Volume 21 - Numero 6Supplemento n. 1, Giugno 2008

ISSN 0394-9303

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First meetingCanadian institutes of health research (Cihr)and italian national institute of health (iss)

memOrAnDUm OF UnDerstAnDing (mOU)steering grOUP (Cimsg)

April 9, 2008istituto superiore di sanità - rome

sPeCiAL engLish issUe

dell’Istituto Superiore di Sanità

www.iss.it

TABLE OF CONTENTS

ABSTRACT

First Meeting Canadian Institutes of Health Research (CIHR) and Italian National Institute of Health (ISS) Memorandum of Understanding (MOU) Steering Group (CIMSG) ............................................................................. 3

Some priority themes in the research agenda of infectious diseases at the ISS: molecular epidemiology, advanced diagnostics of infection and vaccines ............................................................................ 5

Canadian Institutes of Health Research/ Istituto Superiore di Sanità collaborative research................................................................................. 7

Cancer vaccines: ISS research projects and initiatives for promoting national and international collaboration ............................. 8

Transmissible spongiform encephalopathies or prion diseases:research at the ISS ...................................................................................... 10

The Istituto Superiore di Sanità is the leading technical and scientific body of the Italian National Health Service. Its activities include research, clinical trials, control and training in public health; it also serves as a major national clearing-house for technical and scientific information on public health issues.Departments• Cell Biology and Neurosciences• Environment and Primary Prevention• Haematology, Oncology

and Molecular Medicine • Infectious, Parasitic and Immune-Mediated

Diseases• Technology and Health• Therapeutic Research

and Medicines Evaluation• Veterinary Public Health

and Food Safety

National Centres • AIDS• Blood• Chemical Substances• Epidemiology, Surveillance

and Health Promotion • Immunobiologicals Research and Evaluation• Transplant

Technical Services • Biotechnology and Animal Welfare • Data Management, Documentation,

Library and Publishing Activities

President of the Istituto Superiore di Sanità and Responsible Director:

Enrico GaraciEditor in Chief:

Paola De CastroEditing: Anna Maria Rossi

Graphics: Alessandro SpurioPhotos: Luigi Nicoletti

Distribution: Patrizia Mochi, Sara ModiglianiResponsibility for the contents

and opinions expressin in this Newsletter rests solely with the author(s).

Editorial OfficeSettore Attività Editoriali

Istituto Superiore di SanitàViale Regina Elena, 299 - 00161 Roma

Tel: +39-0649902260-2427 Fax +39-0649902253

e-mail: pubblicazioni@iss.it

Iscritto al n. 475/88 del 16 settembre 1988. Registro Stampa Tribunale di Roma© Istituto Superiore di Sanità 2008 Issue completed on July 16, 2008

Printed in-house, ISS Rome

On April 9th, 2008 a meeting between representative scientists from the Canadian Institutes of Health Research (CIHR) and from the Italian

National Institutes of Health (Istituto Superiore di Sanità, ISS) took place to implement collaborative activities by the two Institutions following the signature of the Memorandum of Understanding between Italy and Canada (see Notiziario no. 21, January 2008, p.16). During the meeting the representatives of both Institutions presented an outline of the mission, responsibilities and current actions in the field of infectious diseases and vaccines (both anti-infectious and anti-cancer). The presentations gave rise to a remarkable and highly focused discussion on potential contribution by Canadian and Italian investigators, highlighting common themes of interests. Another meeting between the representatives of the two Institutions will follow concerning stem cells and other frontiers in science. It is too early to draw conclusions about practical implementation of collaborative work but premises are real and optimistic.

Keywords: Vaccines, antibodies, infectious diseases, disease emergence

This special number of Notiziario is published for this very special occasion thanks to the ISS Publishing Unit, in particular Paola De Castro, and Angela Guderzo of Infectious, Parasitic and Immune-Mediated Diseases Department.

FIrST MeeTINg CANADIAN INSTITUTeS OF HeALTH reSeArCH (CIHr) AND ITALIAN NATIONAL INSTITUTe OF HeALTH (ISS)

MeMOrANDUM OF UNDerSTANDINg (MOU) STeerINg grOUp (CIMSg)

April 9, 2008 Istituto Superiore di Sanità, rome

On November 13, 2007, Dr. Alan Bernstein, President of the Canadian Institutes of Health Research (CIHR) and Professor Enrico Garaci, President of the Italian National Institute of Health (ISS), signed the CIHR-ISS Memorandum Of Understanding (MOU), an event that marked a key milestone in

Canada-Italy health research relations. This MOU set the stage for closer bilateral cooperation in four areas: Cancer, Infectious Disease, Vaccine, Stem cells. Guided by the MOU, the first meeting of the MOU Steering Group (CIMSG) was organized by ISS in consultation with the Canadian Embassy in Rome.

The meeting was attended by:

Prof. Antonio Cassone Head, Department of Infectious, Parasitic and Immune-Mediated Diseases, ISS

Prof. Filippo Belardelli Head, Department of Cell Biology and Neurosciences, ISSProf. Maurizio Pocchiari Director, Unit of Degenerative and Inflammatory Neurological Diseases,

Department of Cell Biology and Neurosciences, ISSDr. B. Brett Finlay Governing Council Member CIHR, and Peter Wall Distinguished

Professor Michael Smith Laboratories, University of British Columbia, Vancouver, BC

Dr. Bhagirath Singh Scientific Director, Institute of Infection and Immunity, CIHR, and Professor, University of Western Ontario, London, Ontario

Dr. Emanuele Fiore Scientific Attaché, Italian Embassy, Ottawa, CanadaMr. John Picard Trade Commissioner, Director Science and Technology,

Embassy of Canada, Rome

The meeting of CIMSG was chaired by Prof. Antonio Cassone on behalf of the ISS President Prof. Enrico Garaci. A brief presentation was made by Prof. Antonio Cassone to introduce ISS activities in general and infectious diseases research at ISS in particular. Dr. Bhagirath Singh outlined CIHR activities in health research in Canada and the role of the Institute of Infection and Immunity (CIHR-III) as a potential part-

ner in the MOU areas of infectious diseases, vaccines and immunotherapy.

Prof. Filippo Belardelli outlined the current work going on at ISS in cancer vaccines and possible areas of collaboration in immunotherapy. A list of CIHR fun-ded vaccine projects including cancer projects was pro-vided to CIMSG. Prof. Antonio Cassone, who heads the Infectious Diseases programme at ISS, described u

Not Ist Super Sanità 2008;21(6 Suppl.1):3-4 3

the current research and achievements of ISS in this area. Prof. Maurizio Pocchiari has a major interest in the prion diseases and has numerous European and interna-tional collaborations, which include a project with the PrioNet NCE in Canada. Dr. Brett Finlay outlined the possible opportunities in the area of infectious diseases that will build strong partnerships between Canadian and Italian researchers.

There are already long standing collaborations between Canada and Italy. During the period 2000–2007, CIHR funded over $2 million in grants to Canadian researchers to participate in research projects with colleagues in Italy. This included funding for ope-rating, randomized controlled trial and proof of prin-ciple grants and studentships as well as post-doctoral fellowships. To build on these and other informal interactions, CIMSG identified four possible areas of collaboration in which new activities can be developed and current activities can be strengthened.

Possible areas of collaboration:Infectious Diseases Cancer VaccinesImmunotherapy Prion Diseases

These themes align with the identified priorities in the CIHR-ISS MOU. In some cases such as prion diseases, there are already established partnerships that can be further enhanced. CIMSG also discussed potential collaborations that may arise through the recent Genome Canada (GC)-Italian National Research Council (CNR) MOU in health research where rese-archers in Canada and Italy will be working together to apply for funding opportunity in proteomics, bio-informatics and functional genomics. GC and CNR announced their programme on April 8, 2008 in Rome. As initial goal, CIMSG agreed to focus on the infectious diseases area for developing joint application to apply for the Genome Canada-CNR programme.

Next steps

The next steps of the collaboration will consider the following activities:

i) organizing teleconference and meeting among pro-minent researchers to move the infectious diseases collaboration forward in the next few months;

ii) establishing collaboration between CIHR-III and ISS in systems biology of immunotherapy;

iii) exploring potential collaboration between CIHR and ISS in vaccines research including cancer vac-cines;

iv) determining dates and location of CIMSG next meeting.

It was agreed that various potential partners in Italy and Canada, both in public and private sector, would be engaged in these bilateral activities. The meeting was successful due to logistic support and help provided by Mr. John Picard from the Canadian Embassy in Rome. He also graciously hosted a dinner for the group at the conclusion of the meeting and offered to facilitate fur-ther interactions between ISS and CIHR.

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MeetiNg PrOgraMMe

april 9, 2008

Welcome Prof. enrico garaci, President of iSS

Session 1: Cancer Vaccines Filippo Belardelli

Bhagirath Singh

Session 2: infectious Diseases Maurizio Pocchiari

Brett Finlay

Session 3: anti-infective Vaccine Bhagirath Singh

antonio Cassone

Session 4: Discussion on Next Steps and Wrap-up

Memorandum of Understanding Steering Group

the Department of Infectious, Parasitic and Immune-mediated Diseases is one of the seven Departments which constitute the scientific core

of the Italian National Health Institute (ISS, Istituto Superiore di Sanità). It has the mission of combating infections by whatsoever agent and contrast immunopathological diseases for the best promotion of the health of Italian population. It also provides consultancy and control activity based on the best scientific evidence. Its rese-arch encompasses basic to applied and operational the-mes, and is mostly devoted to find and test new tools to improve the capacity to detect, prevent and control infection, allergy, autoimmunity. To be effective, gene-ration of new tools must be based on advanced research on pathogenesis, antimicrobial immunity and immuno-regulatory or dysregulatory patterns. These three areas, together with molecular epidemiology, represent the basic glue to all other activities performed in more applied fields which essentially deal with diagnosis, vaccines and immu-notherapy.

First, through its statutory role as National Reference Center for microbio-logical surveillance of infectious disease emergences and, secondly, the role assi-gned by international agencies such as the World Health Organization (WHO) and the European Centre for Disease Prevention and Control (ECDC), the ISS is heavily involved in developing, valida-

SOMe prIOrITy THeMeS IN THe reSeArCH AgeNDA OF INFeCTIOUS DISeASeS AT THe ISS:molecular epidemiology, advanced diagnostics of infection, vaccines

Prof. Antonio CassoneHead, Department of Infectious, Parasitic and Immune-Mediated Diseases,

Istituto Superiore di Sanità, Rome

ting and implementing advanced methodology and techniques for rapid diagnosis of emerging infectious agents, their biotyoping, and molecular evolution. This applies to both natural and intentional epidemics. By the contribution of its numerous epidemiolo-gists and molecular microbiologists, the ISS occupies a central role in combating infectious diseases in Italy and constitutes the national focal point for contribu-ting to fighting the infectious emergences at internatio-nal levels. Recent examples of this activity are the ISS work on SARS, Anthrax, Influenza and Chikungunya epidemic. Since infectious diseases have no borders and are actually globalized, international collaboration is here a must, and the ISS wishes to expand every pos-sible collaborative network with investigators of other countries. In this respect, any form of collaboration with brother institutions in Canada is a great opportu-nity.

iStitutO SuPeriOre Di SaNitàitaliaN NatiONal iNStitute OF HealtHwww.iss.it

the istituto Superiore di Sanità is the leading technical and scientific body of the italian National Health Service (SSN). it performs research (basic, applied,translational) to provide the best scientific evidence for the actions taken by SSN. its activities include clinical trials, control and training in public health; it also serves as a major national regulatory body for technical and scientific information on public health issues.

Not Ist Super Sanità 2008;21(6 Suppl.1):5-6 5

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Concerning the areas of vaccines and immuno-therapy, since the benchmark Italian trial of acellular pertussis vaccines the ISS has maintained a remarkable tradition and a national leadership on vaccine research and vaccination policy. including immunotherapy with antibodies and cytokines. This has recently been strengthened by the ongoing efforts on generation of novel vaccines against various deadly diseases, from AIDS and papilloma to tuberculosis and human myco-ses in immunocompromized subjects. Both pre-clinical and clinical works are being performed in collaboration with industrial partners, and funded by extramural grants, mainly received through successful applications to European Community and other international agencies. This is also an area where international col-laboration is mandatory, and the ISS wishes to extend the already existing collaborative network to Canadian investigators in a joint scientific partnership.

relevant selected references

1. Greco, D. et al. A controlled trial of two acellular vaccines and one whole-cell vaccine against pertussis. Progetto Pertosse Working Group. N Engl J Med. 1996 Feb 8;334(6):341-8.

2. Fortini D. et al. Optimization of high-resolution melting analysis for low-cost and rapid screening of allelic variants of Bacillus anthracis by multiple-locus variable-number tandem repeat analysis. Clin Chem. 2007 Jul;53(7):1377-80.

3. Torosantucci A. et al. A novel glyco-conjugate vaccine against fungal pathogens. J Exp Med. 2005 Sep 5;202(5):597-606.

4. Ensoli B. et al. Candidate HIV-1 Tat vaccine develop-ment: from basic science to clinical trials. AIDS. 2006 Nov 28;20(18):2245-61.

5. Rezza G. et al. Infection with chikungunya virus in Italy: an outbreak in a temperate region. Lancet. 2007 Dec 1;370(9602):1840-6.

Infectious diseases

Figure. - Classical and molecular identification of B. anthracis

Definitive identification of colonies of B. anthracis on agar-blood

B.cereus B.anthracis

AAGCGCTATGATTTAGCAA

AAGCGCTACGATTTAGCAA

genotyping of B. anthracis through sequence of hypervariable vrr lociItaly F CACCATGGT------------------------------------------------------------------------CATCAAGGCCACCATCATCACCAAGGTCACCACGGTCATCATGGG---------

Italy C CACCATGGT------------------------------------------------------------------------CATCAAGGCCACCATCATCACCAAGGTCACCACGGTCATCATGGGCATCATCAT

PASTEUR ------------------------------------CACCACGGT------------------------------------CATCATGGGCATCATCATCACCAAGGTCACCACGGTCATCATGGG---------

1761 ITALY ---------------------------------------------------------------------------------CATCAAGGCCACCATCATCACCAAGGTCACCACGGTCATCATGGG---------

2844 ITALY CACCATGGT------------------------------------------------------------------------CATCAAGGCCACCATCATCACCAAGGTCACCACGGTCATCATGGGCATCATCAT

BA1035 ---------CATCATGGACATCACCACCATCAAGGTCACCACGGTCATCATGGACATCACCACCATCAAGGTCACCACGGTCATCAAGGCCACCATCATCACCAAGGTCACCACGGTCATCATGGG---------

J611 CACCATGGT------------------------------------------------------------------------CATCAAGGCCACCATCATCACCAAGGTCACCACGGTCATCATGGGCATCATCAT

A24 ---------CATCATGGACATCACCACCATCAAGGTCACCACGGT------------------------------------CATCAAGGCCACCATCATCACCAAGGTCACCACGGTCATCATGGG---------

VOLLUM CACCATGGT------------------------------------------------------------------------CATCAAGGCCACCATCATCACCAAGGTCACCACGGTCATCATGGGCATCATCAT

BA0015 CACCATGGT------------------------------------------------------------------------CATCAAGGCCACCATCATCACCAAGGTCACCACGGTCATCATGGGCATCATCAT

A46 ---------CATCATGGACATCACCACCATCAAGGTCACCACGGT------------------------------------CATCAAGGCCACCATCATCACCAAGGTCACCACGGTCATCATGGG---------

MOZ-3 ---------CATCATGGACATCACCACCATCAAGGTCACCACGGT------------------------------------------------------------------------------------------

2PT CACCATGGT------------------------------------------------------------------------CATCAAGGCCACCATCATCACCAAGGTCACCACGGTCATCATGGG---------

M 1 2 3 M 4 5 6

cappag

the presentations by the Canadian Colleagues Drs Singh and Finlay essentially dealt with an introduction to the Canadian Institutes of

Health Research (CIHR) remits, historical notes and present constitution, followed by details on one of the 13 Institutes which compose the CIHR, the Institute of Infection and Immunity.

The more general presentation illustrated the CIHR constitution, governance, budgets and international collaborations already in place, particularly in Infectious Diseases. Training opportunities and capacity building schemes were also dealt with. A substantial attention was focussed on the identification of five strategic areas for research in partnership, which included, among others, emerging infections and antimicrobial drug resistance, and vaccine.

For this last strategic area, details were provided on several vaccine initiatives which included a Canadian HIV Vaccine one, with involvement of a partnership with Bill and Melinda Gates Foundation, and provision of infrastructures and logistics for in-house vaccine production and commercialization, in a bench- to -bed approach. An International Vaccine Institute (INTERVAC) was recently built up to reach the above goals. Emphasis on translational research for the benefit of Canadian population was amply and clearly shared by the two speakers. This should not go to the detri-ment of basic approaches which give scientific evidence to health actions and provide always new fundamental bread for future applications in health and technology.

The CIHR Institute of Infection and Immunity was amply illustrated in the second presentation. Strategic

priorities included immunotherapy and preparedness to influenza pandemics, which was recommended as a major research focus in the short term, with a budget in partnership with other institutions amounting to >40 millions dollars for five years. The research topics span the biology of the influenza virus to ethic and social aspects. New approaches to immunotherapy through system biology and better understanding of how the immune system integrates its responses to non-self, self and inflammation are considered critical research themes here.

Then the emphasis was enlarged to the Infectious Diseases Strengths and Centers in Canada with stake-holders and funders. Top funded Projects included the INTERVAC, Viral Hepatitis and Immunodiagnostics/Biotherapeutics. Centers of Excellence in Infectious Diseases throughout Canada were also presented with four Canadian projects funded by the Bill and Melinda Gates Foundation in the Infectious Diseases (ID) area.

The presentation ended by proposing a series of actions to implement CIHR-ISS collaboration star-ting from common identification of research strategic areas in ID and vaccines, and identification of funding opportunities (inclusive of Genome Canada and Bill and Melinda Gates Foundation) to development of partnership with industrial, NGOs and International Organizations. Building on existing opportunities as well as on key players on both sides in ID had special consideration and discussion, and it was suggested that these last actions would be the next necessary steps to make the meeting scientifically useful and fruitful.

CANADIAN INSTITUTeS OF HeALTH reSeArCH/ ISTITUTO SUperIOre DI SANITà COLLAbOrATIve reSeArCH

Bhagirath Singh1 and Brett Finlay2

1Scientific Director, Institute of Infection and Immunity, Canadian Institutes of Health Research2Governing Council Member, Canadian Institutes of Health Research

Not Ist Super Sanità 2008;21(6 Suppl.1):7 7

8 Not Ist Super Sanità 2008;21(6 Suppl.1):8-9

CANCer vACCINeS: ISS reSeArCH prOJeCTS AND INITIATIveS FOr prOMOTINg NATIONALAND INTerNATIONAL COLLAbOrATION

Filippo BelardelliHead, Department of Cell Biology and Neurosciences,

Istituto Superiore di Sanità, Rome

models have generated new knowledge on how we should act on cells of the immune system, including dendritic cells, in order to break tolerance against tumor-associated antigens and enhance the antitumor immune response in patients. In order to meet the great expectations consistent with the recent research progress, coordination initia-tives aimed at promoting national and international collaboration are particularly important in this field. Over the last 10 years, ISS has organized several inter-national meetings on cancer vaccines and immuno-therapy. To promote translational research in the area of cancer biotherapy, it has recently activated an ISS GMP facility (FaBioCell) specifically devoted to the preparation of new cell products, including dendritic cells, to be used in clinical studies. Moreover, in the context of the recently activated ISS project launched by the Italian Ministry of Health for Alliance against Cancer (i.e., the Italian Network of Comprehensive Cancer Institutes), the ISS has supported the creation of national networks for promoting translational rese-arch on cancer, including a network specifically aimed at promoting clinical studies in the field of cancer immunotherapy and biotherapies. The ISS Department of Cell Biology and Neurosciences is also currently playing a coordina-tion role in Italy in the preparatory phases of the construction of the European infrastructures for bio-

New approaches are needed to face the global problem of cancer and the development of cancer vaccines represents important chal-

lenges with a great potential impact on public health. The research group has been working for more than 30 years in the field of cancer immunotherapy. The main contributions include the characte-rization of the mechanisms of antitumor action of interferon, the development of novel methods for the generation of highly active dendritic cells to be used for therapeutic vaccination in cancer patients and the identification of new and effective strategies for combining cancer vaccines with other therapeutic interventions, including chemotherapy. An ensem-ble of studies performed in both mouse and human

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medical research, including EATRIS (European Advanced Translational Research Infrastructure in Medicine) and ECRIN (European Clinical Research Infrastructures Network and Biotherapy Facilities). The final goal is to establish a strategic coopera-tion among public health institutions, national research institutes, industries, representatives of regulatory bodies and patients’ organizations in order to overcome bottlenecks and avoid useless fragmentation and duplication at the European level. While all this is expected to have a general positive impact in several fields of biomedical research, addressing these issues in a comprehensive manner will be particularly

important for providing cancer immunotherapy the chance of fully demonstrating its potential of beco-ming an effective standard strategy for patient care.

- Dendritic cells from monocytes or CD34+ cells- Selection and expansion of stem cells- Selection and expansion of lymphocytes - Expansion of antigen-specific T cell clones - Genetically modified cells from patients

Cancer vaccines

10 Not Ist Super Sanità 2008;21(6 Suppl.1):10-11

TrANSMISSIbLe SpONgIFOrM eNCepHALOpATHIeS Or prION DISeASeS:reSeArCH AT THe ISS

Maurizio Pocchiari Director, Unit of Degenerative and Inflammatory Neurological Diseases,

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome

the appearance of Bovine Spongiform Encephalopathy (BSE) in the UK in the second half of the '80s was definitely unexpected by all

scientists in the prion field. The epidemic of BSE rea-ched a peak in the early '90s and then stably decreased with only a few cases still observed nowadays. Despite the prompt response of British authorities to protect human health, an enormous amount of BSE conta-minated meat products entered into the human food chain with the consequence of an outbreak of human BSE cases (variant Creutzfeldt-Jakob Disease, vCJD) in young adults all over Britain.

Evidence of a link between BSE and vCJD is based on several factors but the first alarm was launched by the epidemiological observation that unusual cases of Creutfeldt-Jakob Disease (CJD) in young adults have occurred only in the UK and not in other European countries where an efficient network of CJD surveillan-ce has been in force since 1993. The conclusive evidence has been based on the isolation of the same prion strain in cattle with BSE and in patients with vCJD. In the last years, vCJD infection has also occurred in four reci-pients of blood taken from individuals incubating the disease suggesting a possible spread of infection from

Countries with established national surveillance

Countries with limited surveillance

Figure - Creutzfeldt-Jakob Disease (CJD) surveillance systems in the world

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human to human and the raise of new concerns for public health. BSE spread all over Europe, with exception of a few countries, and in other non-European countries (Israel, Japan, Canada, and USA) likely because of export of contaminated ruminant feed from Britain. In most European countries, however, measurements to protect human health were taken much later than in the UK with a possible risk in the future of small outbreaks of vCJD virtually in all countries where BSE has occurred or where meat products were imported from countries with a high risk of BSE. Variant CJD has so far been identified outside the UK in 10 countries with the majority of cases in France (23 patients since 1996). There are still many public health concerns in this field due to uncertainties about the basic knowledge of the infectious agent, its extreme resistance to inactiva-tion procedures, and the emergences of novel diseases in cattle, sheep, and wild ruminants. Whether these newly recognized diseases in animals might cause disease in humans is still debatable but the lessons we learned

from the BSE crisis should warn us to take the risk of prion diseases in great consideration. The EU surveillance network of CJD and related disorders, together with the European Centre for Disease Prevention and Control (ECDC), has imple-mented the surveillance activity in all EU countries and has recently developed a common database with the aim to quickly identify any atypical case of CJD that can be linked to novel prion disease outbreaks in animals. Research in the field of prion diseases is very active in the ISS and includes clinical, diagnostic, and epidemiological activities with the aim to identify atypical prion strains in humans, pre-clinical markers of disease, and novel genes involved in the pathogenesis of prion disorders. Other research activity is directed to a better understanding of pathogenesis with the aim to determine the efficiency of different routes of infection and to understand the molecular basis for the occur-rence of the “species barrier” effect, to investigate novel compounds with anti-prion effects, and to improve methods for the inactivation of prions from food and biological samples.

Photos from the preliminary meeting to the Memorandum of understanding between the italian and Canadian delegations. istituto Superiore di Sanità - November 13, 2007

For ISS: Enrico Garaci (President); Filippo Belardelli, Antonio Cassone, Maurizio Pocchiari, Ruggero De Maria Marchiano.For CIHR: Alan Bernstein (President), Abigail Forson.For the Canadian Embassy in Italy: Alex Himelfarb (Ambassador), John Picard.

Prion diseases

Inserto BEN

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