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The missiles struck a compound on the outer skirts of Miranshah, in the North Waziristan region, killing four, one official said.
The attack triggered a fire in the building and flames could be seen from the roof of houses in Miranshah, five kilometres away, residents reported.
The drone attack and the casualties were confirmed by two other security officials.
The strike was the first since US-Pakistan relations plunged to their lowest level after the November 26 helicopter strikes on a border check post which killed 24 Pakistani soldiers.
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