidiano, nos quais as variáveis GPM e CRM se comportaram de modo similar e melhores, em relação às dietas controle negativo (desafiadas) e inclusão de ácidos orgânicos.Os ácidos o... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The use of organic acids in chickens diets can influence gastrointestinal tract microorganisms and conditions. Therefore, a study was conducted in which 840 broiler chicks of Cobb® lineage were used, distributed in a randomized design with seven replicates and 30 birds per pen. The treatments were: T1 basal diet - without the addition of additives (DB) - unchallenged birds; T2 basal diet - without the addition of additives (DB) - challenged birds; T3 + DB organic acids challenged birds; T4 DB + antibiotic and anticoccidial - challenged birds. The organic acids were a blend composed by lactic acid (40%), propionic acid (5%) and butyric acid (1%). The chickens were challenged by oral inoculation at 11 days of age with Eimeria acervulina, E. maxima and E. tenella. At 10, 14 and 21 days blood samples were taken from previously identified birds for immunological analysis: erythrocy televels, blood leukocytes, total protein, glucose, albumin, hematocrit, hemoglobin, total leukocytes count. Performance data were evaluated in periods of 1-7, 1-14, 1-21 and 1-42 days. The performance data at 42 days showed the efficiency of the negative control treatment (no challenge) and antibiotic plus anticoccidial, where the GPM and CRM variables behave in a similar way, and therefore better than the diets of the negative control (challenged) and organic acids inclusion. Organic acids added to the diet during the breeding cycle showed no satisfactory effect on performance that characterize as a p... (Complete abstract click electronic access below) / Mestre

Zum Studium des prophylaktischen Einflusses ausgewählter antibiotischer Leistungsförderer [Avilamycin (10 ppm), Avoparcin (15 ppm), Virginiamycin (20 ppm)] und ionophorer Antikokzidia [Monensin (100 ppm), Narasin (70 ppm)] sowie des metaphylaktischen bzw. therapeutischen Einsatzes von Tylosin [Tylan 0,5 g/l H2O] auf das Auftreten und die Ausprägung der Clostridium (Cl.) perfringens-Enterotoxämie (CPE) wurden Untersuchungen an insgesamt 33 Versuchsgruppen mit 825 Broilerküken durchgeführt. Die Erkrankung konnte mittels intraduodenaler Inokulation einer Vollkultur Cl. perfringens Typ A (ATCC 3624) sicher reproduziert werden. Die Morbiditätsrate betrug in allen infizierten Gruppen 100 %. An klinischer Symptomatik zeigte sich hauptsächlich profuser wässriger Durchfall. Schwerere Störungen, Apathie und Anorexie, waren selten und in allen beobachteten Fällen vom schnellen Tod des betreffenden Tieres begleitet. Allgemein fiel auf, daß die infizierten und nicht medikamentierten Tiere schneller und länger erkrankten. Bei infizierten und unmedikamentierten Tieren ergab sich eine Mortalitätsrate von 16 bis 36 %, in den medikamentierten Gruppen maximal 8 %. Tylosin zeigte eine sehr gute metaphylaktischen bzw. therapeutische Wirkung. Die Lebendmasseentwicklung betrachtend, konnte Avoparcin unter den Leistungsförderern beste Ergebnisse erzielen. Ähnliche Resultate wurden in den Kombinationsgruppen [Avilamycin plus Monensin oder Narasin] bzw. mittels Narasin erreicht. In absteigender Reihenfolge zeigten Avilamycin, Virginiamycin und Monensin eine geringere leistungsfördernde Wirkung. Die Bestimmung fäkaler bzw. ileozäkaler Clostridienkonzentrationen lebender, respektive verendeter Hühner erbrachte nur wenige und relativ unbedeutende statistisch gesicherte Korrelationen zu anderen Ergebnissen. Es konnten keine Zusammenhänge zwischen Erregerzahl und Lebendmassezunahme, bzw. Todesursache, aufgedeckt werden. Die Resultate aus allen Versuchen zusammenfassend, müssen den Kombinationen von Avilamycin mit Narasin bzw. Monensin beste Effekte hinsichtlich einer positiven Beeinflussung CPE-bedingter Morbidität, Mortalität und Lebendmasseverluste bescheinigt werden. Tylosin war in der Lage, die Verlustzahlen durch CPE rasch zu senken. Für die Ausprägung kompensatorischer Effekte hinsichtlich der Lebendmasseverluste unter der Infektion muß mit einer größeren Zeitspanne gerechnet werden. Die Polyether und auch Avilamycin sind als Futtermittelzusatzstoffe für die europäische Geflügelhaltung zugelassen. Durch die ständige Kokzidiosebedrohung in den Hühnerbeständen kann auf einen prophylaktischen Einsatz antikokzidieller Futtermittelzusatzstoffe momentan nicht verzichtet werden. Es ist zu vermuten, daß es durch den simultanen Einsatz von Polyether und Leistungsförderer zu einer positiven Beeinflussung der schädigenden Wechselwirkungen von Kokzidien und Cl. perfringens im Darm kommt. Bei vorhandener Empfindlichkeit der Eimerien sollte dies sowohl die Bekämpfung von CPE als auch von Kokzidiosen begünstigen. Der positive Eindruck von Avoparcin spielt, bedingt durch das europaweite Verbot, momentan für die Praxis keine Rolle. Die Entwicklungstendenzen auf dem Sektor antibiotisch wirksamer Futtermittelzusatzstoffe, eng verknüpft mit der bakteriellen Resistenzproblematik, werden in der Arbeit ausführlich diskutiert. / Investigations with 825 chickens in 33 trials were performed in order to find out the prophylactic effect of selected antibiotic growth promoters [avilamycin (10 ppm), avoparcin (15 ppm) virginiamycin (20 ppm)] and polyether ionophore antibiotics [monensin (100 ppm), narasin (70 ppm)] on the incidence of Clostridium (Cl.) perfringens enterotoxemia (CPE) in chickens as well as the therapeutic resp. metaphylactic influence of tylosin [Tylan 0,5 g/l H20]. The enterotoxemia could be reproduced regularly by intraduodenal infection with high numbers of vegetative cells of Cl. perfringens type A (ATCC 3624). The morbidity rate always reached 100 %. In spite of a profuse and watery diarrhoea the chickens normally showed no further considerable disturbances of the general status. Apathy or anorexia were rather rare and immediately followed by Exitus letalis of the related chickens. It was striking that the infected and non-medicated broilers contracted the disease more quickly and for a longer time. The mortality rate among the infected and non-medicated animals was 16 to 36 %, among the medicated groups max. 8 %. Tylosin showed a considerable metaphylactic effect in decreasing CPE mortality. The avoparcin group showed the best weight gain among the growth promoters, comparable to the results by means of the combinations [avilamycin + monensin or narasin] or narasin only. Decreasingly avilamycin, virginiamycin and monensin were less successful. Analysing the faecal resp. ileocecal quantities of Cl. perfringens adduced only a few statistically guaranteed correlation with other results. There was no causal connection between numbers of Cl. perfringens and life weight development. It was impossible to discover a numerical threshold of germs responsible for the death of the chickens. Summarising all the results of the entire attempts the combinations of avilamycin and narasin resp. monensin were the most effective concerning the reduction of morbidity, mortality and life weight losses by CPE. By application of tylosin it was possible to stop the mortality rate quickly. But it needs more time to achieve reductions of the CPE related weight losses. The two polyethers and also avilamycin are still admitted in the European Union. Currently an abandonment of anticoccidial feed supplements seems to be impossible due to the present danger of coccidiosis in poultry. By means of monensin/narasin plus avilamycin the adverse health effects of interactions of both pathogens should be reduced. Presupposing susceptibility of the coccida this should be a notable contribution to a better controlling and to the prevention of CPE and coccidiosis, too.